Inflammation and Repair (part 1)

inflammation

coordinated response of vascularized tissue to infection or injury

core goals of inflammation

contain threat, remove damaged material, initiate repair

triggers of inflammation

PAMPs (pathogen-associated), DAMPs (damage-associated), foreign material, immune rxns, chemical injury

neutrophils

rapid recruitment, phagocytosis, granule release, microbicidal activity

monocytes/macrophages

clear debris and integrate defense, resolution, and repair

eosinophils, basophils, mast cells

specialized tissue, allergy, parasite, and neuroimmune responses

lymphocytes and dendritic cells

link innate sensing to adaptive immunity

stromal and vascular cells

endothelium, epithelium, and fibroblasts actively shape inflammation

neutrophils (extended)

early responders: exit blood rapidly and attack microbes by phagocytosis, granules, ROS, and extracellular traps, mitochondrial activity can support degranulation and contribute to endothelial dysfunction in systemic infection

eosinophils

specialized granulocytes: type 1 immunity, allergy, parasite defense, tissue regulation

display temporal and tissue specific states rather than one uniform phenotype

basophils

circulating granulocytes: release histamine and type 2 cytokines after immunoglobulin E (IgE) dependent or innate activation

neuroimmune role: basophil derived signals can participate in bidirectional communication w/ sensory and autonomic pathways

mast cells

tissue sentinels: rapidly release vasoactive and inflammatory mediators from preformed granules, mast cell circuits can amplify or restrain local symptoms and tissue responses

monocytes

recruited, can acquire tissue resident programs, phagocytosis, cytokine production, antigen presentation, efferocytosis, tissue repair

monocyte -> macrophage differentiation is shaped by tissue entry, local cues, and residence time

macrophages

resident, may be embryonically seeded, phagocytosis, cytokine production, antigen presentation, efferocytosis, tissue repair

recognition and attachment

pattern-recognition and opsonin receptors bind target

engulfment

actin remodeling encloses particle in a phagosome

killing and degradation

phagolysosomes deploy ROS, NO, proteases, hydrolases

efferocytosis

removes apoptotic cells and helps switch the tissue toward repair

steps of phagocytosis and intracellular destruction

recognition -> engulfment -> phagosome -> phagolysosome -> killing and degradation (ROS, NO, lysosomal enzymes)

ROS (microbicidal burst)

activated phagpcytes generate superoxide, hydrogen peroxide, and downstream oxidants

ROS (signaling)

controlled ROS modify redox-sensitive pathways and antimicrobial responses

ROS (collateral injury)

xs or poorly contained ROS damage lipids, proteins, DNA, vascular barriers

ROS (antioxidant defenses)

enzymes, molecules, cellular signaling

enzymes (antioxidant defense)

superoxide dismutase, catalase, glutathione peroxidase

molecules (antioxidant defense)

glutathione, vit C, vit E

cellular signaling (antioxidant defense)

Nrf2 pathway turns on genes that increase protective defenses

mediators of inflammation (sources)

cell-derived mediators are released/synthesized; plasma-derived systems are activated as cascades

mediators of inflammation (action)

bind specific receptors and act locally, transiently, and in regulated combinations

mediators of inflammation (outcome)

amplify defense, limit injury, initiate active resolution thru specialized pro-resolving mediators (SPMs)

mediators of inflammation (steps)

microbes or necrotic cell -> inflammation mediators -> ligand-receptor binding -> signaling cascades -> inflammatory outcome and/or initiate resolution

cell-derived mediator (histamine; serotonin)

rapid vasodilation and permeability changes

cell-derived mediator (eicosanoids; pro-resolving lipids)

vascular tone, leukocyte behavior, pain, fever, resolution

cell-derived mediator (cytokines; chemokoines)

endothelial activation, recruitment, systemic responses

plasma derived mediators (complement; linins; coagulation)

opsonization, leukocyte recruitment, permeability, proteolysis

efferocytosis signals; SPMs

stop recruitment, clear cells, restore homeostasis

histamine

stored in mast-cell and basophil granules, released rapidly after immune/physical stimulation (when allergen is encountered), produces arteriolar dilation and increased venular permeability

serotonin

platelets are an important peripheral source and can coordinate vascular, immune, and sensory signaling

eicosanoids and pro-resolving mediators

membrane FA are enzymatically converted into short-lived lipid mediators, prostaglandins, leukotrienes

prostaglandins

modulate vasodilation, pain, fever, platelet function

leukotrienes

promote vascular pemeability, bronchoconstriction, leukocyte recruitment

specialized pro-resolving mediators

actively limit recruitment and support efferocytosis and tissue recovery

cytokines (main job)

coordinate immune cell activation and communication, "what should the immune system do?"

cytokines (clinical effect)

inflammation, fever, immune activation, tissue effects

cytokines (examples)

