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SOCS-3 negatively regulates innate and adaptive immune mechanisms in acute IL-1–dependent inflammatory arthritis
Peter K.K. Wong, … , Andrew W. Roberts, Ian P. Wicks
Peter K.K. Wong, … , Andrew W. Roberts, Ian P. Wicks
Published June 1, 2006
Citation Information: J Clin Invest. 2006;116(6):1571-1581. https://doi.org/10.1172/JCI25660.
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Research Article Autoimmunity

SOCS-3 negatively regulates innate and adaptive immune mechanisms in acute IL-1–dependent inflammatory arthritis

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Abstract

RA is an autoimmune disease characterized by sustained imbalance between pro- and antiinflammatory immune mechanisms. The SOCS proteins are negative regulators of cytokine signaling, but to date there has been little information on their function in disease. The generation of Socs3–/Δvav mice, which lack SOCS-3 in the hematopoietic and endothelial cell compartment, allowed us to explore the role of endogenous SOCS-3 during acute inflammatory arthritis. Joint inflammation in Socs3–/Δvav mice was particularly severe and was characterized by increased numbers of neutrophils in the inflamed synovium, bone marrow, peripheral blood, and spleen. These features were most likely due to increased production of and enhanced responsiveness to G-CSF and IL-6 during arthritis in these mice. Local osteoclast generation and bone destruction were also dramatically increased in the absence of SOCS-3, as was macrophage activation. Finally, SOCS-3 was found to negatively regulate CD4+ T lymphocyte activation, including production of the pleiotropic cytokine IL-17. The absence of SOCS-3 therefore had dramatic effects in this disease model, with a broader impact on cellular responses than SOCS-1 deficiency. These findings provide direct in vivo evidence that endogenous SOCS-3 is a critical negative regulator of multiple cell types orchestrating inflammatory joint disease.

Authors

Peter K.K. Wong, Paul J. Egan, Ben A. Croker, Kristy O’Donnell, Natalie A. Sims, Sarah Drake, Hiu Kiu, Edward J. McManus, Warren S. Alexander, Andrew W. Roberts, Ian P. Wicks

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Figure 2

SOCS-3 deficiency is associated with increased osteoclast numbers.

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SOCS-3 deficiency is associated with increased osteoclast numbers.
(A an...
(A and B) Frontal sections through an arthritic Socs3–/Δvav knee joint showing H&E-stained synovitis (S) containing numerous granulocytes (boxed area) with several multinucleated osteoclasts (large arrows) eroding into bone (Bn; A) and TRAP-stained osteoclasts (small arrows; B). (C) TRAP+ cells on the periosteal surfaces of arthritic joints per high-power field (hpf) were counted by an investigator blinded to the experimental groups (mean ± SEM; n = 5 mice per group, pooled from 2 independent experiments). (D) Histomorphometry was performed by an investigator blinded to the experimental groups. OcS/BS, ratio of osteoclast surface to bone surface; ObS/Bs, ratio of osteoblast surface to bone surface; BV/TV, trabecular bone volume. Values are mean ± SEM; n = 8–10 male mice per group at 8–12 weeks of age. Similar findings were seen in female mice. (E and F) Representative images of von Kossa–stained tibiae of male 8-week-old WT (E) and Socs3–/Δvav (F) mice showing differences in trabecular bone volume. White boxes show secondary spongiosa region used for histomorphometric measurements. Magnification, ×400 (A and B); ×100 (E and F). *P < 0.05 versus WT and Socs3+/Δvav.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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