Exercise hormone irisin alleviates rheumatoid arthritis by removing dysfunctional mitochondria

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. Numerous clinical studies have revealed that exercise is extremely beneficial for the outcome of RA. However, the underlying mechanism remains poorly understood. In the present study, we investigated the therapeutic efficacy of irisin, an exercise hormone, on K/BxN serum and collagen-induced arthritis (CIA), two well established mouse models for RA research. Mechanistically, irisin interacted with ITGAV (integrin subunit alpha V) and ITGB5 (integrin subunit beta 5) to activate mitophagy and remove leaked mitochondrial DNA (mtDNA) and reactive oxygen species (ROS), which suppressed the activation of NLRP3 (NLR family pyrin domain containing 3) inflammasome and then hindered the pathological process of experimental arthritis. Notably, the beneficial effects of irisin on the treatment of experimental arthritis were significantly abolished in mice with atg5 (autophagy related 5) conditional knockout in myeloid cells (atg5^fl/flLyz2). Our study elucidated the underlying mechanism through which exercise alleviated experimental arthritis and offered a feasible therapeutic strategy for RA.Abbreviations: 3-MA: 3-methyladenine Ac-TUBA: acetylated TUBA; ACP5: acid phosphatase 5, tartrate resistant; AIM2: absent in melanoma 2; ANOVA: analysis of variance; ATP: adenosine triphosphate; BAF: bafilomycin A₁; BV:TV: bone volume per total volume; BMD: bone mineral density; BMDMs: bone marrow-derived macrophages; CASP1: caspase 1; CTSB: cathepsin B; CIA: collagen-indcued arthritis; DNM1L: dynamin 1 like; CYCS: cytochrome c, somatic; EtBr: ethidium bromide; FNDC5: fibronectin type III domain containing 5; FL-GSDMD: GSDMD full length; GSDMD: gasdermin D; HE: hematoxylin and eosin; iBMDMs: immortalized bone marrow-derived macrophages; IL1B: interleukin 1 beta; IL6: interleukin 6; IL18: interleukin 18; LDH: lactate dehydrogenase; LPS: lipopolysaccharide; MAP1LC3: microtubule associated protein 1 light chain 3; MSU: monosodium urate; mtROS: mitochondrial reactive oxygen species; mtDNA: mitochondrial DNA; NLRC4: NLR family CARD domain containing 4; NLRP1: NLR family pyrin domain containing 1; NLRP3: NLR family pyrin domain containing 3; NT-GSDMD: GSDMD N-terminal fragment; NAC: N-acetylcysteine; ox-mtDNA: oxidized mitochondrial DNA; PYCARD: PYD and CARD domain containing; PRKAA: protein kinase AMP-activated catalytic subunit alpha 1; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RA: rheumatoid arthritis; ROS: reactive oxygen species; SD: standard deviation; SiO₂: silicon dioxide; SQSTM1: sequestosome 1; Tb.Th: trabecular thickness; Tb.N: trabecular number; Tp.Sp: trabecular separation; TNF/TNF-α: tumor necrosis factor; TOMM20: translocase of outer mitochondrial membrane 20; TUBA: tubulin alpha; ULK1: unc-51 like autophagy activating kinase 1; WT: wild type.