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Neutrophils as the key mediators of antibody-mediated arthritis and edema: The central role of Syk

  • Author(s): Elliott, Emily R.
  • Advisor(s): Lowell, Clifford A.
  • Rosen, Steven
  • et al.
Abstract

The K/BxN serum transfer model of arthritis is critically dependent on FcγR signaling events mediated by the Syk tyrosine kinase. However, the specific cell types in which this signaling is required are not known. We report that deletion of Syk kinase in neutrophils, achieved using sykf/f MRP8-cre+ mice, blocks disease development in serum transfer arthritis. Sykf/f MRP8-cre+ mice show no evidence of joint disease, characterized by joint swelling, immune cell infiltrate, pannus formation, and bone and cartilage erosion. Using mixed chimeric mice, containing both wild type and sykf/f MRP8-cre+ neutrophils, we find no impairment in recruitment of Syk-deficient neutrophils to the inflamed joint, though they are less capable of producing cytokines. They also display an increased apoptotic rate compared to wild type cells in the same joint. To our surprise, the mast cell-deficient c-kitsh/sh mice developed robust arthritis following serum transfer while c-kitW/Wv mice did not, suggesting that previous conclusions concerning the central role of mast cells in this model may need to be revised. Basophil-deficient mice also responded normally to K/BxN serum transfer.

Sykf/f MRP8-cre+ mice also display reduced deposition of pathogenic anti-GPI Abs in the joint following K/BxN serum transfer. Additionally, sykf/f MRP8-cre+ mice manifest poor edema formation at three and eight hours following formation of cutaneous immune complexes (Arthus reaction). This defect is most pronounced at the eight-hour timepoint, while mast cell deficient c-kitsh/sh animals show no defect in edema at any time point. Histamine is a powerful vasoactive molecule, but the histamine receptor 1 (H1R) antagonist pyrilamine maleate only inhibits edema in c-kitsh/sh mice, and only at the three-hour timepoint. Thus, at early timepoints neutrophils are able to compensate for the lack of mast cells in a partially H1R-dependent mechanism. Together, these data suggest that neutrophil-dependent recognition of immune complexes contributes significantly to changes in vascular permeability during the early phases of immune complex disease. In contrast, very early joint-specific edema, induced by systemic immune complexes, is unaffected in sykf/f MRP8-cre+ mice, suggesting that the mechanism behind edema varies depending on the tissue site and/or the time point after induction.

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