Novel signaling pathways in lupus pathogenesis

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 DESCRIPTION (provided by applicant): ABSTRACT Generation of high affinity autoantibodies resulting from aberrant T-B collaboration underlies the pathogenesis of Systemic Lupus Erythematosus (SLE). In addition to abnormalities in T-B collaboration, emerging evidence indicates that deregulated interactions between T cells and myeloid cells also contribute to the pathophysiology of SLE. Precise regulation of the cross-talk amongst different cellular compartments is thus essential for the prevention of autoimmunity and a detailed understanding of the molecular mechanisms underlying these interactions can provide key insights into SLE pathogenesis. Our laboratory has previously implicated aberrant activation of ROCK2, a serine-threonine kinase, in the deregulated ability of T cells from autoimmune mice to produce IL-17 and IL-21. We have furthermore demonstrated that ROCK2 controls IL-17 and IL-21 production via its ability to phosphorylate IRF4, a transcription factor that is absolutely required for the production of these two cytokines. In line with these results we have also shown that administration of Fasudil, a ROCK inhibitor, ameliorates disease in lupus-prone mice such as MRL/lpr and NZB/W F1 mice. While our initial studies focused on the role of the ROCK-IRF4 axis in the T cell compartment, we have recently explored the possibility that the ROCKs may play a broad role in the regulation of immune responses. We have found that stimulation of B cells with aCD40 and IL-21 leads to the activation of ROCK2 and to the phosphorylation of IRF4. Phosphorylation of IRF4 in B cells then modulates its ability to regulate plasma cell differentiation by controlling the expression of key target genes. We have furthermore discovered that, in macrophages, ROCK activation leads to the phosphorylation of another IRF, IRF8, which shares a high degree of homology with IRF4, and that this step, in turn, regulates the production of BAFF. Importantly, we have conducted a pilot cross-sectional study that has shown that, as compared to healthy controls, ˜50-60% of SLE patients exhibit a high level of ROCK activity. We thus now propose that aberrant ROCK activation can promote the development of SLE via its ability to control the function of multiple cell compartments and a broad genetic program that, in addition to effects on T cell function, also encompasses effects on the function of B cells and myeloid cells. The specific goals of this proposal are: 1) To dissec the regulation and role of the ROCK-IRF4 axis in B cells, 2) To investigate the role of the ROCK-IRF8 axis in macrophage function, 3) To further characterize the aberrancies in ROCK activation observed in SLE patients. Given that ROCK inhibitors have already shown benefits in clinical trials for cardiovascular disorders while exhibiting only minimal side effects, the knowledge derived from the studies described in this proposal could be rapidly translated into a novel therapeutic regimen for the treatment of SLE.