Rho GTPases (which include Rac and RhoA) are molecular switches that play a fundamental role in biology due to their ability to regulate both cytoskeletal dynamics and signaling pathways. Rac and RhoA target different effectors and thus regulate distinct signaling events. Rac and RhoA also cross-regulate each other since activated Rac inhibits RhoA activity and vice versa. One of the major effectors of RhoA is the Rho kinases (or ROCKs). Activation of Rho GTPases plays a key role in immune responses. Guanine nucleotide exchange factors (GEFs) are the major proteins regulating the activation of Rho GTPases. In the course of isolating proteins interacting with IRF4, a transcription factor required for the differentiation of TH-17 cells, we cloned a novel GEF that we termed IBP (IRF-4 Binding Protein), also known as Def6. Since Def6 is the official name of the gene, IBP will be hereafter referred to as Def6. Def6 is highly expressed in T cells, and, upon TCR engagement, activates Rac but not RhoA. Def6 can also be found in the nucleus where it interacts with IRF4. We previously reported that Def6-deficient mice spontaneously develop a lupus-like syndrome. We have recently found that TCR transgenic (DO11.10) Def6-deficient mice spontaneously develop RA-like arthritis. The autoimmune responses in these mice are due to an aberrant ability of CD4+ T cells to produce IL-17 and IL-21 in response to self-antigens. At a molecular level, Def6-deficient T cells exhibit defective Rac activation and an enhanced ability of IRF4 to bind to the IL-17 and IL-21 promoters. Consistent with the notion that Rac activation inhibits RhoA- induced pathways, we have recently observed that the absence of Def6 also leads to increased ROCK2 activity. Importantly, we have found that ROCK2 phosphorylates IRF4 and regulates its ability to control the production of IL-17 and IL-21. In line with these findings, Fasudil, a ROCK inhibitor, blocked the aberrant IL-17 and IL-21 production detected in the absence of Def6 and prevented development of arthritis in Def6-deficient DO11.10 mice. We now propose that the Def6-ROCK2-IRF4 axis regulates the production of IL-17 and IL-21 and that ROCK inhibitors represent a novel approach for the treatment of autoimmune arthritis. The specific goals of this proposal are: 1) To investigate the interplay between Def6 and ROCK2, 2) to delineate the role of T-cell ROCK2 in autoimmune arthritis and 3) to broadly assess the effectiveness of ROCK inhibitors in autoimmune arthritis.
These studies will provide crucial information into the mechanisms controlling the production of potentially pathogenic cytokines like IL-17 and IL-21. Given that ROCK inhibitors have already been used for the treatment of cardiovascular disorders and are well tolerated, the knowledge derived from these studies could also be rapidly translated into novel therapeutic regimens for the treatment of SLE and RA.
|Rozo, Cristina; Chinenov, Yurii; Maharaj, Reena Khianey et al. (2017) Targeting the RhoA-ROCK pathway to reverse T-cell dysfunction in SLE. Ann Rheum Dis 76:740-747|
|Yi, Woelsung; Gupta, Sanjay; Ricker, Edd et al. (2017) The mTORC1-4E-BP-eIF4E axis controls de novo Bcl6 protein synthesis in T cells and systemic autoimmunity. Nat Commun 8:254|
|Weng, Chien-Huan; Gupta, Sanjay; Geraghty, Patrick et al. (2016) Cigarette smoke inhibits ROCK2 activation in T cells and modulates IL-22 production. Mol Immunol 71:115-122|
|Manni, Michela; Gupta, Sanjay; Nixon, Briana G et al. (2015) IRF4-Dependent and IRF4-Independent Pathways Contribute to DC Dysfunction in Lupus. PLoS One 10:e0141927|
|Isgro, Josephine; Gupta, Sanjay; Jacek, Elzbieta et al. (2013) Enhanced rho-associated protein kinase activation in patients with systemic lupus erythematosus. Arthritis Rheum 65:1592-602|
|Biswas, Partha S; Gupta, Sanjay; Chang, Emily et al. (2011) Aberrant ROCK activation promotes the development of type I diabetes in NOD mice. Cell Immunol 266:111-5|
|Biswas, Partha S; Bhagat, Govind; Pernis, Alessandra B (2010) IRF4 and its regulators: evolving insights into the pathogenesis of inflammatory arthritis? Immunol Rev 233:79-96|