González-Sánchez HM, Baek JH, Weinmann-Menke J, Ajay AK, Charles JF, Noda M, Franklin RA, Rodríguez-Morales P, Kelley VR. 2022. IL-34 and protein-tyrosine phosphatase receptor type-zeta-dependent mechanisms limit arthritis in mice. Laboratory investigation; a journal of technical methods and pathology. 102(8):846-858. Pubmed: 35288653 DOI:10.1038/s41374-022-00772-0


Myeloid cell mediated mechanisms regulate synovial joint inflammation. IL-34, a macrophage (Mø) growth and differentiation molecule, is markedly expressed in neutrophil and Mø-rich arthritic synovium. IL-34 engages a newly identified independent receptor, protein-tyrosine phosphatase, receptor-type, zeta (PTPRZ), that we find is expressed by Mø. 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 Mø toward a reparative phenotype, and enhanced Mø 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.
© 2022. The Author(s), under exclusive licence to United States and Canadian Academy of Pathology.

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Ruth Franklin’s laboratory explores the role of the innate immune system in tissue repair and homeostasis, with a focus on the communication between macrophages and non-immune cells within tissues.

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