Which of the health problems below do not

involve inflammation?
A. You get a small cut on your foot when you stepped on
your child’s LEGO block.
B. You catch a cold from your classmate who comes to
tutorial sick because your professors will not tolerate
absences.
C. You get a huge pimple on your forehead. On your wedding
day…
D. You have spent your life eating too much ice cream and
are now a little soft around the middle.
E. You got a sweet new tattoo.
 Inflammation
Too little Too much

• You die from infection • You die from “cytokine storm”

• You die from a blood clot
• You die from cancer,
Alzheimer’s, diabetes, etc.

Mike Mandell, Ph.D.

mmandell@salud.unm.edu
Molecular Genetics and Microbiology
Historical Highlights

Nature Reviews Immunology 2:787-795 (October 2002)

(Calor) (Rubor) (Tumor) (Dalor) (Funtio Lasea)

Overview of inflammation

Local inflammation Systemic inflammation

• Vascular permeability and • Fever
vasodilation increases perfusion • Proliferation of immune cells
of tissue and decreases blood
pressure • Synthesis and release of
immune mediators
• Recruitment of immune cells
• Release of cytokines and
effector molecules
• Blood clotting (thrombosis)
• Tissue damage
Which of the following inaccurately describes the
effects of acute inflammation on the vasculature?
A) Vascular constriction restricts blood flow to interfere with
pathogen dissemination through a hematogenous route.
B) Vascular dilation slows blood velocity, allowing leukocytes to more
easily interact with endothelial cells.
C) Vascular permeability increases to allow soluble antimicrobial
factors access to infected tissue.
D) Systemic inflammation can lead to dangerous hypotension
because of widespread diminution of vascular integrity.
E) I have never heard any of this stuff before.
Which of the following best describes how
vasodilation and vascular permeability increase
following injury/infection?
A) Release of soluble complement anaphylatoxins (C3b, C4b, and
C5b) trigger histamine release by mast cells, and histamine
recognition by endothelial cells increases vascular permeability.
B) Naïve T cells in lymph nodes are activated by antigen presenting
cells, migrate to the periphery, and release IL-4 and IL-10, which
activate JAK/STAT signaling in endothelial cells.
C) Tissue resident phagocytes detect PAMPs and/or DAMPs and
release inflammatory cytokines (e.g. TNF alpha, IL-1 beta) which
activate endothelial cells.
D) I have never heard any of this stuff before.
 Terms:
Acute Inflammation • Exudate-extravascular fluid with protein/cells
• Edema- excessive fluid in interstitial tissue

local tissue damage

vasodilation

erythema (rubor)

temperature (calor)

capillary permeability, fluid accumulation

(edema, pain)

continued chemotaxis
Inflammatory cytokines:
➢ Mobilize neutrophils
➢ Activate the vascular
endothelium
➢ Chemotactic
 Vasodilation and Vascular Permeability

(Some) underlying mediators of vasodilation/vascular permeability:

• Cytokines e.g. IL-1 from macrophages/DC (and other cell types)
• NO from endothelium relaxes vascular muscles
• Histamine from basophils/Mast cells activates endothelial cells, causes gaps
• Prostaglandins + leukotrienes (AA) from eosinophils (and other cell types)
• Cleaved complement components (e.g. C5a)
 IL-1beta:
Inflammasome and IL-1 1) Activates endothelium
2) Activates leukocytes
3) Induces chemokine
PAMP release
4) Stimulates production of
PRR soluble factors by liver
Alarmin 5) Increases prostaglandin
synthesis → fever
6) Many other things…
DAMP
receptor
Nucleus
Damage
to cell

IL-1
Pro-IL-1 Secretion
Assembled Pyroptosis
inflammasome
 Review: Toll-like receptors (TLRs), PRRs, and
PAMPs

PAMP = pathogen molecular pattern

PRR = pattern recognition receptor

Activation of PRRs by their ligands (e.g. TLR4

by LPS) triggers phagocyte activation (antigen
presentation ↑, co-stimulatory molecules ↑,
oxidative burst ↑, inflammatory protein
expression ↑)

PRR activation of antigen-presenting cells is

important for activation of T helper cells
Cytokine signaling: IL-1 as an example

Terms:

Autocrine

Paracrine
Vasodilators
Macrophage Nitric Oxide

Basophil Mast cell

Histamine

Eosinophil Endothelium

Prostaglandins

Platelet Serotonin
Vascular Permeability

Histamine

Leukotrienes

Bradykinin

Complement components
________ are sugar-binding proteins on the
surface of endothelial cells that have low affinity
binding to leukocyte surface molecules, causing
leukocytes to slow down and “roll” along blood
vessel walls.
A) Integrins
B) Chemokine receptors
C) L-selectin
D) E-selectin
E) I have never heard any of this stuff before.
Leukocyte Migration

IL-8
Neutrophils homing to site of immune insult
This pathway, which is present in activated
phagocytes, generates OCl- (hypochlorite; aka
bleach)?

