Eur. J. Immunol. 2015.

45: 21912202

HIGHLIGHTS

DOI: 10.1002/eji.201545493

ECI 2015 Review Series

Versatile myeloid cell subsets contribute to

tuberculosis-associated inflammation
Anca Dorhoi and Stefan H.E. Kaufmann
Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany
Tuberculosis (TB), a chronic bacterial infectious disease caused by Mycobacterium tuberculosis (Mtb), typically affects the lung and causes profound morbidity and mortality
rates worldwide. Recent advances in cellular immunology emphasize the complexity
of myeloid cell subsets controlling TB inflammation. The specialization of myeloid cell
subsets for particular immune processes has tailored their roles in protection and pathology. Among myeloid cells, dendritic cells (DCs) are essential for the induction of adaptive
immunity, macrophages predominantly harbor Mtb within TB granulomas and polymorphonuclear neutrophils (PMNs) orchestrate lung damage. However, within each myeloid
cell population, diverse phenotypes with unique functions are currently recognized,
differentially influencing TB pneumonia and granuloma functionality. More recently,
myeloid-derived suppressor cells (MDSCs) have been identified at the site of Mtb infection.
Along with PMNs, MDSCs accumulate within the inflamed lung, interact with granulomaresiding cells and contribute to exuberant inflammation. In this review, we discuss the
contribution of different myeloid cell subsets to inflammation in TB by highlighting their
interactions with Mtb and their role in lung pathology. Uncovering the manifold nature of
myeloid cells in TB pathogenesis will inform the development of future immune therapies
aimed at tipping the inflammation balance to the benefit of the host.

Keywords: Dendritic cells r Inflammation r Mycobacterium tuberculosis

Neutrophils r Myeloid-derived suppressor cells

Introduction
Mycobacterium tuberculosis (Mtb) continues to kill more individuals on this globe than any other bacterial contagious agent [1].
A breakthrough in disease pathogenesis was achieved by Robert
Koch (18431910) in 1882, who precisely elucidated the etiology
of the disease tuberculosis (TB) [2, 3]. Since then, nearly 1 billion
deaths have been caused by TB, a higher mortality than any other
infectious disease or war in our history [4]. Many attempts have
been made to better understand TB pathogenesis, with the aim
to create appropriate intervention measures. Despite the availability of a TB vaccine, as well as drugs and diagnostics, TB has
not been controlled satisfactorily. In 2013, 9 million new cases

Correspondence: Prof. Stefan H.E. Kaufmann and Dr. Anca Dorhoi

e-mail: kaufmann@mpiib-berlin.mpg.de, dorhoi@mpiib-berlin.mpg.de


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Macrophages

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and 1.5 million deaths were reported [5]. Increasing incidences of

drug-resistant TB with varying severity require novel approaches
for diagnostics, drugs, and vaccines. Accordingly, better knowledge of the immune response in protection and pathology of Mtb
infection is necessary.
At the core of TB pathophysiology are the inflammatory
myeloid cells [6]. The evolutionary success of virulent mycobacteria likely depends on cross-species-conserved mechanisms operative in infected cells [7, 8], which allow bacillary replication and
persistence by fine-tuning pro- and anti-inflammatory networks
[9, 10]. While inflammation-promoting events are essential at the
individual level and drive primary disease progression, balanced
inflammatory mechanisms appear indispensable for Mtb persistence within hosts with latent TB infection (LTBI) [11]. Uncovering Mtbs strategies to modulate inflammation at various stages
of infection represents a cornerstone for the development of disease control measures. Host-directed therapy (HDT) is the most

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Anca Dorhoi and Stefan H.E. Kaufmann

recent approach toward TB treatment. HDT encompasses usage

of host modulators, and as such, requires in-depth knowledge on
cells involved in disease pathogenesis, particularly inflammation
[1214]. In this review, we will focus on the diversity of myeloid
cells that drive and modulate inflammation in TB, and discuss how
different mechanisms of action could be targeted for HDT.

Mycobacterium tuberculosis and its major

counterpart, the mononuclear phagocyte
In the most prevalent form of TB, the lung serves as source of
transmission, port of entry, and site of disease manifestation. Mtb
is spread by expectoration of active TB patients, who produce
aerosols [15, 16]. Investigations in multiple mammalian models
of TB, such as nonhuman primates [17], rabbits [18], mice, and
guinea pigs [19, 20], have shown that promptly after Mtb entry
into the lung, granulomas are formed at the site of Mtb implantation in the lung parenchyma. These granulomas are composed of
mononuclear phagocytes (MPs), neutrophils (PMNs), T and B lymphocytes [21]. As long as the granuloma is structured, it succeeds
in containing Mtb. As a consequence, some 2 billion individuals
live with Mtb lifelong (LTBI) without developing active TB disease.
Up to 5% of Mtb-exposed adolescents and adults develop primary
progressive disease and another ca. 5% of individuals with LTBI
develop active disease, through reactivation of endogenous Mtb or
reinfection with the pathogen from an exogenous source [5, 22].
Clinical signs of TB are first caused by severe impairment of lung
function, and subsequently, by major morphological alterations
of the respiratory parenchyma. Second, most immune mediators exert paracrine effects and orchestrate systemic inflammation
in TB. Macrophages, including activated and transformed MPs,
represent the initiators of, and most abundant cell type within,
TB granulomas [21]. Mtb is a facultative intracellular pathogen
thereby replicating inside cells but also in necrotic areas of TB
granulomas [22]. Mtb is surrounded by a waxy cell wall, which is
responsible for its unique staining behavior as an acid-fast bacillus [23]. More importantly, this complex cell wall contributes to
its effective resistance against numerous immune defense mechanisms, for instance by interfering with phagocytosis and cellular
activation [2426]. It is less clear whether Mtbs waxy cell wall
also plays a role in Mtbs slow replication and persistence [27].
More obvious is the role of the cell wall in the capacity of Mtb to
survive within MPs by interfering with phagosome maturation or
autocrine activation through cytokine production [2832]. MPs,
including blood monocytes and tissue macrophages of different
types, are well-known effector cells against numerous bacterial,
fungal, and protozoal infections and eliminate the etiologic agents
for instance by producing antimicrobial molecules [33]. In TB, MPs
perform a dual function, serving both as a habitat for, and effector
against, Mtb [32] (Table 1).
At the macrophage level, similar to the whole-organism level,
a balanced inflammatory response confers anti-bacterial effects
with limited collateral damage. In other words, both reduced
and enhanced inflammation promote Mtb replication [10].

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Limited inflammation results in improper activation of

macrophages, defective antimicrobial activity, and intracellular
growth of the bacilli. Excessive inflammation promotes recruitment of additional Mtb-permissive cells, cell death, and extracellular replication of the bacilli. Whether or not MPs restrict or
allow Mtb replication depends on early innate immune sensing
of bacteria [34], cell-autonomous mechanisms [35], and responsiveness to soluble, often adaptive immune mediators, such as
cytokines [36, 37]. Host sensing of Mtb by pattern recognition
receptors (PRRs) activates various innate signaling pathways,
i.e. those controlled by adaptor molecules such as myeloid differentiation factor 88 (MyD88)/IL-1 [38, 39] and spleen tyrosine kinase/caspase recruitment domain 9 [40, 41], and results
in cytokine release and cellular activation. These key pathways control the abundance of TB-relevant cytokines, such as
TNF- [38, 42, 43] and IL-10 [40, 41, 44] by gathering signals
from different PRRs. Cytosolic receptors, including the nucleotidebinding oligomerization domain (NOD) receptors (NLRs) members NOD2 and NLRP3 [4549], absent in myeloma (AIM)-2
like receptors (ALRs) (e.g. AIM2) [5052], and nucleic acid sensors (cyclic GMP-AMP synthase, cGAS; stimulator of IFN genes,
STING) [53, 54], have been shown to modulate the abundance
of proinflammatory cytokines (IL-1, IL-6, TNF-) or the release of
chemokines and type 1 IFN in human and murine MPs [5557].
In addition, selected cytosolic sensors, such as STING and cGAS
[53, 5658] or the adaptor MyD88 [59], affect autophagy, a
cell autonomous immune response against intracellular pathogens
[60]. Autophagy bypasses the block in phagosome maturation and
delivers Mtb-containing phagosomes to lysosomal compartments
termed autophagolysosomes [60]. More recently, the aryl hydrocarbon receptor (AhR) has been identified as a cytosolic sensor
for the mycobacterial lipid, phthiocol [61]. AhR activation following Mtb infection elicits the prompt release of TNF-, IL-6, and
IL-12 in murine and human macrophages [61]. TNF-, IL-6, and
IL-12 are activators of MPs and facilitate protective T-helper type
1 responses [37]. Similar effects have been observed in a murine
model of experimental TB. Specifically, AhR has been shown to
limit lung bacillary burdens and Mtb dissemination prior to initiation of T-cell responses, thereby emphasizing that a prototypic
xenobiotic receptor is endowed with critical functions in antibacterial immunity [61]. Multiple immune sensors have been shown
to act in concert to produce cytokines, enabling autocrine activation of infected macrophages. For example, the relevance of TNF/TNFR1 [42] and IL-1/IL-1R1 [6265] for the anti-mycobacterial
activity of murine and human macrophages is well-established,
and roles of additional cytokines, such as GM-CSF, are emerging
[66] and deserve further investigation.
Regarding Mtb replication, IFN- represents the prototypical paracrine activator produced by T cells switching on bactericidal programs in macrophages. The importance of IFN-
for resistance against TB is supported by in natura evidence
in humans and numerous cell-based and animal reports [67].
IFN- has been shown to induce oxidative changes in Mtb-infected
murine macrophages, activates the nitric oxide synthase 2 (NOS2)
[68, 69], promotes antimycobacterial activities of vitamin D [70],
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IL-10/PGE2-activated macrophages

Alternatively activated
macrophages (IL-4)

Monocytes/Macrophages
CD11b+ Ly6C+ CCR2+
Classically activated macrophages
(IFN-/TNF-)

Monocytes CD14+ CD16+

[38;43;46;68;69;71;73]

Mouse in vivo, BMDMs, cell

lines

Mouse in vivo
Mouse in vivo, BMDMs,
human ex vivo
Mouse in vivo, Human ex vivo

Promote (IL-10)/restrain (PGE2) IFN I and control IL-1 release

and cell death.

