Resolution and Chronic Inflammation

Question 1

What are 7 key things that need to happen to reverse inflammation?

Answer 1

1. elimination of pro-inflammatory stimuli
2. inflammatory mediator catabolism
3. endothelial cell junction close to limit extravascular edema fluid accumulation
4. halt immune cell recruitment
5. leukocyte clearance via emigration through lymphatics or apoptosis
6. phagocytosis of bacteria, debris, apoptotic cells (efferocytosis) by MFs
7. regeneration or repair

Question 2

lipid mediators of resolution

what are three specialized proresolving mediators, how are they synthesized?

Answer 2

1. lipopoxins: AA –> 5/15 LOX –> lipopoxins
2. resolvins and protectins: EPA –> E series resolvin; DHA –> protectins and D-series resolvins
3. maresins: DHA –> maresins

Question 3

Describe the consequences of Annexin A1 (Ac2-26), Lipoxin A4, resolvin D1, resolvin E. What do these signal through?

Answer 3

consequences of signaling

• inhibits nuclear translocation of 5-LOX
• reduced secretion of inflammatory cytokines
• less oxidative stress of the mito.
• more effercytosis
• more collagen production
• redeuced pro-inflam proteases (e.g. MMPs)

Annexin A1 (Ac2-26), Lipopoxin A4, resolvin D1 signal via ALX/FPR2

resolvin E1 signals through ChemR23R

Question 4

What are some specialized pro-resolving mediator actions of LXA4?

Answer 4

• reduce PMN-mediated tissue damage
• reduce pain (activate cannabinoid R)
• reduce angiogenesis and cell proliferation
• reduce PMN adhesion
• increase phagocytosis and IL-10 production

Question 5

How do specialized pro-resolving mediators affect neutrophils and monocytes/MFs

Answer 5

neutrophils:

• stop PMN transmigration and chemotaxis
• block prostaglandins and leukotrienes
• reduce cytokine release and TNFa release actions

monocytes/MFs:

• non-phlogisitic monocyte recruitment
• uptake and removal of apoptotic PMN (efferyctosis) and microbial particles by macrophages
• Stem cell differentiation into reparing MF or endothelial cells

Question 6

Describe 4 cellular mediators of resolution

Answer 6

1. inhibition of neutrophil recruitment and apoptosis induction
2. inhibition of monocyte survival and polarization to anti-inflammaotry phenotype
3. supression of T cell-mediated inflammation
4. direct promotion of tissue repair/regeneration

Question 7

What is the difference between M1 MFs and M2 MFs?

Answer 7

• M1: pro-inflammatory, bacteriocidal, phagocytic
• M2: anti-inflammatory, matrix producing, pro-angiogenesis, pro-wound healing

Question 8

What is efferocytosis?

Answer 8

the process of clearnce of apoptosis by phagocytosis –> non-inflammatory

Question 9

Give examples of find-me signals

Answer 9

S1P, ATP/UTP, LPC

Question 10

Give examples of eat-me signals, what do these cause?

Answer 10

PS, calcreticulin –> actin reorganization/phagocytosis

Question 11

Give examples of do-not-eat-me signals, what do these cause?

Answer 11

CD47, MHC-I –> inhibit phagocytosis

Question 12

What responses to effercytosing macrophages create?

Answer 12

1. Treg induction via IL-10, TGFb –> immunosuppressive mechanisms
2. lipid mediators –> resolution
3. IGF-1 –> repair and angiogenesis
4. FGF –> fibrosis

Question 13

What are the differences between repair and regeneration?

Answer 13

repair:

• after major damage
• growth and adaptation restores tissue architecture and function
• scar formation
• may result in structural abnormalities and impaired function

regeneration:

• after minor damage/cell has high regenerative capacity (e.g. liver)
• new growth completely restores damage tissues to normal state
• no scar formation
• no permanent damage

Question 14

Give examples of things that cause regeneration, repairm and fibrosis

Answer 14

• regeneration: skeletal muscle after exercise, liver regenation, superficial skin wound
• repair: myocardial infarction, deep excisional skin wound
• fibrosis (persisitant tissue damage): cirrhosis

Question 15

What causes chronic inflammation?

Answer 15

persistance of inflammatory stimuli, failure to resolve inflammation, or autoimmunity

Question 16

Give examples of central tolerance and peripheral tolerance. What happens if these fail?

Answer 16

Central:

• negative selection in thymus
• B cell development in BM
• regulatory cell development

peripheral:

• activation without co-stim/inflammation signals (signals 2 and 3) –> deletion, anergy
• regulatory cells –> suppression
• ignorance: immunoprivileged organs (sequesteration of auto-Ag)

failure of central and peripheral tolerance –> escape of autoreactive adaptive immune cells

Question 17

Name and describe 7 ways to break tolerance

Answer 17

1. molecular mimicry - foreign Ag similar to self Ag –> corss reaction
2. duel TCR activation - T cell with 2 TCRs and one of those is autoreactive and gets activated
3. super-Ag activation - Ag-independent activation, super-Ag cross links TCR wihtout Ag presentation –> cytokine storm
4. bystander activation - inflammation against foreign Ags activates autoreactive memory cells via pro-inflam cytokines
5. epitope signaling - activated pAPC present foreign and self Ag + has costim molecules from PRR activation –> self-peptide gets loaded onto MHC-II + (costim + cytokines from PRR to actual foreign Ag) –> activated autoreactive Th cell
6. loss of immune privilege - previously sequestered self-Ags find its way to pAPCs –> activate autoreactive Th cell
7. cyrptic Ag - inflammation –> novel processing of Ags –> self-Ag degraded differently and presented to autoreactive Th cell

Question 18

What is dysbiosis?

Answer 18

“uncomfortable gut”

leaky gut –> commensal bacteria migrate to blood –> pamps

Question 19

How can chronic inflammation cause cancer?

Answer 19

1. constant activation of IS –> immune exhaustion and senescence –> reduced surveillance of cancer cells
2. ROS and RNS cause DNA damage
3. cytokines and growth factors that promote proliferation
4. prostaglandins
5. favourable tumor environment –> promotes metastasis