Phosphorylation of IRF4 by ROCK2 regulates IL-17 and IL-21 production and the development of autoimmunity in mice

Biswas, Partha S.; Gupta, Sanjay; Chang, E. B.; Li, Song; Stirzaker, Roslynn A.; Liao, James K.; Bhagat, Govind; Pernis, Alessandra B.

doi:10.1172/jci42856

Cited by 203 publications

(259 citation statements)

References 76 publications

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“…ROCK2 is induced during Th17-skewing conditions and regulates IL-17 secretion via a STAT3/IRF4/RORgtdependent mechanism in mice and humans (13,(15)(16)(17). Histological assessment revealed that baseline pSTAT3, IRF4, RORgt, and ROCK2 staining were greater, whereas ROCK1 expression was diminished in lesional skin in comparison with nonlesional skin (Fig.…”

Section: Resultsmentioning

confidence: 94%

“…Additionally, several groups demonstrated that ROCK2 specifically contributes to regulation of IL-17 secretion in mice and humans (13,15). To explore whether plasma IL-17 levels could be used to monitor response to the KD025 treatment, peripheral blood samples were collected on a monthly basis and cytokine levels were measured by using a Quanterix Simoa platform for biomolecule detection.…”

Section: Resultsmentioning

confidence: 99%

“…Rho-associated kinase (ROCK)2 was shown recently to be implicated in the regulation of autoimmunity in mice and humans (13)(14)(15). Previous findings demonstrated that oral administration of a selective ROCK2 inhibitor (KD025) in healthy subjects decreases IL-17 and IL-21 secretion induced by ex vivo stimulation (15 immunosuppressive T cell subsets via concurrent regulation of STAT3/STAT5 phosphorylation (16)(17)(18).…”

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confidence: 99%

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Cutting Edge: Selective Oral ROCK2 Inhibitor Reduces Clinical Scores in Patients with Psoriasis Vulgaris and Normalizes Skin Pathology via Concurrent Regulation of IL-17 and IL-10

Zanin-Zhorov

Weiss

Trzeciak

et al. 2017

The Journal of Immunology

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Targeted inhibition of Rho-associated kinase (ROCK)2 downregulates the proinflammatory T cell response while increasing the regulatory arm of the immune response in animals models of autoimmunity and Th17-skewing human cell culture in vitro. In this study, we report that oral administration of a selective ROCK2 inhibitor, KD025, reduces psoriasis area and severity index scores by 50% from baseline in 46% of patients with psoriasis vulgaris, and it decreases epidermal thickness as well as T cell infiltration in the skin. We observed significant reductions of IL-17 and IL-23, but not IL-6 and TNF-α, whereas IL-10 levels were increased in peripheral blood of clinical responders after 12 wk of treatment with KD025. Collectively, these data demonstrate that an orally available selective ROCK2 inhibitor downregulates the Th17-driven autoimmune response and improved clinical symptoms in psoriatic patients via a defined molecular mechanism that involves concurrent modulation of cytokines without deleterious impact on the rest of the immune system.

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Section: Resultsmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Cutting Edge: Selective Oral ROCK2 Inhibitor Reduces Clinical Scores in Patients with Psoriasis Vulgaris and Normalizes Skin Pathology via Concurrent Regulation of IL-17 and IL-10

Zanin-Zhorov

Weiss

Trzeciak

et al. 2017

The Journal of Immunology

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“…The Rho kinase family members, consisting of Rho-associated kinase 1 (ROCK1) and ROCK2, are serine-threonine kinases that are activated by Rho GTPases and mediate the phosphorylation of downstream targets in cells (9). Recent studies have demonstrated that ROCK2 regulates the production of both IL-21 and IL-17 and plays an essential role in the development of autoimmunity in mice (10,11). Indeed, pan ROCK inhibition was reported to effectively down-regulate ongoing autoimmune response in animal models (11,12).…”

mentioning

confidence: 99%

“…Recent studies have demonstrated that ROCK2 regulates the production of both IL-21 and IL-17 and plays an essential role in the development of autoimmunity in mice (10,11). Indeed, pan ROCK inhibition was reported to effectively down-regulate ongoing autoimmune response in animal models (11,12). Additionally, ROCK activity was found to be up-regulated in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) (13,14), when the production of both IL-21 and IL-17 is deregulated, but to date there is no evidence of selective ROCK2 involvement in the regulation of proinflammatory cytokines in humans.…”

