Isoform-specific targeting of ROCK proteins in immune cells

Abstract

Rho-associated kinase 1 (ROCK1) and ROCK2 are activated by Rho GTPase and control cytoskeleton rearrangement through modulating the phosphorylation of their down-stream effector molecules. Although these 2 isoforms share more than 90% homology within their kinase domain the question of whether ROCK proteins function identically in different cell types is not clear. By using both pharmacological inhibition and genetic knockdown approaches recent studies suggest that the ROCK2 isoform plays an exclusive role in controlling of T-cell plasticity and macrophage polarization. Specifically, selective ROCK2 inhibition shifts the balance between pro-inflammatory and regulatory T-cell subsets via concurrent regulation of STAT3 and STAT5 phosphorylation, respectively. Furthermore, the administration of an orally available selective ROCK2 inhibitor effectively ameliorates clinical manifestations in experimental models of autoimmunity and chronic graft-vs.-host disease (cGVHD). Because ROCK2 inhibition results in the suppression of M2-type macrophages while favoring polarization of M1-type macrophages, ROCK2 inhibition can correct the macrophage imbalance seen during age-related macular degeneration (AMD). In summary, the exclusive role of ROCK2 in immune system modulation argues for the development and testing of isoform-specific ROCK2 inhibitors for the treatment of inflammatory disorders.

WITHDRAWN: Macrophage-targeting Fasudil treatment protects liver from the ischemia/reperfusion injury by promoting M2 macrophage polarization

“…ROCK is a key regulator of actin organization and thus a regulator of cell migration [46]. The function of ROCK in macrophage regulation 20 is contradictory [19,47]. Our studies demonstrated that ROCK inhibitor could polarize macrophage to M2 phenotype and protect the liver from IRI.…”

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

“…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.…”

“…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.…”

Challenges of selecting pharmacotherapy for macular edema the need for better and combination therapies

“…therapies reassures that macular edema is maximally treated. Future therapies should be focused on deactivating inflammatory cells [24,25].…”