IL-1, IL-6, TNF-a

cytokines (clinical relevance)

helps explain systemic and local inflammatory findings

chemokines (main job)

direct immune cells where to go

chemokines (clinical effect)

recruitment of neuts, monocytes, lymphoctes, etc.

chemokines (examples)

CXCL8/IL-8, CCL2

chemokines (clinical relevance)

helps explain cellular infiltration at site of inflammation

CCL2

can organize antibacterial immune recruitment in skin

complement system

circulating and intracellular complement components form interconnected proteolytic and signaling networks

C3b (complement)

opsonizes targets and promotes phagocytosis

C3a and C5a (complement)

increase inflammation, C5a is a potent leukocyte chemoattractant and activator

C5b-9 (complement)

forms MAC on susceptible targets

PRRs (pattern-recognition receptors)

sensors that recognize microbial or tissue-danger signals

PAMPs (pathogen-associated molecular patterns)

microbial danger signals

DAMPs (damage-associated molecular patterns)

signals of sterile tissue injury

NF-kB (nuclear factor kappa B)

txn factor that turns on inflammatory genes

NLRP3

inflammasome sensor involved in detecting cellular stress/damage

IL-1B (interleukin 1 B)

potent pro-inflammatory cytokine

pattern recog. leading to clinical inflammation (steps)

detect danger (PAMP and DAMP) -> signal 1: priming (PRR activation) -> NF-kB activation -> signal 2: activation (NLRP3 inflammasome assembly causes Caspase-1 activation) -> pro-IL-1B to IL-1B -> clinical effect (inflammation)

1) detect danger

innate immune cells use PRRs to sense PAMPs and DAMPs

2) signal 1: priming

PRR activation causes NF-kB activation which increases txn of NLRP3 and pro-IL-1B

3) signal 2: activation

cellular stress/danger triggers NLRP3 inflammasome assembly which causes Caspase-1 activation, and therefore turns pro-IL-1B to IL-1B

4) clinical effect

IL-1B drives inflammation through: fever, leukocyte recruitment, endothelial activation, tissue inflammation

acute inflammation (4 Rs)

recognition, recruitment, removal, regulation and resolution

recognition

resident cells detect microbes, damage, or immune triggers

recruitment

vascular changes deliver plasma proteins and leukocytes

removal

phagocytes eliminate microbes and dead tissue

regulation and resolution

anti-inflammatory and pro-resolving signals terminate recruitment and initiate repair

major components of acute inflammation

vascular response, leukocyte recruitment, termination/repair

vascular response

vasodilation and increased permeability deliver fluid and plasma proteins

leukocyte recruitment

rolling, adhesion, transmigration, chemotaxis, and activation move cells to the site

termination/repair

clearance, efferocytosis, and pro-resolving signals restore homeostasis or lead to fibrosis

vascular changes

vasodilation, permeability, stasis

vasodilation

histamine and NO increase local blood flow -> rednesss and heat

permeability

endothelial gaps or barrier injury allow proetin-rich fluid to enter tissue -> edema

stasis

plasma loss concentrates erythrocytes and slows flow, favoring leukocyte margination

lymphatic vessels

remove xs fluid, soluble antigen, debris, and migrating immune cells

draining nodes

organize antigen presentation and adaptive immunne activation

collateral damage

ROS, proteases, complement, cytotoxic lymphocytes can injure nearby host tissue

immune0mediated disease

when recognition is misdirected or regulation fails -> inflammatory response becomes principal cause of organ injury

inflammation-mediated tissue injury determinants

tissue damage reflects trigger persistence, response intensity, location, and success of resolution and repair

rolling (leukocyte extravasation)

endothelial selectins form transient bonds w/ leukocyte ligands

activation (leukocyte extravasation)

chemokines trigger inside-out signaling that increases integrin affinity

firm adhesion (leukocyte extravasation)

activated integrins bind endothelial immunoglobulin-family ligands

transmigration and chemotaxis (leukocyte extravasation)

leukocytes cross venules and follow tissue gradients to inflammatory focus

leukocyte extravasation steps

rolling -> chemokine activation -> firm adhesion -> transmigration -> chemotaxis

outcomes of acute inflammation

complete resolution, abscess formation, chronic inflammation, fibrosis

complete resolution

removal of inciting agent, clearance of apoptotic cells and iinflammatory exudate, and restoration of tissue homeostasis

abscess formation

pyogenic infection can produce localized collection of neuts, liquefactive necrosis, and cellular debris

chronic inflammation

persistent infection, ongoing injury, or failed resolution sustains inflammatory cell activation and delays tissue repair

fibrosis

extensive tissue destruction or impaired regeneration shifts repair toward fibroblast activation, ECM deposition, and scar formation