Mechanism Of FABP4 Secreted By M1-like Macrophages Aggravating Rheumatoid Arthritis

Background:Rheumatoid arthritis(RA),as the most common chronic inflammatory arthritis mainly destroying joints,is a complex pathological process involving persistent synovitis,angiogenesis,cartilage degradation and bone erosion,affecting～1%of the population around the world[1-4].The pathogenesis of RA is complicated and still not completely clarified.In the last decade,important advances in our understanding of the relationships between inflammation,the immune response,angiogenesis and adipokines have been achieved.Recent data have demonstrated that adipokines are important mediators of the inflammatory and immune response in RA[5,6].Andres Cerezo L et al.had found fatty acid-binding protein 4(FABP4)as a novel adipokine was upregulated in the serum and synovial fluid of RA patients[7].Chen S et al.had reported that elevated expression of FABP4 was associated with disease activity in RA patients[8].However,the specific role and underlying mechanism of FABP4 in RA isn’t clear.Objective:To investigate the role and mechanism of FABP4(fatty acid-binding protein 4)in rheumatoid arthritis(RA)progression,and evaluate its potential as a therapeutic target in RA.Methods:FABP4 expression was detected in the synovial tissue of RA patients and RA mouse model.RA mouse model was administrated with recombinant FABP4 or BMS309403(FABP4-specific inhibitor)to explore the role of FABP4 in RA progression.Endothelial cells(EC),fibroblast like synoviocytes(FLS)and chondrocytes were treated with recombinant FABP4 or BMS309403 to investigate the effects of FABP4 on these cells in vitro.Mice with a specific deletion of tuberous sclerosis complex 1(TSC1)or Rheb1 in the myeloid lineage were generated as a model to identify the regulation mechanism of FABP4 expression and secretion in RA synovial tissue.Anagliptin(is clinically used to treat type 2 diabetes and can reduce the concentration of FABP4 in the blood of diabetic patients)was used to explore the therapeutic value and potential significance of FABP4 in RA.Results:Increased FABP4 expression was observed in synovial Ml-polarized macrophages of RA patients and RA mice.Recombinant FABP4 promoted the proliferation,migration,invasiveness and production of inflammatory cytokines of EC and FLS,enhanced EC tube formation and dysregulated chondrocyte metabolism.BMS309403 could inhibit the effect of FABP4 in these cells.Moreover,recombinant FABP4 promoted synovitis,angiogenesis and cartilage degeneration in RA mouse model.BMS309403 effectively inhibited the pathological effects of FABP4 in RA progression.Activation of the mTORC1 stimulated M1-polarized macrophages to secrete FABP4 to exacerbated RA progression,while suppressing mTORC1 activation could inhibit FABP4 expression in Ml-polarized macrophages to prevent RA development.Treatment with anagliptin inhibited FABP4 expression in synovial M1-polarized macrophages to alleviate experimental RA progression.Conclusion:FABP4 secreted by M1-polarized macrophages promotes synovitis,angiogenesis and cartilage degradation to exacerbate experimental RA progression.BMS309403 and anagliptin can inhibit FABP4 to alleviate RA development.Hence,FABP4 may represent a potential target for RA therapy.