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confidence: 99%

Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism

Zanin-Zhorov¹,

Weiss²,

Nyuydzefe³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

201

214

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Rho-associated kinase 2 (ROCK2) regulates the secretion of proinflammatory cytokines and the development of autoimmunity in mice. Data from a phase 1 clinical trial demonstrate that oral administration of KD025, a selective ROCK2 inhibitor, to healthy human subjects down-regulates the ability of T cells to secrete IL-21 and IL-17 by 90% and 60%, respectively, but not IFN-γ in response to T-cell receptor stimulation in vitro. Pharmacological inhibition with KD025 or siRNA-mediated inhibition of ROCK2, but not ROCK1, significantly diminished STAT3 phosphorylation and binding to IL-17 and IL-21 promoters and reduced IFN regulatory factor 4 and nuclear hormone RAR-related orphan receptor γt protein levels in T cells derived from healthy subjects or rheumatoid arthritis patients. Simultaneously, treatment with KD025 also promotes the suppressive function of regulatory T cells through up-regulation of STAT5 phosphorylation and positive regulation of forkhead box p3 expression. The administration of KD025 in vivo down-regulates the progression of collagen-induced arthritis in mice via targeting of the Th17-mediated pathway. Thus, ROCK2 signaling appears to be instrumental in regulating the balance between proinflammatory and regulatory T-cell subsets. Targeting of ROCK2 in man may therefore restore disrupted immune homeostasis and have a role in the treatment of autoimmunity.T he immune response is a delicate balancing act, protecting the integrity of the host organism from foreign invaders while not causing autoimmune reactivity (1). IL-21 and IL-17 are proinflammatory cytokines produced by T-helper 17 (Th17) cells that are involved in the pathogenesis of many autoimmune diseases (2-5). The generation of Th17 cells is induced by a combination of several cytokines including transforming growth factor-β (TGF-β1), IL-1β, IL-6, and IL-23, and involves the activation of transcription factors, such as RAR-related orphan receptor (ROR) γt, RORα, IFN regulatory factor (IRF) 4, and signal transducer and activator of transcription 3 (STAT3) (2, 6, 7). However, the signaling pathways that lead to activation of this transcriptional profile are poorly understood and remain unclear.Rho GTPase-mediated signaling pathways play a central role in the coordination and balancing of T-cell-mediated immune responses, including T-cell receptor (TCR)-mediated signaling, cytoskeletal reorganization, and the acquisition of the appropriate T-cell effector program (8). The Rho kinase family members, consisting of Rho-associated kinase 1 (ROCK1) and ROCK2, are serine-threonine kinases that are activated by Rho GTPases and mediate the phosphorylation of downstream targets in cells (9). Recent studies have demonstrated that ROCK2 regulates the production of both IL-21 and IL-17 and plays an essential role in the development of autoimmunity in mice (10, 11). Indeed, pan ROCK inhibition was reported to effectively down-regulate ongoing autoimmune response in animal models (11,12). Additionally, ROCK activity was found to be up-regulated in patients w...

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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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Phosphorylation of IRF4 by ROCK2 regulates IL-17 and IL-21 production and the development of autoimmunity in mice

Cited by 203 publications

References 76 publications

Cutting Edge: Selective Oral ROCK2 Inhibitor Reduces Clinical Scores in Patients with Psoriasis Vulgaris and Normalizes Skin Pathology via Concurrent Regulation of IL-17 and IL-10

Cutting Edge: Selective Oral ROCK2 Inhibitor Reduces Clinical Scores in Patients with Psoriasis Vulgaris and Normalizes Skin Pathology via Concurrent Regulation of IL-17 and IL-10

Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism

Rho signaling research: history, current status and future directions

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