Macrophage metabolic exhaustion and PANoptotic cell death drive chronic tissue inflammation in rheumatoid arthritis.

In the autoimmune disease rheumatoid arthritis, the inflammatory response evolves from protective to pathogenic, causing tissue destruction. Rheumatoid synovitis persists despite the presence of pro-repair SELENOPhiMerTK+CD206+ macrophages, suggesting that these cells acquire pro-arthritogenic functions. Patient-derived synovial SELENOPhiMerTK+CD206+ macrophages produced high concentrations of the complement component C1q and concurrently expressed its receptor, C1QBP. Stimulation of these macrophages with C1q induced metabolic exhaustion, characterized by diminished ATP production, cleavage of mitochondrial nicotinamide adenine dinucleotide (NAD), and accumulation of cyclic ADP ribose (cADPR). This metabolic crisis was driven by the mitochondrial enzyme Sterile alpha and Toll/interleukin-1 receptor (TIR) motif containing 1 (SARM1), which catalyzed the conversion of NAD into cADPR, triggering PANoptotic and pro-inflammatory macrophage death. In vivo experiments demonstrated that C1q treatment exacerbated synovitis, whereas SARM1 inhibition conferred therapeutic benefit. These findings identify the NAD+ hydrolase SARM1 as a marker of metabolically stressed macrophages and an executor of pro-inflammatory macrophage death during autoimmune tissue inflammation.