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.

Public Health Relevance

These studies will delineate the signaling pathways, which, if deregulated, can lead to the development of Systemic Lupus Erythematosus (SLE), a prototypical systemic autoimmune disorder characterized by hypergammaglobulinemia, autoantibody production, and multi-organ involvement. In particular, these studies will provide critical insights into the role of the ROCK kinases in this disease. 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 be rapidly translated into novel therapeutic regimens for the treatment of SLE.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR064883-04
Application #
9394777
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Mancini, Marie
Project Start
2015-03-16
Project End
2019-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Hospital for Special Surgery
Department
Type
DUNS #
622146454
City
New York
State
NY
Country
United States
Zip Code
10021
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 71:115-22
Ricker, Edd; Chowdhury, Luvana; Yi, Woelsung et al. (2016) The RhoA-ROCK pathway in the regulation of T and B cell responses. F1000Res 5:
Pernis, Alessandra B; Ricker, Edd; Weng, Chien-Huan et al. (2016) Rho Kinases in Autoimmune Diseases. Annu Rev Med 67:355-74
Chandrasekaran, Uma; Yi, Woelsung; Gupta, Sanjay et al. (2016) Regulation of Effector Treg Cells in Murine Lupus. Arthritis Rheumatol 68:1454-66
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