Background/Purpose: The Rho GTPases, Rac and RhoA, play a key role in immune responses by regulating both cytoskeletal reorganization and gene expression. RhoA exerts many of its effects by activating Rho kinases (ROCKs). Aberrant ROCK activation has been implicated in the pathogenesis of various cardiovascular, renal, and neurological disorders. As such, ROCK inhibitors have emerged as potential treatments for these diseases. Recent studies have demonstrated that, in T cells, Rho kinases can regulate the production of IL-17 and IL-21, two cytokines associated with the development of multiple autoimmune disorders including Systemic Lupus Erythematosus (SLE). ROCK inhibition has previously been shown to ameliorate the cytoskeletal abnormalities of SLE T cells suggesting that SLE patients may exhibit aberrant ROCK activation. The goal of this study was to measure ROCK activity in SLE patients and its relationship with clinical and immunological aspects of SLE.

Methods: We performed a cross sectional study of 28 SLE patients and 25 healthy controls matched for age (31.1 ± 9.1 years vs (31.8 ± 8.2), gender (79% female vs 92%) and race. Mean SLEDAI 4.0 ± 2.4 (Range: 0-10) and physician global assessment 0.8 ± 0.7 (Range: 0-2). Peripheral blood mononuclear cell (PBMC) lysates were used for ROCK kinase activity assays. Cytokine and chemokine profiles in plasma were analyzed via ELISA.

Results: PBMCs from SLE patients expressed significantly higher levels of ROCK activation compared to healthy controls, 1.251 (IQR 0.5-1.6) vs. 0.5645 (IQR 0.5-0.6), respectively (p=0.0015). There were two distinct subgroups of SLE patients: those with high (ROCK^high) and low (ROCK^low) ROCK levels; 16/28 (57%) patients were in the ROCK^high group. Using linear regression models, disease duration, lymphocyte count, and azathioprine use were identified as independent predictors of ROCK activity (p≤0.02). There was no significant difference in IL-17 and IL-21 plasma levels between SLE patients and healthy controls.  CCL20 levels from SLE patients were, however, significantly elevated compared to healthy controls, 16.1 pg/ml (IQR 10-23) vs. 10.2 pg/ml (IQR 7.1-15.5), respectively (p=0.02). Consistent with previous studies, SLE patients expressed significantly higher BAFF levels when compared to controls, 1144 pg/ml (IQR 706-1609) vs. 762.8 pg/ml (IQR 661-829), respectively (p=0.009). There was no correlation between ROCK levels and SLEDAI, cytokine profiles, autoantibodies, or renal disease.

Conclusion: Enhanced ROCK activity was seen in a subgroup of SLE patients and was associated with disease duration, lymphocyte count, and azathioprine use. Given the multiple links between CCL20 and Th17 cells, the elevated levels seen in SLE suggest a role for Th17 cells in the pathogenesis of SLE. These data support the concept that the RhoA/ROCK pathway could represent an important therapeutic target for the treatment of SLE and that measurement of ROCK activation in SLE patients may be utilized to assess the efficacy of therapies, such as ROCK inhibitors, aimed at inhibiting this pathway. Following SLE patients prospectively is necessary to further characterize ROCK levels over time and establish their relationship with disease activity and/or medications.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/enhanced-rock-activation-in-patients-with-systemic-lupus-erythematosus/