MyD88 and PKD1 play an essential role in the development of spontaneous polyarthritis in IL-1 receptor antagonist deficient mice

Abstract IL-1 is an important cytokine that is secreted by various cells, including synovial cells, and can induce the production of proinflammatory mediators. Due to the excessive and uncontrolled IL-1 signaling, IL-1R antagonist knockout mice (IL-1rnKO) develop spontaneous polyarthritis that mimics some pathogenic features of human rheumatoid arthritis (RA). MyD88 is a key signaling adaptor molecule for toll-like receptors (TLRs) and IL-1R. We have previously identified protein kinase D1 (PKD1) to play an indispensable role in the MyD88-dependent proinflammatory response. MyD88 and PKD1 may therefore confer regulatory role on arthritis development in IL- 1rnKO mice. To investigate this, we examined the synovial cell, T cell, and B cell responses, and the incidence and severity of arthritis in IL-1rnKO mice that are deficient in MyD88 or PKD1. We found that MyD88 deficiency and PKD1 deficiency inhibited the development of polyarthritis as well as reduced the levels of synovial macrophages in IL-1rnKO. T cells isolated from lymph nodes expressed significantly reduced CCR6, CXCR3, IFNγ, and IL-17 in MyD88-deficient IL-1rnKO mice. BAFF-R and TACI levels in splenic marginal zone precursor cells (MZP) and maturation of MZP to marginal zone B cells were significantly reduced in MyD88-deficient IL- 1rnKO mice. We are currently investigating whether PKD1 also play a regulatory role in T cell and B cell responses during the pathogenic course of arthritis in IL-1rnKO mice. Taking together, our results suggest that MyD88 and PKD1 play a critical role in the pathogenesis of arthritis in IL-1rnKO. Further insights into PKD1 and its role in arthritis development will contribute to better understanding innate signaling in the development of RA.