Mechanistic insights into PAMP and DAMP driven activation of NETosis in autoimmune disorders

Neutrophil extracellular trap (NET) formation, commonly known as NETosis, is an innate immune response where neutrophils release chromatin structures embedded with antimicrobial proteins to combat pathogens. While NETosis plays a critical role in host defense, dysregulated NETosis is increasingly implicated in the pathogenesis of autoimmune disorders, including systemic lupus erythematosus, rheumatoid arthritis, and antiphospholipid syndrome. Central to this process are pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), which act as potent triggers for NETosis. PAMPs, derived from microbial components, and DAMPs, released from damaged host tissues, engage pattern recognition receptors (PRRs) to activate intracellular signaling cascades leading to NET formation. Emerging evidence highlights the dual role of NETosis in modulating immune responses: while it facilitates microbial clearance, excessive or prolonged NETosis exacerbates autoimmunity by exposing self-antigens and perpetuating inflammation. This review explores the mechanistic insights into PAMP- and DAMP-driven NETosis, their interplay in autoimmune pathophysiology, and their potential as therapeutic targets to mitigate disease progression.