2. Academic Validation
  3. Macrophage metabolic exhaustion and PANoptotic cell death drive chronic tissue inflammation in rheumatoid arthritis

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

  • Immunity. 2026 Apr 14;59(4):970-987.e6. doi: 10.1016/j.immuni.2026.01.019.
Tao Huang 1,  Yoshinori Takashima 1,  Jitendra Kumar 1,  Jose Morales 1,  Kevin Le 1,  Zhensheng Hu 1,  Selene Rubino 1,  Robert T Trousdale 2,  Gerald J Berry 3,  Jorg J Goronzy 4,  Cornelia M Weyand 5
Affiliations

Affiliations

  • 1 Department of Medicine, Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA; Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA; Department of Cardiology, Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA.
  • 2 Department of Orthopedic Surgery, Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA.
  • 3 Department of Pathology, School of Medicine, Stanford University, Stanford, CA 94305, USA.
  • 4 Department of Medicine, Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA; Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA; Department of Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA.
  • 5 Department of Medicine, Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA; Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA; Department of Cardiology, Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA; Department of Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA. Electronic address: [email protected].
PMID: 41794034 DOI: 10.1016/j.immuni.2026.01.019
Abstract

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.

Keywords

C1Q-binding protein; C1q; NAD; NAD(+) hydrolase; PANoptosis; SARM1; cADPR; metabolic exhaustion; rheumatoid arthritis; tissue macrophage.

Figures
Products