IL-34 and protein-tyrosine phosphatase receptor type-zeta-dependent mechanisms limit arthritis in mice

Myeloid cell mediated mechanisms regulate synovial joint inflammation. IL-34, a macrophage (Mo) growth and differentiation molecule, is markedly expressed in neutrophil and Mo-rich arthritic synovium. IL-34 engages a newly identified independent receptor, protein-tyrosine phosphatase, receptor-type, zeta (PTPRZ), that we find is expressed by Mo. As IL-34 is prominent in rheumatoid arthritis, we probed for the IL-34 and PTPRZ-dependent myeloid cell mediated mechanisms central to arthritis using genetic deficient mice in K/BxN serum-transfer arthritis. Unanticipatedly, we now report that IL-34 and PTPRZ limited arthritis as intra-synovial pathology and bone erosion were more severe in IL-34 and PTPRZ KO mice during induced arthritis. We found that IL-34 and PTPRZ: (i) were elevated, bind, and induce downstream signaling within the synovium in arthritic mice and (ii) were upregulated in the serum and track with disease activity in rheumatoid arthritis patients. Mechanistically, IL-34 and PTPRZ skewed Mo toward a reparative phenotype, and enhanced Mo clearance of apoptotic neutrophils, thereby decreasing neutrophil recruitment and intra-synovial neutrophil extracellular traps. With fewer neutrophils and neutrophil extracellular traps in the synovium, destructive inflammation was restricted, and joint pathology and bone erosion diminished. These novel findings suggest that IL-34 and PTPRZ-dependent mechanisms in the inflamed synovium limit, rather than promote, inflammatory arthritis. As IL-34, a macrophage growth factor, is elevated in RA patients, it is considered a therapeutic target. Unexpectedly, inflammatory arthritis in IL-34 null mice and the newly identified IL-34 receptor, PTPRZ, null mice worsened disease. Through macrophage mediated mechanisms, IL-34 and PTPRZ-dependent events limited apoptotic neutrophil rich synovial inflammation and joint destruction. These findings counter the assumption that IL-34 is harmful in RA, and fuel further studies before designing a therapeutic approach for this illness.

Automated summary

Myeloid cell mediated mechanisms regulate synovial joint inflammation. IL-34 and PTPRZ limit arthritis by reducing neutrophil recruitment and intra-synovial neutrophil extracellular traps, thereby alleviating synovial and bone erosion. IL-34 and PTPRZ levels are elevated in rheumatoid arthritis patients and correlate with disease activity.