[82;83]

[148]
[44;81]

[75;76]
[77;78]

[32;70;72]

Human primary cells ex vivo,

cell lines

Mouse BMDM
Mouse in vivo, BMDMs

[85;86;95]

[101]

[101]

[84;103]

[84;109;110]

Mouse in vivo

Human ex vivo, mouse hybrid

Human ex vivo, mouse hybrid

Prevent hyperinflammation in hypoxic granulomas.

Support Mtb replication (deactivation by IL-10).

Undergo apoptosis/necrosis depending on bacterial load.

Restrain mycobactericidal mechanisms.

Mouse in vivo

Undergo cell death post-infection and promote leukocyte

recruitment.
Migrate towards Mtb stimuli, produce reactive metabolites
and pro- and anti-inflammatory cytokines, limit Mtb
replication in transfer models.
Support Mtb replication, increased frequency in active TB,
refractory to differentiation into DCs.
Permissive for Mtb replication, contribute to activation of
T-cells in draining lymph nodes.
Restrain Mtb replication.

Monocytes CD14+ CD16

Mouse in/ex vivo, human

ex vivo

Allow Mtb replication and Mtb cytosolic egression.

(Continued)

[6;26;28;32;3437;42;44;50;
5962;74]
[84;93;103;104]

All models
Mouse in vivo

[107;145;146]

NHP

Uptake of Mtb upon implantation in alveoli.

[24;25;29;30;3841;4549;5154;
5658;83;87]

Mouse in vivo, BMDMs, cell

lines

Alveolar macrophages

[31;55;88]

References

Human primary cells ex vivo,

cell lines, biopsies

Phagocytose Mtb, unable to kill bacteria, allow Mtb

persistence.
Sense Mtb through multiple PRRs (TLRs, CLRs, ALRs, NLRs,
CDS).
Release immune mediators, such as cytokines/chemokines
(pro/anti-inflammatory), peptides, eicosanoids, ROS/RNS.
Mycobactericidal upon activation.

Macrophages

Model

Function

Cell population/subpopulation

Table 1. Role of myeloid cell subsets in tuberculosis

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HIGHLIGHTS

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[84;92;103;104;115;116;121
126;129;134]
[107;115]
[117]
[138;139]
[140142]

Mouse in vivo
Mouse in vivo
Human ex vivo
Human ex vivo
Human primary cells ex vivo,
biopsies, BAL
Mouse in vivo, ex vivo

NHP
Cattle
Human primary cells ex vivo,
BAL
Mouse in/ex vivo

Contain bacteria and allow Mtb cytosolic egression.

Release cytokines.
Phagocytose Mtb, release cytokines, prime T-cells.
Release cytokines.
Phagocytose / contain Mtb.
Sense Mtb through multiple PRRs (TLRs, CLRs).
Contribute to activation of T-cells.
Antimycobacterial activity.
Promote lung damage, granuloma caseation and cavitation.
Release immune mediators, such as cytokines/chemokines
(pro/anti-inflammatory), reactive metabolites, neutrophil
extracellular traps.

[93-95]

Notes: ALR, AIM2-like receptor; BAL, bronchoalveolar lavage BMDC, Bone marrow-derived dendritic cell; BMDM, Bone marrow-derived macrophage; CDS, cytosolic DNA sensors; CLR, Ctype lectin receptor; DC: dendritic cell; GM-CSF, granulocyte-macrophage colony-stimulating factor;G-MDSC, Granulocytic myeloid-derived suppressor cell; IFN-, interferon gamma; IL-1,
interleukin-1 beta; M-MDSC, monocytic myeloid-derived suppressor cell; Mtb, Mycobacterium tuberculosis; NHP, nonhuman primate; NLR, nucleotide-binding oligomerization domain receptor;
NOD, nucleotide-binding oligomerization domain; pDC, plasmacytoid dendritic cell; PGE2, prostaglandin; PRR, pattern-recognition receptor; RNS, reactive nitrogen species; ROS, reactive oxygen
species; TLR, Toll-like receptor; TNF-, tumor necrosis factor alpha.

Phagocytose Mtb.
Suppress T-cell responses.
Promote lung damage.
Release immune mediators, such as cytokines
(pro/anti-inflammatory).

[92;103;104;109]
[108]
[99]
[99]
[112;118120;135;136;154;155]

Mouse in vivo

Prime T-cells.

[32;36;37;83]

[32;34;36;37;44;62;93;150;151]

Mouse in vivo, BMDCs

Anca Dorhoi and Stefan H.E. Kaufmann

Myeloid-derived suppressor cells

(M-MDSC/
G-MDSC)

CD103+ CD11c+
CD1c+
pDC
Neutrophils

CD11b+ CD11c+

[127;144;149]
[88;89;96-100]

Human ex vivo
Human primary cells ex vivo

[63;65;66]
[28;102]

Mouse BMDMs, cell lines

Mouse in/ex vivo

Mouse in vivo, ex vivo

Promote inflammation.

Transformed macrophages (foamy,

epithelioid, giant)

[64;70;7981]

References

Human ex vivo

Model

Allow Mtb persistence.

Phagocytose Mtb, unable to kill bacteria.
Sense Mtb through multiple PRRs (TLRs, CLRs, NLRs).
Prime T-cells.
Release immune mediators, such as cytokines
(pro/anti-inflammatory).
Release cytokines.

Restrain Mtb replication by induction of antimicrobial

peptides, boosting autocrine activation and unknown
mechanisms.

Anti-mycobacterial macrophages
(vitamin D /GM-CSF/ IL-1)

Dendritic cells

Function

Cell population/subpopulation

Table 1. Continued

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upregulates GTPases, and fosters autophagy in human and mouse

macrophages [71, 72]. NOS2 is the rate-limiting enzyme for NO
synthesis, a mycobactericidal molecule [33, 73]. GTPases comprising the MX, GBP, and IRG subfamilies are induced by IFNs
and play critical roles in controlling infections with intracellular
bacteria or viruses [74]. IFN- also modulates cell death patterns
in Mtb-infected murine macrophages. IFN- promotes apoptosis
via NO release and subsequent caspase 3/7 activation [75] or
fosters necrosis [76] in heavily infected macrophages by inducing caspase-dependent DNA fragmentation, caspase-independent
lactate dehydrogenase, and high-mobility group-box-1 protein
release and mitochondrial injury. Opposing effects on Mtb replication have been described for IL-4 [77, 78] and IL-10 [44]. Moreover, particularly in human macrophages, IL-10 has been shown
to interfere with the vitamin D/cathelicidin pathway [79, 80] for
control of virulent mycobacteria [81]. Innate IFNs, such as IFN I,
underlie more complex regulation of the anti-TB response. At the
MP level, IFN I restricts antimycobacterial effector molecules, such
as IL-1 [82, 83] by promoting the release of regulatory cytokines
such as IL-10. In addition, IFN I has been shown to promote early
cell death in alveolar macrophages during murine TB [84] and
boosts the release of chemoattractants for MPs [8486], thus contributing to the spread of infection and pulmonary inflammation
in infected rodents.
Macrophages [isolated from PBMCs in humans or bone marrow
(BM)-derived in mice] have been extensively employed as an Mtb
host-cell model. Macrophage responses are thoroughly characterized, including transcriptional changes upon infection [69, 87].
Apparently, macrophages share several response patterns with
DCs [88, 89]. DCs are a heterogeneous population of professional
APCs of primarily myeloid origin, with some subsets derived from
monocytes and others from unique precursor cells [90, 91]. Their
role in the instruction of acquired immunity is well established
[90]. Less, however, is known about the responses of DC subsets (e.g. conventional DCs, CD103+ mucosal DCs, plasmacytoid
DCs), against Mtb, despite the fact that certain populations, such
as conventional DCs [92], have been shown to be heavily infected
by Mtb in murine models of infection (Table 1). Recent studies in
rodents support a model in which partnership between various DC
subsets is required for induction of adaptive immunity. In cooperation, conventional DCs migrating to draining lymph nodes [93],
monocyte-derived DCs, and lymph node-resident DCs present Mtb
antigens to T cells [94, 95]. Human studies have largely focused
on pathogen sensing molecules expressed by DCs [96, 97] and
the capacity of monocyte-derived DCs to release cytokines upon
ex vivo challenge with Mtb [89, 98]. More recently, cross-talk
between DC subsets, CD1c+ myeloid DCs, and pDCs [99], has
been reported for human cells, too. In agreement with essentiality
of DCs for TB control in mice, a requirement for DCs with intact
migratory features has been indicated by recent genetic investigations in humans [100].
Currently, the phenotypic and functional diversity of MPs
is increasingly acknowledged [91] and therefore investigations
delineating roles of MP subsets in inflammation during TB are
required. Similar to diversity of DC subsets, various monocyte