A) Phagocyte oxidase
B) Chloroxidation
C) Oxidative respiration
D) Respiratory/oxidative burst
E) I have never heard any of this stuff before.
 Macrophage/neutrophil activation: cells in
beast mode
• Cytokines, chemokines, PAMPs and DAMPs can activate
leukocytes
• Enhanced endothelial binding/transmigration
• Enhanced phagocytic activity
• Up-regulation of phagocyte oxidase/iNOS: ROS and RNI
pumped into phagosome
• NETosis of neutrophils
• Release of pro-inflammatory cytokines and DAMPs
M1 or classically activated macs
Activating
stimuli
 A 17 year old, previously healthy
female sustains a minor puncture
wound on her right hand. Which
of the following does not help to
restrict bacteria to the initial site
of infection?

A) Neutrophil nets trap bacteria in fibers of extruded chromatin.

B) Dendritic cells phagocytose bacteria at the wound site and traffic
them to lymph nodes.
C) Fibrin polymers, formed during blood clotting, restrict the
bacterium’s blood stream access.
D) I have never heard any of this stuff before.
Blood clotting is part of inflammation

• Purpose: block access to infectious agents and/or contain infectious agents

• Many connections between innate immunity & clotting
• Inappropriate blood clotting caused by inflammation can be very dangerous
• Molecular mechanisms of clot formation covered in later block
Systemic Inflammation
Histamine
--pre-formed and stored in
granules for quick release

--mast cells are primary

source

--Primary early mediatory

of increased vascular
permeability

--antihistamines block H1
receptor

https://image.shutterstock.com/z/stock-vector-mechanism-of-action-of-
histamine-and-target-organs-immune-responses-365696942.jpg
Arachidonic acid
PGE2 HYPOTHALAMUS
metabolites control
inflammation
FEVER

ASTHMA!!

ALSO ANTI-INFLAMMATORY
Acute Phase Proteins

Binds free hemoglobin,

sequesters Fe
Blood
clotting

Complement
Aid in
immune cell
Binds phosphocholine,
homing
activates complement
 Clinical tests for inflammation
• C reactive protein (CRP): liver-produced opsonin,
production increased by IL-6
• Erythrocyte sedimentation rate (ESR): Fibrinogen
aggregates RBCs, settle out of suspension faster
• D-dimer: degradation product of fibrin, indicates clot
formation
• Complement C3: levels reduced due to continual
cleavage
• Complete blood count with differential (CBC with
Diff): could indicate elevated proliferation of immune
cell types in response to infection
• Temperature:
Clinical Examples of Leukocyte-
mediated Chronic Inflammation
Disorder Cell/Mediator Initiator Symptom
Arthritis lymphocytes, autoimmunity Joint
macrophages inflammation/pain
Asthma eosinophils, IgE Allergen, Irritant Airway
Inflammation
Atherosclerosis macrophages Oxidized LDL Clogged arteries
uptake by
macrophages
Chronic Transplant lymphocytes, Lymphocyte Fibrosis of the
rejection cytokines response to vessels of the
transplanted tissue transplanted tissue
Pulmonary fibrosis macrophages, Inhalation of scarring in the lung
fibroblasts pollutants,
cigarette smoke
Cancers (e.g. Macrophages, T DNA damage by
colon, lung, gastric, cells ROS, NO. Pro-
skin) survival anti-
apoptosis signals
How does the body put the brakes on
inflammation?

• Pathogens (hopefully) eliminated

• Cytokines/acute phase proteins have short half-lives
• Activated cellular signaling proteins deactivated/degraded
• Effectors can also be immunosuppressive (e.g. NO)
• Neutrophils die and are cleared by macrophages
• Macrophages release growth factors (TGF-β) and metabolites
(polyamines), recruit fibroblasts, release IL-10, express suppressive
cell surface ligands
• Suppressive cells (Tregs) release immuno-modulatory cytokines (IL-
10)
Resolution of Inflammation
 Inflammation does not always resolve!

Objective 4
 Causes of Acute Inflammation
1. Infection
2. Physical Injury –cuts, burns
3. Foreign Bodies – splinters, sutures
4. Immune Reaction – allergy, hypersensitivity
5. Toxicity – exogenous or endogenous
Immune and non-immune cells release mediators
of inflammation
Mediator Produced by: Function(s)
Cytokines (e.g. Interferon γ; (macrophages, T Recruit immune cells, guide
IL-1β) lymphocytes, others) immune cell activation,
enhance endothelial
adhesion, lots more (fever)
Chemokines (e.g. MCP-1) Immune and “non-immune” Chemo-attractant for
cells immune cells
Histamine Mast cells Vasodilation, endothelial
activation, many systemic
effects
Arachidonic acid metabolites Mast cells and others Various local and systemic
(e.g. prostaglandins, effects (pain, fever)
leukotrienes)
ROS and RNI Macrophages and Kill microbes; cause tissue
neutrophils damage but also help with
immune suppression