PPARG activation by pioglitazone promotes mitophagy and inhibits the NLRP3 inflammasome to alleviate arthritic joint inflammation and bone damage

Rheumatoidarthritis (RA) is an autoimmune disease accompanied by joint swelling,stiffness, and pain, leading to a sharp decline in quality of life. However,the treatment of RA still faces numerous challenges. Clinical studies indicatethat specific hypoglycemic agents alleviate the symptoms of RA, while the potentialmolecular mechanism remains unknown. Herein, we initially assess the efficacyof various categories of anti-diabetic medications including biguanides, GLP1R(glucagon like peptide 1 receptor) agonists, SLC5A2/SGLT2 (solute carrierfamily 5 member 2) inhibitors, DPP4 (dipeptidyl peptidase 4) inhibitors,sulfonylureas, thiazolidinediones, and insulin analog in RA models ofcollagen-induced arthritis (CIA) and serum-transfer arthritis (STA). Resultsdemonstrate that solely thiazolidinediones (pioglitazone [PIOG]) confersuperior efficacy, whereas the other anti-diabetic agents provide minimal or notherapeutic benefits. Mechanistically, thiazolidinediones (PIOG) activatesPPARG/PPARγ (peroxisome proliferator activated receptor gamma) to promotemitophagic flux, thereby inhibiting aberrant NLRP3 inflammasome activation andreducing pro-inflammatory factors IL1B/IL1-BETA (interleukin 1 beta) and IL18 (interleukin18) release. Notably, loss of autophagy either genetically or pharmacologicallysubstantially diminishes the anti-inflammatory effects of PIOG both in vitroand in vivo. In summary, these results offer new mechanistic insight intodisease crosstalk and support the translational value of thiazolidinedionesPIOG as a candidate for precision therapy in RA or multimorbidity of RA and type2 diabetes mellitus (T2DM). Abbreviations: 3-MA: 3-methyladenine; ACP5/TRAP: acid phosphatase 5, tartrate resistant; AIM2: absent in melanoma 2; ALUM: aluminum hydroxide adjuvant; ANOVA: analysis of variance; PYCARD/ASC: PYD and CARD domain containing; ATP: adenosine triphosphate; BMDM: bone marrow-derived macrophage; BV:TV: bone volume:tissue volume; CIA: collagen-induced arthritis; DAPI: 4’,6-diamidino-2-phenylindole; DNA: deoxyribonucleic acid; ELISA: enzyme-linked immunosorbent assay; FG: Fast Green; GFP: green fluorescent protein; GSDMD: gasdermin D; IL1B/IL1-BETA: interleukin 1 beta; IL18: interleukin 18; LDH: lactate dehydrogenase; LPS: lipopolysaccharide; Micro-CT: micro-computed tomography; MSU: monosodium urate; mtDNA: mitochondrial DNA; mtROS: mitochondrial reactive oxygen species; NAC: N-acetylcysteine; NLRP1B: NLR family, pyrin domain containing 1B; NLRP3: NLR family, pyrin domain containing 3; NLRC4: NLR family, CARD domain containing 4; OGTT: oral glucose tolerance test; PBS: phosphate-buffered saline; PINK1: PTEN induced putative kinase 1; PIOG: pioglitazone; PPARG/PPARγ: peroxisome proliferator activated receptor gamma; RA: rheumatoid arthritis; ROS: reactive oxygen species; STA: serum transfer arthritis; STZ: streptozotocin; T2DM: type 2 diabetes mellitus; Tb.N: trabecular number; Tb.Sp: trabecular separation; Tb.Th: trabecular thickness; THP-1: human monocytic leukemia cell line; TNF/TNF-α: tumor necrosis factor; TOMM20: translocase of outer mitochondrial membrane 20.