C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

HIGHLIGHTS

populations (patrolling versus inflammatory) [91] have been

reported. Recent studies indicate that human monocyte subsets differentially respond to Mtb infection (Table 1). Investigations in an ex vivo and in a hybrid mouse model have shown
that CD16+ monocytes better sustain bacillary replication and
migrate faster toward Mtb compared to CD16 monocytes [101].
Moreover, disease-related macrophage phenotypes, such as transformed macrophages (epithelioid, foamy, giant), arise in TB [102]
further emphasizing their versatility. Different animal models,
such as inbred, hybrid or humanized mice, and nonhuman primates, have revealed that contribution of distinct MP populations
to the pool of Mtb-infected cells varies during infection or granuloma stage [84, 92, 101, 103107]. A burst size model, which
predicts range of bacterial load per infected myeloid cell, has been
recently established in the mouse [103]. Investigations in murine
models have also underlined diverse roles for DC subsets. Capacity to produce inflammatory mediators (IL-1, TNF-, IL-12) in
situ upon infection has been revealed for conventional DCs and
CD103+ DCs [83, 108]. Similarly, conserved region of difference1(RD1)-dependent cytosolic Mtb egression has been unveiled
for various lung-residing MPs, including alveolar macrophages
and lung CD11b+ CD11c+ DCs [109] thus showing that cytosolic translocation is not occurring just ex vivo [110]. The RD1 locus
harbors multiple pathogenicity factors in Mtb [111]. As exemplified above, efforts to ascertain functions of diverse MP populations
in TB are undertaken. The consequences for Mtb survival upon cellular activation, trafficking/cell-autonomous events, and precisely
how MP subsets tailor inflammation in TB still need to be established.

Neutrophils and myeloid regulatory cells

Although MPs are generally viewed as the main host cell counterpart of Mtb, PMNs can also serve as bacterial reservoirs [112].
These fast-responding myeloid cells have been implicated in both
protective and destructive processes (Table 1) [113, 114]. Experimental murine and nonhuman primate models [84, 103, 115, 116]
and cattle TB [117] indicate that PMNs are recruited early to the
lung during virulent Mtb infection. Antibacterial capacities have
been unveiled based on analysis of ex vivo cultures of PMNs [118]
or total leukocytes [119, 120], but direct Mtb killing by PMNs
within the lung has not been demonstrated unequivocally. The
outcome of PMN depletion studies largely depends on the model
used, and underlines versatile roles of these myeloid cells. In resistant mice (C57BL/6 inbred strain), early PMN depletion indicates
their contribution to T-cell priming [121, 122] and granuloma
assembly [123]. Investigations in susceptible mice (129S2, DBA2,
and I/St inbred strains), which mimic primary progressive TB
at least in partinstead reveal a detrimental, disease-promoting
activity of PMNs [84, 124, 125]. These effects are imprinted before
onset of adaptive immunity in the 129S2 model [84]. During early
Mtb infection, lung-resident cells mainly attract PMN accumulation into lung tissue by release of CXCR2 cognates [116, 122].
CXCL1 and CXCL2 are produced by myeloid cells upon Mtb
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stimulation [116]. The main PMN chemoattractant produced early

during pulmonary TB is CXCL5 [116]. It is released primarily by
pneumocytes upon sensing of TLR-2 agonists from Mtb, such as
lipopeptides [116]. Abundance of CXCR2 cognates follows discrete spatial and temporal kinetics. It largely influences hyperinflammation, which is characterized by heightened accumulation
of leukocytes and tissue destruction [116]. A tissue chemokine signature with CXCL5 playing a critical role in TB pathogenesis has
been identified in various murine infection models [124, 126].
At later stages of infection, additional sources, such as transformed macrophages, can contribute to pulmonary abundance of
CXCL5, as recently suggested for active TB in humans [127]. The
tissue dynamics of PMNs and local inflammation can be regulated, in addition, by PMN cell-intrinsic mechanisms [128, 129].
Posttranscriptional regulation of PMN chemoattractants through
microRNA (miR), with impact on TB outcome, has been deciphered in mice [129]. In particular, PMNs accumulate miR-223
during their ontogeny, and miR-223 directly targets CXCL2, CCL3,
and IL-6. This intrinsic regulation is responsible for recruitment
of PMNs into the lung during Mtb infection and modulates systemic availability of PMNs, likely by impacting on granulopoiesis
[129]. In addition, PMNs have been shown to modulate their tissue dynamics by means of cellular stores of S100A8/9 proteins
[115]. These proteins, also released by MPs such as macrophages
[130132], are abundant in PMN granular content and act as
alarmins [133]. Serum abundance of S100A8/9 correlates with
TB severity in humans and Mtb-infected experimental animals. In
contrast, IFN- restricts both lung accumulation of PMNs and their
survival [134]. The harmful role of PMNs in scenarios of failed
immunity and active TB disease suggests PMNs as amenable cellular targets for HDT. While factors orchestrating the tissue dynamics of PMNs are increasingly characterized, less is known about
tissue fate of PMNs and their interactions with Mtb and other cells
recruited to the lung. In vitro studies have described the propensity of Mtb to induce necrosis in human PMNs [135] in a process
depending on RD-1-encoded proteins [135, 136]. Whether or not,
and how PMNs are disposed of within the infected lungs and the
consequences for inflammation will need further investigations.
The group of myeloid cells harboring Mtb and fine-tuning
inflammation in TB disease has been recently expanded to include
immature myeloid-derived suppressor cells (MDSCs), also known
as regulatory myeloid cells [137]. The association between MDSCs
and inflammation has long been investigated in cancer biology,
but the roles of MDSCs in bacterial infections are only recently
emerging. The first investigation on MDSCs in TB identified these
immature cells in pleural effusions and blood of TB patients [138].
Importantly, the number of MDSCs is reduced after chemotherapy, suggesting that MDSCs are part of the exuberant inflammatory response accompanying active TB. Subsequent studies have
confirmed the systemic presence of MDSCs in TB patients [139].
Experimental mouse models (TB-susceptible I/St mice) indicate
that Mtb fosters the generation of MDSCs in bone marrow, and
that susceptibility to infection and lethal inflammation is associated with systemic (blood and spleen) accumulation of MDSCs
and the presence of MDSC-like cells in the lung parenchyma

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[140]. More recently, careful analysis of MDSC kinetics in the

lung of C57BL/6 and 129S2 mice has demonstrated that MDSC
accumulation is part of the general inflammatory response to
Mtb, although their dynamics has been shown to be augmented
in a susceptible host developing primary progressive TB [141].
MDSCs have been shown to restrict selected T-cell responses by
mechanisms dependent on close proximity to target cells, and by
release of NO [141, 142]. Similar to macrophages and PMNs,
MDSCs harbor bacilli, and release proinflammatory (IL-1, IL-6)
and anti-inflammatory (IL-10) mediators, thereby indicating their
complex role in this disease [141]. Taken together, MDSCs represent cellular components of the myeloid cell network contributing
to TB pathogenesis (Table 1). Excessive frequencies of MDSCs
exacerbate inflammation and worsen disease outcome. Therefore,
MDSCs are host defense components, which are required at optimal frequencies during Mtb infection. The concept of just right
level is already established in TB for selected humoral factors,
such as TNF- [143]. The beneficial effects of drug-induced MDSC
ablation on overt inflammation in TB and lung pathology [141]
indicates that MDSCs are also candidate cellular targets for HDT
against active TB disease.

Myeloid cells in lung immunopathology

The stability of granulomas is conditioned by various mechanisms controlling cell-intrinsic and -concerted responses.
Regarding myeloid cell diversity, it is now generally accepted that
polarized macrophages with fluctuating phenotypes affect intragranulomatous events [144]. These polarized macrophages, such
as classically (IFN- activated, termed M1)/alternatively (IL-4 activated, termed M2) activated or deactivated macrophages, release
proinflammatory (e.g. TNF-) or anti-inflammatory (IL-10) mediators [145, 146]. The spectrum of activated macrophages expands
beyond these phenotypes [147]. Polarized macrophages in addition modify the metabolic milieu via enzymatic products (NO
M1, L-arginine metabolites M2, lipids) [107, 148, 149]. Accordingly, macrophages can modulate granuloma outcome depending
on their phenotype, location, and interaction partners [144, 145].
In contrast to macrophages, DCs are highly motile within granulomas, but with limited migratory capacities [150, 151]. MDSCs
have been detected inside TB granulomas and classical interaction
partners for MDSCs in situ, namely T lymphocytes, have been validated in experimental TB in mice [141]. The ability of MDSCs to
either exit granulomas or interact with additional myeloid types
or other cells residing in granulomas needs to be explored.
The expansion of granulomas affects lung functionality by limiting oxygen-exchange space as fundamental respiratory function,
thereby contributing to TB clinical symptomatology. TB transmission occurs when granulomas rupture as a consequence of
caseation, allowing the entry of Mtb into airways. If Mtb enters
the blood stream and lymphatics as a result of caseation, it can
infect distant organs [15]. Enzymatic MP products, such as matrix
metalloproteases [152, 153] promote cavitation following necrosis and caseation. PMNs are also important drivers for cavitation
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HIGHLIGHTS

