DAMPs, PAMPs, and Alarmins: From Mechanism to Therapy

Immune surveillance hinges on the precise regulation of molecular sentinels to maintain the equilibrium between physiological homeostasis and pathological distress. Central to this process is the sensing of exogenous pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs), or alarmins. Traditionally, PAMPs and DAMPs were categorized as triggers for local protective host defense or maladaptive inflammatory cascades. Recent insights have unveiled an expanded functional framework for these signals, where they orchestrate systemic processes, notably including trained immunity and interorgan communication. Despite these advances, existing reviews lack a unified synthesis that integrates classical functions with novel concepts. This review narratively synthesizes molecular sources, sensing mechanisms, and regulatory networks that control PAMP and DAMP signaling, followed by their diverse functions in modulating both immune and nonimmune landscapes. Critically, we dissect the intricate interplay between PAMPs and DAMPs, a dimension overlooked in prior reviews. We further discuss their contributions to various human diseases, highlighting their context-dependent functions in different conditions. Finally, we evaluate their emerging role in biomarkers and therapies. By integrating classical concepts with recent discoveries, this review provides a comprehensive framework for understanding how danger signals shape human health and disease, offering insights for biomarker development and immunomodulatory therapies.