Objectives To define the cell type (myeloid vs other cells) specific effect of interleukin 1 (IL-1) receptor antagonist (IL-1Ra) deficiency on the acute inflammatory phase of arthritis.
Methods Arthritis was induced by K/BxN serum transfer in wild-type (WT), IL-1Ra-deficient (IL-1Ra−/−) and conditional knockout mice. In the latter, IL-1Ra production was specifically targeted in myeloid cells (IL-1RaΔM) or in both hepatocytes and myeloid cells (IL-1RaΔH+M). Arthritis severity was clinically evaluated and ankle sections were scored for synovial inflammation and cartilage erosion. Quantitative RT-PCR, western blot and immunohistochemical analyses measured expression, localisation and cellular sources of the different IL-1Ra isoforms in arthritic joints.
Results Total and myeloid cell-specific IL-1Ra deficiency was associated with increased arthritis severity, although disease incidence was similar to that of WT mice. Increased clinical scores were associated with exacerbated synovial inflammation. All IL-1Ra isoforms, except for intracellular (ic)IL-1Ra2, were expressed in arthritic joints of WT mice. In contrast, production of secreted (s)IL-1Ra and icIL-1Ra3 isoforms was markedly decreased in arthritic joints of both IL-1RaΔM and IL-1RaΔH+M mice. Immunohistochemical and western blot analyses suggested that the icIL-1Ra1 isoform is produced primarily by synovial fibroblasts.
Conclusion Myeloid cell-derived IL-1Ra, including both sIL-1Ra and icIL-1Ra3 isoforms, controls articular inflammation during the acute phase of K/BxN serum transfer-induced arthritis.
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Funding This work was supported by the Swiss National Science Foundation grants 310030-135195 (to CG) and 310030-134691 (to GP), the Rheumasearch Foundation,and the Institute of Arthritis Research.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
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