Figure 1. Schema of different myeloid cell

types with shared and specific activities in
tuberculosis (TB) granulomas. Caseating granulomas typically present a necrotic center surrounded by mononuclear phagocytes
(MPs), including macrophages (M) in different stages of activation and transformation and dendritic cells (DCs), polymorphonuclear neutrophils (PMNs), myeloid regulatory cells/myeloid-derived suppressor cells
(MDSCs), and lymphocytes. (A) Macrophages
represent the major myeloid cell population containing Mycobacterium tuberculosis (Mtb)
inside granulomas. Macrophages release multiple mediators upon infection or following activation, such as cytokines, chemokines, and
enzymatic products downstream of nitric oxide
synthase 2 (NOS2) or arginase 1. Macrophages
produce matrix metalloproteases, which contribute to granuloma cavitation and tissue
remodeling. (B) PMN-derived factors, like granular proteases, in addition participate in tissue liquefaction. PMNs recruited to granulomas
through chemokine gradients or self-contained
granular proteins (S100A8/9) foster granuloma
cavitation and exhibit tissue-damaging features, which promote disease exacerbation and
TB transmission. (C) DCs release cytokines
and chemokines, thereby supporting in situ
inflammatory processes. DCs are highly motile
within granulomas and have a critical role
in stimulating antigen-specific T lymphocytes.
(D) In contrast, MDSCs inhibit proliferation and
cytokine release by T-cells during TB. MDSCs
contain Mtb and produce selected proinflammatory and regulatory cytokines upon interaction with bacteria. Frequencies of myeloid cells,
their activation modes, secretory capacities,
and spatiotemporal positioning inside granulomas and relative to other cell types, orchestrate the fate of TB granulomas, and implicitly,
disease outcome, and transmission.

[154]. Early studies of human TB granulomas have suggested a

high content of dying neutrophils [155]. More recently, results
from murine TB models [153], and analyses of human specimens
[112] have raised interest in how PMNs contribute to granuloma
cavitation. Moreover, identification of PMNs and their products
at the cavity wall and in necrotizing granulomas [154] suggest a
provocative hypothesis with a partnership between PMNs and MPs
relevant for maintenance of TB immunity, shaping intralesional
biofilm formation by Mtb and TB pathology [156]. It remains
to be established whether or not PMNs, possibly subpopulations
of PMNs, or MDSC subsets join forces to promote granuloma
caseation and cavitation.

ment of disease severity and inform about therapeutic options.

As illustrated in this review, recent findings have broadened our
knowledge of TB pathogenesis by emphasizing the versatile nature
of myeloid populations and subpopulations contributing to TBassociated inflammation (Fig. 1). Future research should aim to
integrate distinct myeloid phenotypes in inflammatory interaction
networks, uncover their dynamic features, de- or refine key interaction hubs and assess their suitability for HDT in TB.

Concluding remarks

Acknowledgments: We thank Mary Louise Grossman for excellent help preparing the manuscript and Diane Schad for graphical assistance. This work was supported by European Unions
Seventh Framework Program project SysteMTb (HEALTH-F32009-241587); the European Unions Horizon 2020 project
TBVAC2020 (grant no. 643381); the German Federal Ministry of Education and Research (Bundesministerium f
ur Bildung
und Forschung, BMBF) Infect ERA project Anti-Bacterial Immune

Improvement of TB control urgently calls for faster diagnosis and

prognosis, as well as more effective preventive and therapeutic
measures. The search for biomarkers has repeatedly converged
upon myeloid cells. Transcriptional signatures [157], soluble factors [115], and frequencies of selected myeloid cells, such as PMNs
[158] and MDSCs [138, 141] could contribute to the assess
C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eji-journal.eu

2197

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Anca Dorhoi and Stefan H.E. Kaufmann

Regulation (ABIR) (grant no. 031A404); and Institut Merieux

Research Grants Programme.

Eur. J. Immunol. 2015. 45: 21912202

composition of tuberculous granulomas in Thorbecke and outbred New

Zealand White rabbits. Vet. Immunol. Immunopathol. 2008. 122: 167174.
19 Clark, S., Hall, Y. and Williams, A., Animal models of tuberculosis:
guinea pigs. Cold Spring Harb. Perspect. Med. 2014. 5: a018572.

Conflict of interest: The authors have no commercial or financial

conflict of interest.

20 Orme, I. M. and Basaraba, R. J., The formation of the granuloma in

tuberculosis infection. Semin. Immunol. 2014. 26: 601609.
21 Ramakrishnan, L., Revisiting the role of the granuloma in tuberculosis.
Nat. Rev. Immunol. 2012. 12: 352366.

References

22 Gengenbacher, M. and Kaufmann, S. H. E., Mycobacterium tuberculosis:

success through dormancy. FEMS Microbiol. Rev. 2012. 36: 514532.
23 Goren, M. B., Cernich, M. and Brokl, O., Some observations of mycobac-

1 WHO. Tuberculosis Fact Sheet no. 104. WHO, Geneva, 2015.

terial acid-fastness. Am. Rev. Respir. Dis. 1978. 118: 151154.

2 Koch, R., Die Aetiologie der Tuberculose (Nach einem in der physiologis-

24 Glickman, M. S., Cox, J. S. and Jacobs, W. R., Jr., A novel mycolic acid

gehaltenem Vortrage). Berliner

chen Gesellschaft zu Berlin am 24.Marz

cyclopropane synthetase is required for cording, persistence, and viru-

klin.Wochenschr. 1882. 19: 221230.

lence of Mycobacterium tuberculosis. Mol. Cell 2000. 5: 717727.

3 Kaufmann, S. H. E., Robert Koch, the Nobel Prize, and the ongoing threat
of tuberculosis. N. Engl. J. Med. 2005. 353: 24232426.
4 Paulson, T., Epidemiology: a mortal foe. Nature 2013. 502: S2S3.
5 WHO. Global Tuberculosis Report 2014. WHO Press, Geneva, 2014.
6 Philips, J. A. and Ernst, J. D., Tuberculosis pathogenesis and immunity.
Annu. Rev. Pathol. 2012. 7: 353384.
7 Bos, K. I., Harkins, K. M., Herbig, A., Coscolla, M., Weber, N., Comas,
I., Forrest, S. A. et al., Pre-Columbian mycobacterial genomes reveal
seals as a source of New World human tuberculosis. Nature 2014. 514:
494497.

25 Makinoshima, H. and Glickman, M. S., Regulation of Mycobacterium

tuberculosis cell envelope composition and virulence by intramembrane
proteolysis. Nature 2005. 436: 406409.
26 Torrelles, J. B. and Schlesinger, L. S., Diversity in Mycobacterium tuberculosis mannosylated cell wall determinants impacts adaptation to the
host. Tuberculosis 2010. 90: 8493.
27 Kieser, K. J. and Rubin, E. J., How sisters grow apart: mycobacterial
growth and division. Nat. Rev. Microbiol. 2014. 12: 550562.
28 Russell, D. G., Mycobacterium tuberculosis and the intimate discourse of
a chronic infection. Immunol. Rev. 2011. 240: 252268.

8 Comas, I., Coscolla, M., Luo, T., Borrell, S., Holt, K. E., Kato-Maeda, M.,

29 Goren, M. B., DArcy, H. P., Young, M. R., and Armstrong, J. A., Preven-

Parkhill, J. et al., Out-of-Africa migration and Neolithic coexpansion of

tion of phagosome-lysosome fusion in cultured macrophages by sul-

Mycobacterium tuberculosis with modern humans. Nat. Genet. 2013. 45:

fatides of Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. USA 1976. 73:

11761182.

25102514.

9 Cambier, C. J., Falkow, S. and Ramakrishnan, L., Host evasion and

30 Indrigo, J., Hunter, R. L., Jr. and Actor, J. K., Cord factor trehalose

exploitation schemes of Mycobacterium tuberculosis. Cell 2014. 159: 1497

6,6-dimycolate (TDM) mediates trafficking events during mycobacterial

1509.

infection of murine macrophages. Microbiology 2003. 149: 20492059.

