Complement in systemic lupus erythematosus across time and space: from tolerance to tissue injury and from extracellular to intracellular functions.

The complement system plays a paradoxical role in systemic lupus erythematosus physiopathology, acting both as a protective mechanism and as a driver of tissue injury, depending on disease stage. Neutrophil extracellular traps (NETs) further exacerbate disease activity by promoting complement activation and autoantigen exposure, forming an amplifying inflammatory loop. Lupus nephritis remains challenging to monitor using conventional complement biomarkers such as CH50, C3, and C4; the utility of anti-C1q, anti-ficolin, and anti-C1s antibodies, along with tissue-based markers such as renal C4d and C5b-9 deposits, as markers of disease activity and prognosis, is discussed. Interestingly, noncanonical functions of complement, including intracellular roles in immune cell metabolism regulation, have been recently described. Understanding the crosstalk between complement, NETs, and immune metabolism may provide new targets for therapeutic intervention.