A DAMP is an endogenous molecule whose location, concentration, or chemical state signals that a cell is stressed, damaged, or dying. Recognition of DAMPs by pattern-recognition receptors is the first step that turns a cell-intrinsic stress into an inflammatory signal.
Where the signals come from
- Mitochondrial DNA released into the cytosol or extracellular space; it carries unmethylated CpG motifs that resemble bacterial DNA and is detected by cGAS-STING and TLR9.
- ATP released from damaged cells; high extracellular ATP activates the P2X7 receptor, a strong inflammasome trigger.
- Uric acid crystals and other aggregated metabolites that form when cells die and are phagocytosed.
- HMGB1, a nuclear protein that normally binds DNA; when it escapes the nucleus it acts as a potent extracellular cytokine-like signal.
- Exposed or misfolded proteins and oxidized lipids that appear when proteostasis or membrane integrity fails.
Recognition is not pathogen-specific
The receptors that read DAMPs are the same family used for pathogen detection. TLRs on the plasma membrane and endosome, cytosolic sensors such as cGAS-STING and the NOD-like receptors, and the RIG-I-like helicases all respond to structural features rather than to a specific organism. A cell that has lost mitochondrial integrity and leaks its own DNA therefore triggers the same downstream cascade as a cell infected by a bacterium. This is why sterile stress, such as ischemia or metabolic overload, produces genuine inflammation.
DAMP release is graded, not binary. A small amount of cytosolic DNA or a transient ATP pulse can be cleared without a full inflammatory response. The response becomes tissue-level only when DAMP production exceeds local clearance and the signal reaches immune cells.