Targeting the RhoA-ROCK pathway to reverse T-cell dysfunction in SLE

Rozo, Cristina; Chinenov, Yurii; Maharaj, Reena Khianey; Gupta, Sanjay; Leuenberger, Laura; Kirou, Kyriakos A.; Bykerk, Vivian P.; Goodman, Susan M.; Salmon, Jane E.; Pernis, Alessandra B.

doi:10.1136/annrheumdis-2016-209850

Cited by 70 publications

(49 citation statements)

References 38 publications

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“…In addition, RhoA functions through activation of its immediate downstream effectors such as Rho‐associated protein kinase (ROCK), mDia, and protein kinase N . Blockade of ROCK activity by its specific inhibitors Y27632 or fasudil is associated with the downregulation of Th17 function and improvement for several autoimmune and inflammatory diseases, such as systemic lupus erythematosus, OVA‐induced murine allergic lung inflammation, and viral myocarditis . Thus, ROCK likely contributes to RhoA‐regulated Th17 signaling and differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…42 As we have shown that RhoA promotes mTOR signaling in activated T cells and RhoA promotes Th2 differentiation through glycolysis, 11 it will be interesting to determine whether mTOR-regulated glycolysis contributes to RhoA-mediated Th17 differentiation in future. In addition, RhoA functions through activation of its immediate downstream effectors such as Rho-associated protein kinase (ROCK), mDia, and protein kinase N. 43 Blockade of ROCK activity by its specific inhibitors Y27632 or fasudil is associated with the downregulation of Th17 function and improvement for several autoimmune and inflammatory diseases, such as systemic lupus erythematosus, 44 OVA-induced murine allergic lung inflammation, 45 and viral myocarditis. 46 Thus, ROCK likely contributes to RhoA-regulated Th17 signaling and differentiation.…”

Section: Discussionmentioning

confidence: 99%

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Ablation of RhoA impairs Th17 cell differentiation and alleviates house dust mite-triggered allergic airway inflammation

Yang

Kalim

et al. 2019

Journal of Leukocyte Biology

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Asthma is a heterogeneous chronic airway inflammation in which Th2 and Th17 cells are key players in its pathogenesis. We have reported that RhoA of Rho GTPases orchestrated glycolysis for Th2 cell differentiation and allergic airway inflammation by the use of a conditional RhoA‐deficient mouse line. However, the role of RhoA in Th17 cells remains to be elucidated. In this study, we investigated the effects of RhoA deficiency on Th17 cells in the context of ex vivo cell culture systems and an in vivo house dust mites (HDM)‐induced allergic airway inflammation. We found that RhoA deficiency inhibited Th17 differentiation and effector cytokine secretion, which was associated with the downregulations of Stat3 and Rorγt, key Th17 transcription factors. Furthermore, loss of RhoA markedly suppressed Th17 and neutrophil‐involved airway inflammation induced by HDM in mice. The infiltrating inflammatory cells in the lungs and bronchoalveolar lavage (BAL) fluids were dramatically reduced in conditional RhoA‐deficient mice. Th17 as well as Th2 effector cytokines were suppressed in the airways at both protein and mRNA levels. Interestingly, Y16, a specific RhoA inhibitor, was able to recapitulate the most phenotypes of RhoA genetic deletion in Th17 differentiation and allergic airway inflammation. Our data demonstrate that RhoA is a key regulator of Th17 cell differentiation and function. RhoA might serve as a potential novel therapeutic target for asthma and other inflammatory disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ablation of RhoA impairs Th17 cell differentiation and alleviates house dust mite-triggered allergic airway inflammation

Yang

Kalim

et al. 2019

Journal of Leukocyte Biology

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“…Intriguingly, while KD025 suppresses Th17 differentiation through decreased STAT3 phosphorylation, it accelerates regulatory T cell (Treg) differentiation through enhanced STAT5 phosphorylation. The effect of KD025 to suppress IL‐17 and IL‐21 production was then confirmed in PBMCs from patients with rheumatoid arthritis, graft‐versus‐host disease, systemic lupus erythematosus and inflammatory bowel diseases . Further, recent Phase 2 studies showed that oral administration of KD025 reduces clinical scores in psoriasis patients with concomitant decrease in plasma levels of IL‐17 and IL‐23 and increase in that of IL‐10 .…”