10 Kaufmann, S. H. and Dorhoi, A., Inflammation in tuberculosis: interac-

31 Kang, P. B., Azad, A. K., Torrelles, J. B., Kaufman, T. M., Beharka,

tions, imbalances and interventions. Curr. Opin. Immunol 2013. 25: 441

A., Tibesar, E., DesJardin, L. E. et al., The human macrophage man-

449.
11 Dorhoi, A. and Kaufmann, S. H., Perspectives on host adaptation in
response to Mycobacterium tuberculosis: modulation of inflammation.
Semin. Immunol. 2014. 26: 533542.
12 Kaufmann, S. H., Lange, C., Rao, M., Balaji, K. N., Lotze, M., Schito, M.,
Zumla, A. I. et al., Progress in tuberculosis vaccine development and
host-directed therapiesa state of the art review. Lancet Respir. Med.
2014. 2: 301320.
13 Hawn, T. R., Matheson, A. I., Maley, S. N. and Vandal, O., Host-directed
therapeutics for tuberculosis: can we harness the host? Microbiol. Mol.
Biol. Rev. 2013. 77: 608627.
14 Zumla, A., Rao, M., Parida, S. K., Keshavjee, S., Cassell, G., Wallis, R.,
Axelsson-Robertsson, R. et al., Inflammation and tuberculosis: hostdirected therapies. J. Intern. Med. 2015. 277: 373387.
15 Kaufmann, S. H. E., Tuberculosis vaccines: time to think about the next
generation. Semin. Immunol. 2013. 25: 172181.
16 Dye, C. and Williams, B. G., The population dynamics and control of
tuberculosis. Science 2010. 328: 856861.
17 Lin, P. L., Pawar, S., Myers, A., Pegu, A., Fuhrman, C., Reinhart, T. A.,
Capuano, S. V. et al., Early events in Mycobacterium tuberculosis infection
in cynomolgus macaques. Infect. Immun. 2006. 74: 37903803.
18 Mendez, S., Hatem, C. L., Kesavan, A. K., Lopez-Molina, J., Pitt, M. L.,
Dannenberg, A. M., Jr. and Manabe, Y. C., Susceptibility to tuberculosis:


C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

nose receptor directs Mycobacterium tuberculosis lipoarabinomannanmediated phagosome biogenesis. J. Exp. Med. 2005. 202: 987999.
32 Lugo-Villarino, G. and Neyrolles, O., Manipulation of the mononuclear
phagocyte system by Mycobacterium tuberculosis. Cold Spring Harb. Perspect. Med. 2014. 4: a018549.
33 Bogdan, C., Nitric oxide synthase in innate and adaptive immunity: an
update. Trends Immunol. 2015. 36: 161178.
34 Kleinnijenhuis, J., Oosting, M., Joosten, L. A., Netea, M. G. and Van, C.
R., Innate immune recognition of Mycobacterium tuberculosis. Clin. Dev.
Immunol. 2011. 2011: 405310.
35 MacMicking, J. D., Cell-autonomous effector mechanisms against
Mycobacterium tuberculosis. Cold Spring Harb. Perspect. Med. 2014. 4: pii:
a018507.
36 Etna, M. P., Giacomini, E., Severa, M. and Coccia, E. M., Pro- and antiinflammatory cytokines in tuberculosis: a two-edged sword in TB pathogenesis. Semin. Immunol. 2014. 26: 543551.
37 Torrado, E. and Cooper, A. M., Cytokines in the balance of protection
and pathology during mycobacterial infections. Adv. Exp. Med. Biol. 2013.
783: 121140.
38 Fremond, C. M., Yeremeev, V., Nicolle, D. M., Jacobs, M., Quesniaux,
V. F. and Ryffel, B., Fatal Mycobacterium tuberculosis infection despite
adaptive immune response in the absence of MyD88. J. Clin. Invest. 2004.
114: 17901799.

www.eji-journal.eu

HIGHLIGHTS

Eur. J. Immunol. 2015. 45: 21912202

39 Mayer-Barber, K. D., Barber, D. L., Shenderov, K., White, S. D., Wilson,

55 Wassermann, R., Gulen, M. F., Sala, C., Perin, S. G., Lou, Y., Rybniker,

M. S., Cheever, A., Kugler, D. et al., Caspase-1 independent IL-1beta

J., Schmid-Burgk, J. L. et al., Mycobacterium tuberculosis differentially

production is critical for host resistance to Mycobacterium tuberculosis

activates cGAS- and inflammasome-dependent intracellular immune

and does not require TLR signaling in vivo. J. Immunol. 2010. 184: 3326
3330.

responses through ESX-1. Cell Host. Microbe 2015. 17: 799810.

56 Watson, R. O., Bell, S. L., MacDuff, D. A., Kimmey, J. M., Diner, E.

40 Zhang, X., Majlessi, L., Deriaud, E., Leclerc, C. and Lo-Man, R., Coacti-

J., Olivas, J., Vance, R. E. et al., The cytosolic sensor cGAS detects

vation of Syk kinase and MyD88 adaptor protein pathways by bacteria

Mycobacterium tuberculosis DNA to induce type I interferons and activate

promotes regulatory properties of neutrophils. Immunity 2009. 31: 761

771.
41 Dorhoi, A., Desel, C., Yeremeev, V., Pradl, L., Brinkmann, V., Mollenkopf, H. J., Hanke, K. et al., The adaptor molecule CARD9 is essential
for tuberculosis control. J. Exp. Med. 2010. 207: 777792.
42 Dorhoi, A. and Kaufmann, S. H., Tumor necrosis factor alpha in
mycobacterial infection. Semin. Immunol. 2014. 26: 203209.

autophagy. Cell Host. Microbe 2015. 17: 811819.

57 Collins, A. C., Cai, H., Li, T., Franco, L. H., Li, X. D., Nair, V. R., Scharn,
C. R. et al., Cyclic GMP-AMP synthase is an innate immune DNA sensor
for Mycobacterium tuberculosis. Cell Host. Microbe 2015. 17: 820828.
58 Watson, R. O., Manzanillo, P. S. and Cox, J. S., Extracellular M. tuberculosis DNA targets bacteria for autophagy by activating the host DNAsensing pathway. Cell 2012. 150: 803815.

43 Scanga, C. A., Bafica, A., Feng, C. G., Cheever, A. W., Hieny, S. and

59 van der Vaart, M., Korbee, C. J., Lamers, G. E., Tengeler, A.

Sher, A., MyD88-deficient mice display a profound loss in resistance

C., Hosseini, R., Haks, M. C., Ottenhoff, T. H. et al., The DNA

to Mycobacterium tuberculosis associated with partially impaired Th1

damage-regulated autophagy modulator DRAM1 links mycobacterial

cytokine and nitric oxide synthase 2 expression. Infect. Immun. 2004.

recognition via TLP-MYD88 to authophagic defense. Cell Host. Microbe

72: 24002404.

2014. 15: 753767.

44 Redford, P. S., Murray, P. J. and OGarra, A., The role of IL-10 in immune
regulation during M. tuberculosis infection. Mucosal. Immunol. 2011. 4:
261270.
45 Gandotra, S., Jang, S., Murray, P. J., Salgame, P. and Ehrt, S., Nucleotidebinding oligomerization domain protein 2-deficient mice control infection with Mycobacterium tuberculosis. Infect. Immun. 2007. 75: 51275134.
46 Mishra, B. B., Rathinam, V. A., Martens, G. W., Martinot, A. J., Kornfeld, H., Fitzgerald, K. A. and Sassetti, C. M., Nitric oxide controls the
immunopathology of tuberculosis by inhibiting NLRP3 inflammasomedependent processing of IL-1beta. Nat. Immunol. 2013. 14: 5260.
47 Dorhoi, A., Nouailles, G., Jorg, S., Hagens, K., Heinemann, E., Pradl,
L., Oberbeck-Muller, D. et al., Activation of the NLRP3 inflammasome
by Mycobacterium tuberculosis is uncoupled from susceptibility to active
tuberculosis. Eur. J. Immunol. 2012. 42: 374384.
48 Walter, K., Holscher, C., Tschopp, J. and Ehlers, S., NALP3 is not necessary for early protection against experimental tuberculosis. Immunobiology 2010. 215: 804811.
49 McElvania, T. E., Allen, I. C., Hulseberg, P. D., Sullivan, J. T., McCann,
J. R., Sandor, M., Braunstein, M. et al., Granuloma formation and
host defense in chronic Mycobacterium tuberculosis infection requires
PYCARD/ASC but not NLRP3 or caspase-1. PLoS One. 2010. 5: e12320.
50 Briken, V., Ahlbrand, S. E. and Shah, S., Mycobacterium tuberculosis and
the host cell inflammasome: a complex relationship. Front Cell Infect.
Microbiol. 2013. 3: 62.
51 Saiga, H., Kitada, S., Shimada, Y., Kamiyama, N., Okuyama, M., Makino,
M., Yamamoto, M. et al., Critical role of AIM2 in Mycobacterium tuberculosis infection. Int. Immunol. 2012. 24: 637644.

60 Deretic, V., Autophagy in tuberculosis. Cold Spring Harb. Perspect. Med.

2014. 4: a018481.
61 Moura-Alves, P., Fae, K., Houthuys, E., Dorhoi, A., Kreuchwig, A., Furkert, J., Barison, N. et al., AhR sensing of bacterial pigments regulates
antibacterial defence. Nature 2014. 512: 387392.
62 Cooper, A. M., Mayer-Barber, K. D. and Sher, A., Role of innate cytokines
in mycobacterial infection. Mucosal. Immunol. 2011. 4: 252260.
63 Jayaraman, P., Sada-Ovalle, I., Nishimura, T., Anderson, A. C., Kuchroo,
V. K., Remold, H. G. and Behar, S. M., IL-1beta promotes antimicrobial
immunity in macrophages by regulating TNFR signaling and caspase-3
activation. J. Immunol. 2013. 190: 41964204.
64 Verway, M., Bouttier, M., Wang, T. T., Carrier, M., Calderon, M., An,
B. S., Devemy, E. et al., Vitamin D induces interleukin-1beta expression: paracrine macrophage epithelial signaling controls M. tuberculosis
infection. PLoS Pathog. 2013. 9: e1003407.
65 Mayer-Barber, K. D., Andrade, B. B., Oland, S. D., Amaral, E. P., Barber, D.
L., Gonzales, J., Derrick, S. C. et al., Host-directed therapy of tuberculosis
based on interleukin-1 and type I interferon crosstalk. Nature 2014. 511:
99103.
66 Rothchild, A. C., Jayaraman, P., Nunes-Alves, C. and Behar, S. M.,
iNKT cell production of GM-CSF controls Mycobacterium tuberculosis. PLoS
Pathog. 2014. 10: e1003805.
67 Fortin, A., Abel, L., Casanova, J. L. and Gros, P., Host genetics of
mycobacterial diseases in mice and men: forward genetic studies of
BCG-osis and tuberculosis. Annu. Rev. Genomics Hum. Genet. 2007. 8: 163
192.
68 Chan, J., Xing, Y., Magliozzo, R. S. and Bloom, B. R., Killing of vir-

52 Shah, S., Bohsali, A., Ahlbrand, S. E., Srinivasan, L., Rathinam, V. A.,

ulent Mycobacterium tuberculosis by reactive nitrogen intermediates

Vogel, S. N., Fitzgerald, K. A. et al., Cutting edge: Mycobacterium tuber-

produced by activated murine macrophages. J. Exp. Med. 1992. 175:

culosis but not nonvirulent mycobacteria inhibits IFN-beta and AIM2

inflammasome-dependent IL-1beta production via its ESX-1 secretion
system. J. Immunol. 2013. 191: 35143518.

