The DAMP Theory: Concepts, Evidence, and Implications

The concept of damage-associated molecular patterns (DAMPs), derived from Polly Matzinger’s danger hypothesis in 1994, provides a theoretical framework for understanding immune system recognition and response to cellular distress in the absence of pathogens. DAMPs, released by stressed, dying, or dead cells, serve as host signals that initiate, sustain, and amplify inflammatory responses. These molecular patterns are essential in mediating the interaction between innate and adaptive immunity, elucidating the mechanisms behind immune cell recruitment and activation across a range of pathological states. This review systematically explores the evolution of the DAMP hypothesis, detailing the classification, biogenesis, and cellular origins of DAMPs, along with their associated signaling pathways and release mechanisms. Furthermore, it discusses the clinical implications of DAMPs and examines their therapeutic potential in various pathological conditions, underscoring their increasing significance in medical research and therapeutic innovation.