Inflammation Flashcards
Pro inflammatory cytokines
TNF, IL1 IL6, most Chemokines (CCL2 CCL3)
Anti inflammatory cytokines
IL4, IL10, IL13, TGF-B
Antiviral cytokines
IFN-a, IFN-b
B-cell activating cytokines
IL4, IL5, IL6, IL21
T-cell activating cytokines
IFN-y, IL2, IL4, IL12
Macrophages activating cytokines
IFN-y
Eosinophil and mast cell activating cytokines
IL3, IL4, IL5, IL13
Order of leukocyte infiltration in response to inflammation
Neutrophil spike (pro-inflammatory cytokines released), Macrophage spike (anti-inflammatory cytokines relased), lymphocytes come in (adaptive T cells/B cells too), and then resolution
Plasma vs serum
Plasma has clotting factors as well, Serum lacks clotting factors. None have RBC or WBC
Lymphocyte characteristics
Large circular nucleus, little else
Monocyte characteristics
dumb-bell-shaped nucleus, little else
Macrophages
Derived from monocytes and larger cells
Neutrophils
Large granules and polarized
Eosinophils
Crystallized granules staining with eosin in H&E stain
Basophils
Dense granules staining cytoplasmic blue in H&E stain
Symptoms of inflammation
redness, swelling, heat, pain, LOF
Steps of WBCs entering site of inflammation
1) tethering/rolling. Selectins bind to epithelial cells. 2) integrin activation. Endothelial cells have vesicles filled with chemokines/cytokines and release them, which activates integrin on WBCs. Integrins slow roll drastically. 3) Stable adhesion, integrins anchor WBC and they search for ways to pass endothelial to enter basement membrane. 4) Diapedesis. Can either be paracellular (between) or transcellular (through)
IL1 interacts with receptor, what happens?
IL1R is a type1 cytokine receptor that activates NF-kB and MAPK
IL1 antagonist
IL1ra. drug analog: Anakinra
IL6, IL2, IL3 interacts with receptor, what happens?
Type 1 Tyrosine Kinase receptor and activates JAK-STAT signaling. 1) receptor dimerization. 2) Dimerization activates JAK phosphorylation of cytokine receptor. 3) Recruits STATs phosphrylated by JAK. 4) Phosphorylated STATs dimerize and translocate to nucleus to activate genes
JAK-STAT inhibitors
Ruxolitinib, Tofacitinib. Both treat rheumatoid arthritis and psoriasis
TNFa interacts with receptor, what happens?
TNFa interacts with TNFa-R induces both gene transcription AND apoptosis, depending on downstream complexes because the TNFa-R has a “death domain” that allows for TRADD to bind (leads to apoptosis) or TRAF (gene transcription)
Clinical actions of TNFa
low levels: local inflammation, leukocyte activation, endothelial activation
moderate levels: systemic inflammation - fever, liver inflammation, leukocyte proliferation
high levels: septic shock
Negative regulators of TNFa
AU-Rich elements in the 3’UTR of oncogenes (including TNFa) allows destruction of TNFa. KO of ARE have chronic inflammation
Complement system activation
inactive proteins are cleaved by proteases to generate active components to promote inflammation and opsonize pathogens to promote clearance/ C1/C3/C5 become C3a, 4a, C5a
C3a, C4a, C5a roles
Complement system proteins that have anaphylatoxin activity to degranularize mast cells and increase vascular permeability and smooth muscle contraction and increase leukocyte recruitment.
Exogenous chemoattractants
f-MLP (bacterial peptides), Lipids from damaged membranes (LPS)
Endogenous chemoattractants
Complement proteins (C3a,4a,5a), Platelet activating factor, chemokines, leukotrienes, LPA (lysophosphophatic acid)
GPCR desensitization
Can happen when chronic agonist binding leads to destruction of receptors. This is known as homologous desensitization (same receptor binding). The same can happen with heterologous desensitization (different GPCR inactivates upstream receptor)
Relationship between cytokines and cell movement
GPCRs help to move pseudopods. Increase cytokines binding = more protein aggregation towards site of injury. PI3y is absolutely necessary for this movement.
Role of PIP3 in polarization
PIP3 accumulates on leading edge (from GPCR and PI3Ky activity) and amplified via positive feedback loop, PIP3 and Rho GTPases (Rac). PIP3/Rac(Cdc42) then helps recruit actin polymerization. PIP3 phosphatase and PTEN localizes sides and back to decrease PIP3. Rho activation is at the trailing end and mediates actin/myosin contraction and resolution of adhesion events
Role of CCL2
increased microvascular permeability, edema and lymph flow
Cells of the adaptive immune system
T cells, B cell (CD4+, CD8+), NK T cells
Cells of the Innate Immunity
Dendritic cell, Mast cell, Macrophage, Basiphil, Eosinophil, ?neutrophil, Natural Killer Cell, Complement protein, NK T cell
Innate effectors
NFkB, IFN, IL-1
What types of receptors are in the pattern recognition pathways?
Toll-Like receptors (TLR), NLR (nucleotide-like receptors), RLR (Rig-like receptors)- short 20-30bases receptor, cytosolic DNA receptor
What pathway does TLRs activate?
NFkB
What pathway does NLRs activate?
Caspase
What is a major source of DAMPs
mitochondrial factors, HMGB, HSP, Purine
Types of phagocytosis
Zipper (building around), sinking (invaginating), coiling (going around one sinded)
What are the four major chemotactic factors and and how far do they act?
FAR Chemokines, complement cascade “by-products,” eicosanoids, Microbial products CLOSE
Zipper phagocytosis MOA
FcyRI -> activates P13K -> activates Rac / PIP2/3 for actin growth. VERY FAST
Sinking Phagocytosis MOA
C3R -> RhoA -> F-actin disruption. Slower. Might be beneficial for proper lysosomal fusion, recruitment of other vesicles, preventing the organism from getting into the cell
Describe respiratory burst
Using NADPH oxidase to transfer electrons into the phagosome to produce superoxides, which are toxic
What are NETs released by polymorphonuclear neutrophils and what do they do?
NETs, as their acronym suggests, traps bacteria and occur in 1/3 of neutrophils after apoptosis
Stages of resolution of inflammation
STOP new neutriphil infiltration (eliminating DAMPS/PAMPs and putting out anti-inflammatory mediatirs. SINK, reducing inflammatory receptors and inducing antagonists. KILL induce apoptosis in leukocytes and eliminate debree (Efferocytosis). SKEW reprogram macrophages
What is cPLA2
an inflammatory protein in the granules of neutrophils, mast cells, macrophages, and platelets and they are released in response to pro inflammatory cytokines. It is the central regulator of arachadonic acid from phospholipids
what is COX?
COX is an enzyme that is produced in response to inflammation that converts arachidonic acid to prostaglandin. Prostaglandins can be both resolving and inflammatory inducing
What are foam cells? What are they derived from?
Foam cells are differentiated from macrophages/monocytes and consume lipids/debris
