Complement and inflammasome crosstalk in chronic inflammation

Chronic inflammation underlies a broad range of human diseases, including autoimmune disorders, neurodegeneration, and metabolic syndromes. While acute inflammation is essential for pathogen clearance and tissue repair, persistent activation leads to tissue damage and disease progression. Two key innate immune pathways, the complement system and inflammasomes, are crucial mediators of inflammation and are increasingly recognized as interdependent effectors that sustain chronic inflammatory states. This review examines the mechanistic crosstalk between complement activation and inflammasome signaling, with an emphasis on the NLRP3 inflammasome. We first outline how complement pathways drive inflammation through cell recruitment, cytokine induction, and failure of regulatory checkpoints. Next, we review the triggers, regulation, and persistence of inflammasome activation, highlighting the central role of NLRP3 and its engagement by diverse danger signals in chronic disease. In the main section, we detail multiple mechanistic intersections between the two systems, including shared activation triggers such as reactive oxygen species and mitochondrial damage, direct priming and activation of inflammasomes by complement components (e.g., C3a, C5a, MAC), and feedback loops driven by inflammasome-derived cytokines (IL-1β, IL-18) that enhance complement activity and immune cell recruitment. We further illustrate these interactions across disease contexts, including gout, atherosclerosis, rheumatoid arthritis, systemic lupus erythematosus, and Alzheimer's disease. In each case, complement and inflammasomes form a self-amplifying loop that exacerbates inflammation and tissue damage. We also examine the dual role of C1q as both an enhancer and suppressor of inflammasome activation, depending on the cellular and molecular environment. Finally, we discuss therapeutic strategies targeting these pathways. Complement inhibitors (e.g., eculizumab, avacopan), inflammasome inhibitors (e.g., MCC950), and IL-1β blockers (anakinra) show clinical promise, and dual-targeting approaches may offer synergistic benefit. Understanding the interplay between complement and inflammasomes provides critical insight into the persistence of inflammation and opens new avenues for precise immunomodulation in chronic diseases.