11111122.
69 Ehrt, S., Schnappinger, D., Bekiranov, S., Drenkow, J., Shi, S., Gingeras,
T. R., Gaasterland, T. et al., Reprogramming of the macrophage tran-

53 Dey, B., Dey, R. J., Cheung, L. S., Pokkali, S., Guo, H., Lee, J. H. and Bishai,

scriptome in response to interferon-gamma and Mycobacterium tubercu-

W. R., A bacterial cyclic dinucleotide activates the cytosolic surveillance

losis: signaling roles of nitric oxide synthase-2 and phagocyte oxidase.

pathway and mediates innate resistance to tuberculosis. Nat. Med. 2015.

J. Exp. Med. 2001. 194: 11231140.

21: 401406.

70 Fabri, M., Stenger, S., Shin, D. M., Yuk, J. M., Liu, P. T., Realegeno,

54 Manzanillo, P. S., Shiloh, M. U., Portnoy, D. A. and Cox, J. S., Mycobac-

S., Lee, H. M. et al., Vitamin D is required for IFN-gamma-mediated

terium tuberculosis activates the DNA-dependent cytosolic surveillance

antimicrobial activity of human macrophages. Sci. Transl. Med. 2011. 3:

pathway within macrophages. Cell Host. Microbe 2012. 11: 469480.

104ra102.


C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eji-journal.eu

2199

2200

Anca Dorhoi and Stefan H.E. Kaufmann

Eur. J. Immunol. 2015. 45: 21912202

71 MacMicking, J. D., Taylor, G. A. and McKinney, J. D., Immune control

87 Keller, C., Lauber, J., Blumenthal, A., Buer, J. and Ehlers, S., Resistance

of tuberculosis by IFN-gamma-inducible LRG-47. Science 2003. 302: 654

and susceptibility to tuberculosis analysed at the transcriptome level:

659.

lessons from mouse macrophages. Tuberculosis 2004. 84: 144158.

72 Gutierrez, M. G., Master, S. S., Singh, S. B., Taylor, G. A., Colombo, M. I.

88 Tailleux, L., Waddell, S. J., Pelizzola, M., Mortellaro, A., Withers, M.,

and Deretic, V., Autophagy is a defense mechanism inhibiting BCG and

Tanne, A., Castagnoli, P. R. et al., Probing host pathogen cross-talk by

Mycobacterium tuberculosis survival in infected macrophages. Cell 2004.

transcriptional profiling of both Mycobacterium tuberculosis and infected

119: 753766.

human dendritic cells and macrophages. PLoS One 2008. 3: e1403.

73 Denis, M., Interferon-gamma-treated murine macrophages inhibit

89 Giacomini, E., Iona, E., Ferroni, L., Miettinen, M., Fattorini, L., Orefici,

growth of tubercle bacilli via the generation of reactive nitrogen inter-

G., Julkunen, I. et al., Infection of human macrophages and dendritic

mediates. Cell Immunol. 1991. 132: 150157.

cells with Mycobacterium tuberculosis induces a differential cytokine gene

74 Kim, B. H., Shenoy, A. R., Kumar, P., Bradfield, C. J. and MacMicking, J.

D., IFN-inducible GTPases in host cell defense. Cell Host. Microbe 2012.
12: 432444.
75 Herbst, S., Schaible, U. E. and Schneider, B. E., Interferon gamma activated macrophages kill mycobacteria by nitric oxide induced apoptosis.
PLoS One 2011. 6: e19105.
76 Lee, J. and Kornfeld, H., Interferon-gamma regulates the death of M.
tuberculosis-infected macrophages. J. Cell Death 2010. 3: 111.
77 Harris, J., De Haro, S. A., Master, S. S., Keane, J., Roberts, E. A., Delgado,
M. and Deretic, V., T helper 2 cytokines inhibit autophagic control of
intracellular Mycobacterium tuberculosis. Immunity 2007. 27: 505517.
78 Kahnert, A., Seiler, P., Stein, M., Bandermann, S., Hahnke, K., Mollenkopf, H. and Kaufmann, S. H., Alternative activation deprives
macrophages of a coordinated defense program to Mycobacterium tuberculosis. Eur. J. Immunol. 2006. 36: 631647.
79 Liu, P. T., Stenger, S., Tang, D. H. and Modlin, R. L., Cutting edge: vitamin D-mediated human antimicrobial activity against Mycobacterium
tuberculosis is dependent on the induction of cathelicidin. J. Immunol.
2007. 179: 20602063.
80 Liu, P. T., Stenger, S., Li, H., Wenzel, L., Tan, B. H., Krutzik, S. R., Ochoa,
M. T. et al., Toll-like receptor triggering of a vitamin D-mediated human
antimicrobial response. Science 2006. 311: 17701773.
81 Teles, R. M., Graeber, T. G., Krutzik, S. R., Montoya, D., Schenk, M.,
Lee, D. J., Komisopoulou, E. et al., Type I interferon suppresses type II
interferon-triggered human anti-mycobacterial responses. Science 2013.
339: 14481453.
82 Novikov, A., Cardone, M., Thompson, R., Shenderov, K., Kirschman,
K. D., Mayer-Barber, K. D., Myers, T. G. et al., Mycobacterium tuberculosis triggers host type I IFN signaling to regulate IL-1beta production in
human macrophages. J. Immunol. 2011. 187: 25402547.
83 Mayer-Barber, K. D., Andrade, B. B., Barber, D. L., Hieny, S., Feng, C.
G., Caspar, P., Oland, S. et al., Innate and adaptive interferons suppress IL-1alpha and IL-1beta production by distinct pulmonary myeloid
subsets during Mycobacterium tuberculosis infection. Immunity 2011. 35:
10231034.
84 Dorhoi, A., Yeremeev, V., Nouailles, G., Weiner, J., III, Jorg, S., Heinemann, E., Oberbeck-Muller, D. et al., Type I IFN signaling triggers
immunopathology in tuberculosis-susceptible mice by modulating lung
phagocyte dynamics. Eur. J. Immunol. 2014. 44: 23802393.
85 Desvignes, L., Wolf, A. J. and Ernst, J. D., Dynamic roles of type I and
type II IFNs in early infection with Mycobacterium tuberculosis. J. Immunol.
2012. 188: 62056215.
86 Antonelli, L. R., Gigliotti, R. A., Goncalves, R., Roffe, E., Cheever, A. W.,
Bafica, A., Salazar, A. M. et al., Intranasal Poly-IC treatment exacerbates
tuberculosis in mice through the pulmonary recruitment of a pathogenpermissive monocyte/macrophage population. J. Clin. Invest. 2010. 120:
16741682.


C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

expression that modulates T cell response. J. Immunol. 2001. 166: 7033

7041.
90 Merad, M., Sathe, P., Helft, J., Miller, J. and Mortha, A., The dendritic
cell lineage: ontogeny and function of dendritic cells and their subsets
in the steady state and the inflamed setting. Annu. Rev. Immunol. 2013.
31: 563604.
91 Guilliams, M., Ginhoux, F., Jakubzick, C., Naik, S. H., Onai, N., Schraml,
B. U., Segura, E. et al., Dendritic cells, monocytes and macrophages: a
unified nomenclature based on ontogeny. Nat. Rev. Immunol. 2014. 14:
571578.
92 Wolf, A. J., Linas, B., Trevejo-Nunez, G. J., Kincaid, E., Tamura, T.,
Takatsu, K. and Ernst, J. D., Mycobacterium tuberculosis infects dendritic
cells with high frequency and impairs their function in vivo. J. Immunol.
2007. 179: 25092519.
93 Khader, S. A., Partida-Sanchez, S., Bell, G., Jelley-Gibbs, D. M., Swain,
S., Pearl, J. E., Ghilardi, N. et al., Interleukin 12p40 is required for dendritic cell migration and T cell priming after Mycobacterium tuberculosis
infection. J. Exp. Med. 2006. 203: 18051815.
94 Srivastava, S. and Ernst, J. D., Cell-to-cell transfer of M. tuberculosis
antigens optimizes CD4 T cell priming. Cell Host. Microbe 2014. 15: 741
752.
95 Samstein, M., Schreiber, H. A., Leiner, I. M., Susac, B., Glickman, M. S.
and Pamer, E. G., Essential yet limited role for CCR2(+) inflammatory
monocytes during Mycobacterium tuberculosis-specific T cell priming. Elife
2013. 2: e01086.
96 Tailleux, L., Schwartz, O., Herrmann, J. L., Pivert, E., Jackson, M.,
Amara, A., Legres, L. et al., DC-SIGN is the major Mycobacterium
tuberculosis receptor on human dendritic cells. J. Exp. Med. 2003. 197:
121127.
97 Geijtenbeek, T. B., Van Vliet, S. J., Koppel, E. A., Sanchez-Hernandez, M.,
Vandenbroucke-Grauls, C. M., Appelmelk, B. and Van, K. Y., Mycobacteria target DC-SIGN to suppress dendritic cell function. J. Exp. Med. 2003.
197: 717.
98 Wang, C., Peyron, P., Mestre, O., Kaplan, G., van, S. D., Gao, Q., Gicquel,
B. et al., Innate immune response to Mycobacterium tuberculosis Beijing
and other genotypes. PLoS One 2010. 5: e13594.
99 Lozza, L., Farinacci, M., Bechtle, M., Staber, M., Zedler, U., Baiocchini, A.,
Del, N. F. et al., Communication between human dendritic cell subsets
in tuberculosis: requirements for naive CD4(+) T cell stimulation. Front
Immunol. 2014. 5: 324.
100 Curtis, J., Luo, Y., Zenner, H. L., Cuchet-Lourenco, D., Wu, C., Lo, K.,
Maes, M. et al., Susceptibility to tuberculosis is associated with variants
in the ASAP1 gene encoding a regulator of dendritic cell migration. Nat.
Genet. 2015. 47: 523527.
101 Balboa, L., Romero, M. M., Basile, J. I., Garcia, C. A., Schierloh, P., Yokobori, N., Geffner, L. et al., Paradoxical role of CD16+CCR2+CCR5+ monocytes in tuberculosis: efficient APC in pleural effusion but also mark
disease severity in blood. J. Leukoc. Biol. 2011. 90: 6975.

