DAMP

**Definition:** DAMPs (also called alarmins) are host-derived intracellular molecules that are normally hidden inside cells and act as "danger signals" when released into the extracellular space after cell injury, necrosis, or stress. They are recognized by the same pattern recognition receptors (PRRs) that detect microbial PAMPs, which is why tissue injury can cause inflammation in the absence of infection (sterile inflammation).

**Common DAMPs and what they signal:** - HMGB1 (nuclear protein): binds TLR2/4 and RAGE - ATP (extracellular): activates P2X7 receptor, which activates the NLRP3 inflammasome - Uric acid / monosodium urate crystals: activate NLRP3 (gout, pseudogout analogs, tumor lysis) - Mitochondrial DNA and N-formyl peptides: bind TLR9 and formyl peptide receptors (neutrophil recruitment); these are bacterial-like because of the endosymbiotic origin of mitochondria - S100 proteins: bind RAGE and TLR4 - Heat shock proteins (HSP60/70) - Cholesterol crystals: activate NLRP3 (atherosclerosis) - Histones and extracellular DNA/RNA - Amyloid-β: NLRP3 (Alzheimer disease)

**Receptors:** TLRs (TLR2, 4, 9), NOD-like receptors (NLRP3 inflammasome), RAGE, C-type lectin receptors (e.g., Clec9A binds F-actin from dead cells), and cytosolic DNA sensors (cGAS-STING).

**Pathophysiology:** PRR engagement activates NF-κB and inflammasome pathways. This leads to transcription of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), caspase-1 cleavage of pro-IL-1β/IL-18 to active forms, neutrophil and macrophage recruitment, and dendritic cell maturation. This is normally protective and promotes tissue repair, but excessive or chronic DAMP signaling is harmful.

**Clinical significance:** - Sterile inflammation after trauma, burns, ischemia-reperfusion injury (MI, stroke), and pancreatitis - Trauma and sepsis-like SIRS: massive DAMP release can cause a systemic inflammatory response, multi-organ dysfunction, and ARDS without infection - Crystal arthropathies: urate crystals in gout, with IL-1 as the key mediator (treated with colchicine, or anakinra/canakinumab in refractory cases) - Atherosclerosis: cholesterol crystals trigger NLRP3 - Autoimmunity: DNA/nucleoprotein complexes in SLE drive TLR7/9 and type I interferon signaling - Cancer: immunogenic cell death releases calreticulin ("eat me" signal), ATP, and HMGB1 to promote antitumor immunity; chronic DAMP-driven inflammation can promote tumorigenesis - Transplant: ischemia-reperfusion injury raises DAMPs, which increases graft immunogenicity

**High-yield contrast:** - PAMPs: conserved microbial structures (LPS, flagellin, peptidoglycan, CpG DNA, dsRNA, β-glucan) recognized by PRRs - DAMPs: endogenous molecules released from damaged host cells and recognized by PRRs - Both pathways converge on NF-κB, which drives acute inflammation

**Exam pearls:** Necrosis releases DAMPs and causes inflammation, whereas apoptosis is generally non-inflammatory because cell contents stay membrane-bound and are cleared by phagocytes. NLRP3 inflammasome activation by DAMPs such as urate crystals, cholesterol, and ATP is a recurring theme, and IL-1 blockade is a therapeutic target.