Administration of fasudil, a ROCK inhibitor, attenuates disease in lupus-prone NZB/W F1 female mice

Abstract

Accumulating evidence from murine studies suggests that the RhoA/ROCK pathway plays an important role in the development of autoimmune disorders. We previously demonstrated that ROCK inhibition ameliorates disease in MRL/lpr mice, a spontaneous model of lupus. This study aimed to explore the protective effects of the ROCK inhibitor fasudil in a distinct model of lupus, NZB/W F1 female mice, to assess the broad applicability of ROCK inhibition for the treatment of lupus. NZB/W F1 female mice were administered fasudil continuously in their drinking water starting at 18 or 24 weeks of age up until 44 weeks of age, or remained untreated. Fasudil treatment significantly improved survival and decreased proteinuria, particularly when treatment was started at 18 weeks. There was also a significant decrease in serum anti-dsDNA autoantibody production, glomerular IgG and C3 deposition, and glomerulonephritis. Analysis of the splenic lymphocyte compartment revealed reduced effector/memory CD4(+) T cell and plasma cell numbers in fasudil treated mice while the frequency of other B cell and T cell subsets was unchanged. These results thus indicate that fasudil can ameliorate disease in NZB/W F1 female mice, suggesting that ROCK inhibition might be broadly effective for the treatment of lupus.

Immunomodulatory effects of H.P. Acthar Gel on B cell development in the NZB/W F1 mouse model of systemic lupus erythematosus

“…Prior studies have demonstrated an association between reduced autoantibodies and improved proteinuria, 29,46 while other investigations suggest that attenuation of proteinuria progression requires a reduction in both circulating autoantibodies and glomerular IgG deposition. 45 Interestingly, while both prednisolone and Acthar reduced glomerular IgG, only Acthar also significantly reduced circulating autoantibodies and the development of severe proteinuria. Acthar, but not prednisolone, also significantly attenuated glomerular C3 immunostaining.…”

Rho Kinases in Health and Disease: From Basic Science to Translational Research

“…This is supported by in vitro demonstration of the role of ROCK signaling in T cell development and function, including adhesion, chemotactic responses, and antigen-dependent activation, as well as the beneficial effect of ROCK inhibition in experimental models of rheumatoid arthritis and lupus (Li et al, 2007;He et al, 2008;Stirzaker et al, 2012). In an attempt to assess the ROCK pathway in human autoimmune diseases, measurement of leukocyte ROCK activity shows that 60% of patients with systemic lupus erythematosus exhibit an increase in ROCK activity (Isgro et al, 2013).…”

T cells and IL-17 in lupus nephritis

“…Our group and others have been reported a dysfunction of the ROCK-ERM-CD44 axis in T cells from SLE patients [59–61]. Pharmacological inhibition of ROCK in lupus-prone mice limited T-cells adhesion and migration leading to decreased the kidney pathology [62, 63]. In addition, ROCK2 was reported to facilitate the activity of interferon regulatory factor 4 (IRF4), which is required for the production of IL-17 and IL-21 [63].…”