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, Alexandra; Weiss, Jonathan M.; Trzeciak, Alissa; Chen, Wei; Zhang, Jingya; Nyuydzefe, Melanie S.; Arencibia, Carmen; Polimera, Seetharam; Schueller, Olivier; Fuentes‐Duculan, Judilyn; Bonifacio, Kathleen M.; Kunjravia, Norma; Cueto, Inna; Soung, Jennifer; Fleischmann, Roy; Kivitz, Alan; Lebwohl, Mark; Núñez, Miguel; Woodson, Johnnie; Smith, Shondra L.; West, Robert F.; Berger, Mark S.; Krueger, James G.; Ryan, John L.; Waksal, Samuel D.

doi:10.4049/jimmunol.1602142

Cited by 73 publications

(70 citation statements)

References 23 publications

(37 reference statements)

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“…KD025, published in 2008, is the first highly selective ROCK2-isoform inhibitor. 17,[63][64][65][66] In addition to the pro-beige adipogenic action of KD025, we have noticed an anti-adipogenic action of KD025 as reflected by reduced perilipin levels in the drug-treated SV cells ( Figure 7D, 7). Indeed, its therapeutic potential has been explored in fibrotic disease, 15 focal cerebral ischemia, 16,61,62 and auto-immune disease.…”

Section: Discussionmentioning

confidence: 89%

“…Indeed, its therapeutic potential has been explored in fibrotic disease, 15 focal cerebral ischemia, 16,61,62 and auto-immune disease. 17,[63][64][65][66] In addition to the pro-beige adipogenic action of KD025, we have noticed an anti-adipogenic action of KD025 as reflected by reduced perilipin levels in the drug-treated SV cells ( Figure 7D, 7). Importantly, both dose-and time-dependent analyses ( Figure 7E; Figure S8A) helped to dissociate the pro-beige adipogenic (mediated by ROCK2 inhibition) and anti-adipogenic (targets are not clear) actions of KD025.…”

Section: Discussionmentioning

confidence: 89%

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ROCK2 inhibition enhances the thermogenic program in white and brown fat tissue in mice

et al. 2019

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The RhoA/ROCK‐mediated actin cytoskeleton dynamics have been implicated in adipogenesis. The two ROCK isoforms, ROCK1 and ROCK2, are highly homologous. The contribution of ROCK2 to adipogenesis in vivo has not been elucidated. The present study aimed at the in vivo and in vitro roles of ROCK2 in the regulation of adipogenesis and the development of obesity. We performed molecular, histological, and metabolic analyses in ROCK2+/− and ROCK2+/KD mouse models, the latter harboring an allele with a kinase‐dead (KD) mutation. Both ROCK2+/− and ROCK2+/KD mouse models showed a lean body mass phenotype during aging, associated with increased amounts of beige cells in subcutaneous white adipose tissue (sWAT) and increased thermogenic gene expression in all fat depots. ROCK2+/− mice on a high‐fat diet showed increased energy expenditure accompanying by reduced obesity, and improved insulin sensitivity. In vitro differentiated ROCK2+/− stromal‐vascular (SV) cells revealed increased beige adipogenesis associated with increased thermogenic gene expressions. Treatment with a selective ROCK2 inhibitor, KD025, to inhibit ROCK2 activity in differentiated SV cells reproduced the pro‐beige phenotype of ROCK2+/− SV cells. In conclusion, ROCK2 activity‐mediated actin cytoskeleton dynamics contribute to the inhibition of beige adipogenesis in WAT, and also promotes age‐related and diet‐induced fat mass gain and insulin resistance.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 89%

ROCK2 inhibition enhances the thermogenic program in white and brown fat tissue in mice

et al. 2019

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“…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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“…To detect palmitoylation, RPE1 cells transfected 48 hours earlier with different Myc-tagged constructs were starved for 1 hour at 37 °C in IM (Glasgow minimal essential medium buffered with 10 mM Hepes, pH 7.4), incubated for 2 hours at 37 °C in IM with 200 µCi/ml 3 H palmitic acid (9, For GDI1 co-immunoprecipitation assay, HEK cells were lysed using 50 mM TRIS base, Triton 2 %, 200 mM NaCl as well as 1 tablet/10 ml protease inhibitor Mini-complete, EDTAfree (Roche). After removal of insoluble fragments via centrifugation at 12,000 g for 25 min, lysates were incubated with 15 µl of GFP-Trap Agarose beads from Chromotek for 1 h at 4 °C on a rotary wheel.…”

Section: Biochemistrymentioning

confidence: 99%

“…Previous findings classify psoriasiform manifestations in the group of AID. In such cases, elevated levels of active RhoA and Rac1 have been reported 9,10 . Recently, Gernez et al reported 4 patients with severe autoinflammation that were successfully treated with IL-1 inhibition and identified 3 distinct de novo heterozygous variants in the C-terminal part of the Cdc42 11 .…”

Section: Introductionmentioning

confidence: 99%

A toxic palmitoylation on Cdc42 drives a severe autoinflammatory syndrome

Bekhouche

Tourville

Ravichandran

et al. 2019

Preprint

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BackgroundAutoinflammatory diseases (AID) result from dysregulation of the first lines of innate immune responses. Recently, development of high throughput genome sequencing technology led to the rapid emergence of important knowledge in the genetic field. About 20 genes have been identified so far in monogenic forms of distinct AID. However, 70-90 % of patients with AID remain without genetic diagnosis. ObjectiveWe report the identification and characterization of a mutation in the C-terminal region of the Rho GTPase Cdc42 in a patient presenting a severe autoinflammatory phenotype. MethodsWe have analyzed the consequences of the mutation on the subcellular localization of the Cdc42 protein using imaging techniques. Molecular studies were performed using proteomic and biochemical experiments to provide mechanistic bases of the observed defects. Functional assays were also conducted using flow cytometry and cytokine production measurements. ResultsWe show that mutant Cdc42 is trapped in the Golgi apparatus due to the aberrant addition of a palmitate that both enhances the interaction of mutant Cdc42 with Golgi membranes and inhibit its extraction by GDP dissociation inhibitor (GDI), thus impairing its cytosol/membrane shuttling. At the functional level, mutant Cdc42 fails to sustain actin filaments polymerization and induces an exacerbated profile of pro-inflammatory cytokine production due to increased NF-B activation. ConclusionsOur study now provides a molecular explanation for mutations that have been identified recently in our AID patient and others in the C-terminal part of Cdc42. Mutations located in this region of Cdc42 impair the intracellular localization of Cdc42, preventing its interaction with the plasma membrane. Thus, our results definitively link mutations in the CDC42 gene to a complex immune-hemato-autoinflammatory phenotype in humans.

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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

Cited by 73 publications

References 23 publications

ROCK2 inhibition enhances the thermogenic program in white and brown fat tissue in mice

ROCK2 inhibition enhances the thermogenic program in white and brown fat tissue in mice

Rho signaling research: history, current status and future directions

A toxic palmitoylation on Cdc42 drives a severe autoinflammatory syndrome

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