Section: Rho Signaling Research In Current Statusmentioning

confidence: 87%

Rho signaling research: history, current status and future directions

2018

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One of the main research areas in biology from the mid‐1980s through the 1990s was the elucidation of signaling pathways governing cell responses. These studies brought, among other molecules, the small GTPase Rho to the epicenter. Rho signaling research has since expanded to all areas of biology and medicine. Here, we describe how Rho emerged as a key molecule governing cell morphogenesis and movement, how it was linked to actin reorganization, and how the study of Rho signaling has expanded from cultured cells to whole biological systems. We then give an overview of the current research status of Rho signaling in development, brain, cardiovascular system, immunity and cancer, and discuss the future directions of Rho signaling research, with emphasis on one Rho effector, ROCK*. *The Rho GTPase family. Rho family GTPases have now expanded to contain 20 members. Amino acid sequences of 20 Rho GTPases found in human were aligned and the phylogenetic tree was generated by ClustalW2 software (EMBL‐EBI) based on NJ algorithm. The subfamilies of the Rho GTPases are highlighted by the circle and labeled on the right side. Rho cited in this review refers to the original members of Rho subfamily, RhoA, RhoB and RhoC, that are C3 substrates, and, unless specified, not to other members of the Rho subfamily such as Rac, Cdc42, and Rnd.

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“…Reduced JNK phosphorylation levels were also found in the same cells (Table 4). 39 ERM phosphorylation in humans has not been assessed previously, and its pathogenic role in HF remains unknown. [11][12][13] Our findings here also show for the first time that in patients with HFrEF, ROCK activation in PBMCs takes place predominantly in T lymphocytes, specifically in CD4 and in CD8 T lymphocytes, which is possibly related to the higher levels of ROCK-dependent pro-inflammatory molecules ICAM-1, Il-6 and IL-8.…”

Section: Rock Pathway Activation In Hfref Patientsmentioning

confidence: 99%

“…In patients with systemic inflammatory diseases, increased ROCK activity is also observed in circulating T lymphocytes. 39 ERM phosphorylation in humans has not been assessed previously, and its pathogenic role in HF remains unknown. In rodents with PBMCs was observed previously in normotensive rats with genetically increased ACE and Ang II levels, 17 which is consistent with the concept of myocardial ROCK activation mirrored in circulating leucocytes.…”

Section: Rock Pathway Activation In Hfref Patientsmentioning

confidence: 99%

Rho‐kinase pathway activation and apoptosis in circulating leucocytes in patients with heart failure with reduced ejection fraction

Ocaranza

Moya

Jalil

et al. 2019

J Cellular Molecular Medi

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Background: Increased Rho-kinase activity in circulating leucocytes is observed in heart failure with reduced ejection fraction (HFrEF). However, there is little information in HFrEF regarding other Rho-kinase pathway components an on the relationship between Rho-kinase and apoptosis. Here, Rho-kinase activation levels and phosphorylation of major downstream molecules and apoptosis levels were measured for the first time both in HFrEF patients and healthy individuals.Methods: Cross-sectional study comparing HFrEF patients (n = 20) and healthy controls (n = 19). Rho-kinase activity in circulating leucocytes (peripheral blood mononuclear cells, PBMCs) was determined by myosin light chain phosphatase 1 (MYPT1) and ezrin-radixin-moesin (ERM) phosphorylation. Rho-kinase cascade proteins phosphorylation p38-MAPK, myosin light chain-2, JAK and JNK were also analysed along with apoptosis.Results: MYPT1 and ERM phosphorylation were significantly elevated in HFrEF patients, (3.9-and 4.8-fold higher than in controls, respectively). JAK phosphorylation was significantly increased by 300% over controls. Phosphorylation of downstream molecules p38-MAPK and myosin light chain-2 was significantly higher by 360% and 490%, respectively, while JNK phosphorylation was reduced by 60%. Catecholamine and angiotensin II levels were significantly higher in HFrEF patients, while angiotensin-(1-9) levels were lower. Apoptosis in circulating leucocytes was significantly increased in HFrEF patients by 2.8-fold compared with controls and significantly correlated with Rho-kinase activation.

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Targeting the RhoA-ROCK pathway to reverse T-cell dysfunction in SLE

Cited by 70 publications

References 38 publications

Ablation of RhoA impairs Th17 cell differentiation and alleviates house dust mite-triggered allergic airway inflammation

Ablation of RhoA impairs Th17 cell differentiation and alleviates house dust mite-triggered allergic airway inflammation

Rho signaling research: history, current status and future directions

Rho‐kinase pathway activation and apoptosis in circulating leucocytes in patients with heart failure with reduced ejection fraction

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