damage-associated molecular pattern

DEFINITION: DAMPs (also called alarmins) are normally intracellular or extracellular matrix molecules that are hidden from the immune system in healthy tissue. When they are released or exposed by cell injury, necrosis, or stress, they act as "danger signals." Immune cells (macrophages, dendritic cells, neutrophils) detect them through pattern recognition receptors (PRRs). This triggers sterile inflammation, meaning inflammation without infection.

COMMON EXAMPLES: - HMGB1 (high-mobility group box 1): a nuclear DNA-binding protein. It signals through TLR4 and RAGE. - ATP (extracellular): signals through P2X7 and activates the NLRP3 inflammasome. - Uric acid / monosodium urate crystals: activate NLRP3. This is the mechanism of gout. - Heat shock proteins (HSP60, HSP70). - Mitochondrial DNA and N-formyl peptides: resemble bacterial products because of the endosymbiont origin of mitochondria. They signal through TLR9 and formyl peptide receptors. - Cell-free/nuclear DNA and RNA (cGAS-STING, TLR9, TLR3/7). - S100 proteins, IL-1α, IL-33. - Cholesterol crystals (atherosclerosis) and amyloid-β: activate NLRP3. - Extracellular matrix fragments (hyaluronan, biglycan).

RECEPTORS AND SIGNALING: - TLRs (TLR2/4/9) signal through MyD88 → NF-κB → transcription of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). - NLRP3 inflammasome (a cytosolic NOD-like receptor complex) activates caspase-1, which cleaves pro-IL-1β and pro-IL-18 into their active forms. It can also cause pyroptosis. Activation usually needs 2 signals: priming (NF-κB) and activation (e.g., K⁺ efflux from ATP or crystals). - RAGE (receptor for advanced glycation end products). - cGAS-STING detects cytosolic DNA → type I interferons.

DAMPs vs. PAMPs: - PAMPs are exogenous and microbial (LPS, flagellin, peptidoglycan, viral dsRNA, CpG DNA). DAMPs are endogenous and come from host cells. - Both are detected by PRRs and both trigger innate immune responses. - Necrosis releases DAMPs and is therefore pro-inflammatory. Apoptosis is generally immunologically silent because the cell contents stay contained.

CLINICAL SIGNIFICANCE: - Sterile inflammation in ischemia-reperfusion injury (MI, stroke), trauma, burns, and pancreatitis. - Gout and pseudogout: crystals activate NLRP3 → IL-1β. Treatments are colchicine and IL-1 blockade (anakinra, canakinumab). - Atherosclerosis: cholesterol crystals activate NLRP3 (CANTOS trial: canakinumab reduced CV events). - SIRS and sepsis-like states after major trauma: circulating DAMPs (mitochondrial DNA, HMGB1) can cause SIRS without infection. This contributes to multiple organ dysfunction syndrome. - Autoimmunity: nucleic acid DAMPs drive SLE (anti-dsDNA, type I IFN signature). - Cancer: immunogenic cell death releases DAMPs (calreticulin exposure, ATP, HMGB1), which promotes anti-tumor immunity. Chronic DAMP-driven inflammation can promote tumorigenesis. - Wound healing and tissue repair: DAMPs initiate acute inflammation and recruit neutrophils and macrophages. Excess or persistent signaling leads to fibrosis and chronic inflammation. - Transplant: ischemia-reperfusion DAMPs increase allograft immunogenicity. - Autoinflammatory diseases: gain-of-function NLRP3 mutations cause cryopyrin-associated periodic syndromes (CAPS), treated with IL-1 inhibitors.

HIGH-YIELD BOARD POINTS: 1. DAMPs = endogenous "danger" signals from injured or necrotic cells. PAMPs = microbial. 2. They act through the same PRRs (TLRs, NLRs) as PAMPs, which produces sterile inflammation. 3. Know the examples: HMGB1, ATP, uric acid, HSPs, mitochondrial DNA. 4. NLRP3 inflammasome → caspase-1 → IL-1β is the core pathway for crystal diseases (gout, atherosclerosis). 5. Necrosis releases DAMPs. Apoptosis typically does not.