www.eji-journal.eu

HIGHLIGHTS

Eur. J. Immunol. 2015. 45: 21912202

102 Russell, D. G., Cardona, P. J., Kim, M. J., Allain, S. and Altare, F., Foamy

117 Cassidy, J. P., Bryson, D. G., Pollock, J. M., Evans, R. T., Forster, F. and

macrophages and the progression of the human tuberculosis granu-

Neill, S. D., Early lesion formation in cattle experimentally infected with

loma. Nat. Immunol. 2009. 10: 943948.

Mycobacterium bovis. J. Comp. Pathol. 1998. 119: 2744.

103 Repasy, T., Lee, J., Marino, S., Martinez, N., Kirschner, D. E., Hen-

118 Jones, G. S., Amirault, H. J. and Andersen, B. R., Killing of Mycobacterium

dricks, G., Baker, S. et al., Intracellular bacillary burden reflects a

tuberculosis by neutrophils: a nonoxidative process. J. Infect. Dis. 1990.

burst size for Mycobacterium tuberculosis in vivo. PLoS Pathog. 2013. 9:

e1003190.

162: 700704.
119 Tan, B. H., Meinken, C., Bastian, M., Bruns, H., Legaspi, A., Ochoa, M.

104 Blomgran, R., Desvignes, L., Briken, V. and Ernst, J. D., Mycobacterium

T., Krutzik, S. R. et al., Macrophages acquire neutrophil granules for

tuberculosis inhibits neutrophil apoptosis, leading to delayed activation

antimicrobial activity against intracellular pathogens. J. Immunol. 2006.

of naive CD4 T cells. Cell Host. Microbe 2012. 11: 8190.

105 Leung, C., Chijioke, O., Gujer, C., Chatterjee, B., Antsiferova, O.,

177: 18641871.
120 Martineau, A. R., Newton, S. M., Wilkinson, K. A., Kampmann, B.,

Landtwing, V., McHugh, D. et al., Infectious diseases in humanized

Hall, B. M., Nawroly, N., Packe, G. E. et al., Neutrophil-mediated

mice. Eur. J. Immunol. 2013. 43: 22462254.

innate immune resistance to mycobacteria. J. Clin. Invest. 2007. 117:

106 Heuts, F., Gavier-Widen, D., Carow, B., Juarez, J., Wigzell, H. and Rotten-

19881994.

berg, M. E., CD4+ cell-dependent granuloma formation in humanized

121 Blomgran, R. and Ernst, J. D., Lung neutrophils facilitate activation of

mice infected with mycobacteria. Proc. Natl. Acad. Sci. USA 2013. 110:

naive antigen-specific CD4+ T cells during Mycobacterium tuberculosis

64826487.

infection. J. Immunol. 2011. 186: 71107119.

107 Mattila, J. T., Ojo, O. O., Kepka-Lenhart, D., Marino, S., Kim, J. H., Eum,

122 Kang, D. D., Lin, Y., Moreno, J. R., Randall, T. D. and Khader, S. A., Pro-

S. Y., Via, L. E. et al., Microenvironments in tuberculous granulomas are

filing early lung immune responses in the mouse model of tuberculosis.

delineated by distinct populations of macrophage subsets and expression of nitric oxide synthase and arginase isoforms. J. Immunol. 2013.
191: 773784.
108 Leepiyasakulchai, C., Ignatowicz, L., Pawlowski, A., Kallenius, G.
and Skold, M., Failure to recruit anti-inflammatory CD103+ dendritic cells and a diminished CD4+ Foxp3+ regulatory T cell pool
in mice that display excessive lung inflammation and increased
susceptibility to Mycobacterium tuberculosis. Infect. Immun. 2012. 80:
11281139.
109 Simeone, R., Sayes, F., Song, O., Groschel, M. I., Brodin, P., Brosch, R.
and Majlessi, L., Cytosolic access of Mycobacterium tuberculosis: critical
impact of phagosomal acidification control and demonstration of occurrence in vivo. PLoS Pathog. 2015. 11: e1004650.
110 van der Wel, N., Hava, D., Houben, D., Fluitsma, D., van, Z. M., Pierson, J., Brenner, M. et al., M. tuberculosis and M. leprae translocate
from the phagolysosome to the cytosol in myeloid cells. Cell 2007. 129:
12871298.
111 Pym, A. S., Brodin, P., Brosch, R., Huerre, M. and Cole, S. T., Loss of
RD1 contributed to the attenuation of the live tuberculosis vaccines
Mycobacterium bovis BCG and Mycobacterium microti. Mol. Microbiol. 2002.
46: 709717.
112 Eum, S. Y., Kong, J. H., Hong, M. S., Lee, Y. J., Kim, J. H., Hwang, S. H.,
Cho, S. N. et al., Neutrophils are the predominant infected phagocytic
cells in the airways of patients with active pulmonary TB. Chest 2010.
137: 122128.
113 Dorhoi, A., Iannaccone, M., Maertzdorf, J., Nouailles, G., Weiner, J., III,
and Kaufmann, S. H., Reverse translation in tuberculosis: neutrophils
provide clues for understanding development of active disease. Front
Immunol. 2014. 5: 36.
114 Lowe, D. M., Redford, P. S., Wilkinson, R. J., OGarra, A. and Martineau,
A. R., Neutrophils in tuberculosis: friend or foe? Trends Immunol. 2012.
33: 1425.
115 Gopal, R., Monin, L., Torres, D., Slight, S., Mehra, S., McKenna, K. C.,
Fallert Junecko, B. A. et al., S100A8/A9 proteins mediate neutrophilic
inflammation and lung pathology during tuberculosis. Am. J. Respir. Crit.
Care Med. 2013. 188: 11371146.
116 Nouailles, G., Dorhoi, A., Koch, M., Zerrahn, J., Weiner, J., III, Fae, K.
C., Arrey, F. et al., CXCL5-secreting pulmonary epithelial cells drive
destructive neutrophilic inflammation in tuberculosis. J. Clin. Invest.
2014. 124: 12681282.


C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

PLoS One 2011. 6: e16161.

123 Seiler, P., Aichele, P., Bandermann, S., Hauser, A. E., Lu, B., Gerard, N. P.,
Gerard, C. et al., Early granuloma formation after aerosol Mycobacterium
tuberculosis infection is regulated by neutrophils via CXCR3-signaling
chemokines. Eur. J. Immunol. 2003. 33: 26762686.
124 Keller, C., Hoffmann, R., Lang, R., Brandau, S., Hermann, C. and
Ehlers, S., Genetically determined susceptibility to tuberculosis in mice
causally involves accelerated and enhanced recruitment of granulocytes. Infect. Immun. 2006. 74: 42954309.
125 Eruslanov, E. B., Lyadova, I. V., Kondratieva, T. K., Majorov, K. B.,
Scheglov, I. V., Orlova, M. O. and Apt, A. S., Neutrophil responses to
Mycobacterium tuberculosis infection in genetically susceptible and resistant mice. Infect. Immun. 2005. 73: 17441753.
126 Marzo, E., Vilaplana, C., Tapia, G., Diaz, J., Garcia, V. and Cardona,
P. J., Damaging role of neutrophilic infiltration in a mouse model of
progressive tuberculosis. Tuberculosis 2014. 94: 5564.
127 Feng, Y., Dorhoi, A., Mollenkopf, H. J., Yin, H., Dong, Z., Mao, L.,
Zhou, J. et al., Platelets direct monocyte differentiation into epithelioidlike multinucleated giant foam cells with suppressive capacity upon
mycobacterial stimulation. J. Infect. Dis. 2014. 210: 17001710.
128 Scapini, P., Lapinet-Vera, J. A., Gasperini, S., Calzetti, F., Bazzoni, F. and
Cassatella, M. A., The neutrophil as a cellular source of chemokines.
Immunol. Rev. 2000. 177: 195203.
129 Dorhoi, A., Iannaccone, M., Farinacci, M., Fae, K. C., Schreiber, J., MouraAlves, P., Nouailles, G. et al., MicroRNA-223 controls susceptibility to
tuberculosis by regulating lung neutrophil recruitment. J. Clin. Invest.
2013. 123: 48364848.
130 Pechkovsky, D. V., Zalutskaya, O. M., Ivanov, G. I. and Misuno, N. I.,
Calprotectin (MRP8/14 protein complex) release during mycobacterial
infection in vitro and in vivo. FEMS Immunol. Med. Microbiol. 2000. 29:
2733.
131 Dhiman, R., Venkatasubramanian, S., Paidipally, P., Barnes, P. F., Tvinnereim, A. and Vankayalapati, R., Interleukin 22 inhibits intracellular
growth of Mycobacterium tuberculosis by enhancing calgranulin A expression. J. Infect. Dis. 2014. 209: 578587.
132 Passey, R. J., Xu, K., Hume, D. A. and Geczy, C. L., S100A8: emerging
functions and regulation. J. Leukoc. Biol. 1999. 66: 549556.
133 Bianchi, M. E., DAMPs, PAMPs and alarmins: all we need to know about
danger. J. Leukoc. Biol. 2007. 81: 15.

