Systemic lupus erythematosus (SLE) is a complex autoimmune disease primarily affecting women of childbearing age. Historically, SLE was attributed to adaptive immune dysfunction. However, recent research highlights the critical role of innate immunity, particularly neutrophils, in disease pathogenesis. Neutrophils contribute through mechanisms such as neutrophil extracellular trap (NET) formation, excessive ROS production, and impaired NET clearance. These processes lead to tissue damage by driving inflammation, promoting autoantibody formation, and causing immune complex deposition. Within this inflammatory milieu, ROS primes and NETs activate the NLRP3 inflammasome in various immune cells, leading to the release of IL-1β and IL-18. These cytokines further amplify ROS accumulation and NETosis, establishing a feed-forward inflammatory loop. In this review, we discuss the role of innate immunity in SLE, with a focus on the interplay between neutrophils, NETosis, oxidative stress and NLRP3 inflammasome activation. Understanding these mechanisms may reveal therapeutic strategies targeting excessive NETosis, enhancing NET clearance mechanisms, and modulating inflammasome or ROS activity to mitigate inflammation and tissue damage in SLE.
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