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Anca Dorhoi and Stefan H.E. Kaufmann

Eur. J. Immunol. 2015. 45: 21912202

134 Nandi, B. and Behar, S. M., Regulation of neutrophils by interferon-

150 Schreiber, H. A., Harding, J. S., Hunt, O., Altamirano, C. J., Hulseberg,

gamma limits lung inflammation during tuberculosis infection. J. Exp.

P. D., Stewart, D., Fabry, Z. et al., Inflammatory dendritic cells migrate

Med. 2011. 208: 22512262.

in and out of transplanted chronic mycobacterial granulomas in mice.

135 Corleis, B., Korbel, D., Wilson, R., Bylund, J., Chee, R. and Schaible, U.
E., Escape of Mycobacterium tuberculosis from oxidative killing by neutrophils. Cell Microbiol. 2012. 14: 11091121.
136 Francis, R. J., Butler, R. E. and Stewart, G. R., Mycobacterium tuberculosis
ESAT-6 is a leukocidin causing Ca2+ influx, necrosis and neutrophil
extracellular trap formation. Cell Death. Dis. 2014. 5: e1474.
137 Gabrilovich, D. I. and Nagaraj, S., Myeloid-derived suppressor cells as
regulators of the immune system. Nat. Rev. Immunol. 2009. 9: 162174.
138 du Plessis, N., Loebenberg, L., Kriel, M., von Groote-Bidlingmaier, F.,
Ribechini, E., Loxton, A. G., van Helden, P. D. et al., Increased frequency
of myeloid-derived suppressor cells during active tuberculosis and after
recent Mycobacterium tuberculosis infection suppresses T-cell function.
Am. J. Respir. Crit. Care Med. 2013. 188: 724732.
139 Yang, B., Wang, X., Jiang, J., Zhai, F. and Cheng, X., Identification of
CD244-expressing myeloid-derived suppressor cells in patients with
active tuberculosis. Immunol. Lett. 2014. 158: 6672.
140 Tsiganov, E. N., Verbina, E. M., Radaeva, T. V., Sosunov, V. V., Kosmiadi, G. A., Nikitina, I. Y. and Lyadova, I. V., Gr-1dimCD11b+ immature
myeloid-derived suppressor cells but not neutrophils are markers of
lethal tuberculosis infection in mice. J. Immunol. 2014. 192: 47184727.

J. Clin. Invest. 2011. 121: 39023913.

151 Egen, J. G., Rothfuchs, A. G., Feng, C. G., Winter, N., Sher, A. and Germain, R. N., Macrophage and T cell dynamics during the development
and disintegration of mycobacterial granulomas. Immunity 2008. 28:
271284.
152 Kubler, A., Luna, B., Larsson, C., Ammerman, N. C., Andrade, B. B.,
Orandle, M., Bock, K. W. et al., Mycobacterium tuberculosis dysregulates
MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial
proliferation. J. Pathol. 2015. 235: 431444.
153 Ong, C. W., Elkington, P. T. and Friedland, J. S., Tuberculosis, pulmonary
cavitation, and matrix metalloproteinases. Am. J. Respir. Crit. Care Med.
2014. 190: 918.
154 Ong, C. W., Elkington, P. T., Brilha, S., Ugarte-Gil, C., Tome-Esteban, M.
T., Tezera, L. B., Pabisiak, P. J. et al., Neutrophil-derived MMP-8 drives
AMPK-dependent matrix destruction in human pulmonary tuberculosis. PLoS Pathog. 2015. 11: e1004917.
155 Medlar, E. M., A study of the process of caseation in tuberculosis. Am. J.
Pathol. 1926. 2: 275290.
156 Orme, I. M., A new unifying theory of the pathogenesis of tuberculosis.
Tuberculosis 2014. 94: 814.

141 Knaul, J. K., Jorg, S., Oberbeck-Mueller, D., Heinemann, E., Scheuer-

157 Cliff, J. M., Kaufmann, S. H., McShane, H., van, H. P. and OGarra, A.,

mann, L., Brinkmann, V., Mollenkopf, H. J. et al., Lung-residing myeloid-

The human immune response to tuberculosis and its treatment: a view

derived suppressors display dual functionality in murine pulmonary

from the blood. Immunol. Rev. 2015. 264: 88102.

tuberculosis. Am. J. Respir. Crit. Care Med. 2014. 190: 10531066.

142 Obregon-Henao, A., Henao-Tamayo, M., Orme, I. M. and Ordway, D.
J., Gr1(int)CD11b+ myeloid-derived suppressor cells in Mycobacterium

158 Abakay, O., Abakay, A., Sen, H. S. and Tanrikulu, A. C., The relationship between inflammatory marker levels and pulmonary tuberculosis
severity. Inflammation 2015. 38: 691696.

tuberculosis infection. PLoS One 2013. 8: e80669.

143 Roca, F. J. and Ramakrishnan, L., TNF dually mediates resistance
and susceptibility to mycobacteria via mitochondrial reactive oxygen
species. Cell 2013. 153: 521534.
144 Lugo-Villarino, G., Hudrisier, D., Benard, A. and Neyrolles, O., Emerging

Abbreviations: AIM: absent in myeloma HDT: host-directed therapy

LTBI: latent TB infection MDSC: myeloid-derived suppressor cell miR:
microRNA MP: mononuclear phagocyte Mtb: Mycobacterium tubercu-

trends in the formation and function of tuberculosis granulomas. Front

losis NLR: NOD receptor NOD: nucleotide-binding oligomerization

Immunol. 2012. 3: 405.

domain NOS2: nitric oxide synthase 2 PMN: polymorphonuclear neu-

145 Marino, S., Cilfone, N. A., Mattila, J. T., Linderman, J. J., Flynn, J. L. and

trophil STING: stimulator of IFN genes TB: tuberculosis

Kirschner, D. E., Macrophage polarization drives granuloma outcome

during Mycobacterium tuberculosis infection. Infect. Immun. 2015. 83: 324
338.
146 Cilfone, N. A., Ford, C. B., Marino, S., Mattila, J. T., Gideon, H. P., Flynn,
J. L., Kirschner, D. E. et al., Computational modeling predicts IL-10 control of lesion sterilization by balancing early host immunity-mediated

Full correspondence: Prof. Stefan H. E. Kaufmann, Department of

Immunology, Max Planck Institute for Infection Biology, Chariteplatz

1, 10117, Berlin, Germany
Fax: +49/30-28460-501
e-mail: kaufmann@mpiib-berlin.mpg.de

antimicrobial responses with caseation during Mycobacterium tuberculosis infection. J. Immunol. 2015. 194: 664677.
147 Murray, P. J., Allen, J. E., Biswas, S. K., Fisher, E. A., Gilroy, D. W.,
Goerdt, S., Gordon, S. et al., Macrophage activation and polarization:
nomenclature and experimental guidelines. Immunity 2014. 41: 1420.
148 Duque-Correa, M. A., Kuhl, A. A., Rodriguez, P. C., Zedler, U.,
Schommer-Leitner, S., Rao, M., Weiner, J., III. et al., Macrophage

Additional correspondence: Dr. Anca Dorhoi, Department of

Immunology, Max Planck Institute for Infection Biology, Chariteplatz

1, 10117, Berlin, Germany.
e-mail: dorhoi@mpiib-berlin.mpg.de
See all the ECI 2015 Reviews at http://onlinelibrary.wiley.com/journal/
10.1002/(ISSN)1521-4141/homepage/eci2015.htm

arginase-1 controls bacterial growth and pathology in hypoxic tuberculosis granulomas. Proc. Natl. Acad. Sci. USA 2014. 111: E4024E4032.
149 Kim, M. J., Wainwright, H. C., Locketz, M., Bekker, L. G., Walther, G. B.,
Dittrich, C., Visser, A. et al., Caseation of human tuberculosis granulomas correlates with elevated host lipid metabolism. EMBO Mol. Med.
2010. 2: 258274.


C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Received: 2/4/2015
Revised: 23/6/2015
Accepted: 29/6/2015
Accepted article online: 3/7/2015

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