Dataset Information

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

ABSTRACT: Deregulated production of interleukin (IL)-17 and IL-21 contributes to the pathogenesis of autoimmune disorders such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Production of IL-17 and IL-21 can be regulated by ROCK2, one of the two Rho kinases. Increased ROCK activation was previously observed in an SLE cohort. Here, we evaluated ROCK activity in a new SLE cohort, and an RA cohort, and assessed the ability of distinct inhibitors of the ROCK pathway to suppress production of IL-17 and IL-21 by SLE T cells or human Th17 cells.ROCK activity in peripheral blood mononuclear cells (PBMCs) from 29 patients with SLE, 31 patients with RA and 28 healthy controls was determined by ELISA. SLE T cells or in vitro-differentiated Th17 cells were treated with Y27632 (a pan-ROCK inhibitor), KD025 (a selective ROCK2 inhibitor) or simvastatin (which inhibits RhoA, a major ROCK activator). ROCK activity and IL-17 and IL-21 production were assessed. The transcriptional profile altered by ROCK inhibitors was evaluated by NanoString technology.ROCK activity levels were significantly higher in patients with SLE and RA than healthy controls. Th17 cells exhibited high ROCK activity that was inhibited by Y27632, KD025 or simvastatin; each also decreased IL-17 and IL-21 production by purified SLE T cells or Th17 cells. Immune profiling revealed both overlapping and distinct effects of the different ROCK inhibitors.ROCK activity is elevated in PBMCs from patients with SLE and RA. Production of IL-17 and IL-21 by SLE T cells or Th17 cells can furthermore be inhibited by targeting the RhoA-ROCK pathway via both non-selective and selective approaches.

SUBMITTER: Rozo C

PROVIDER: S-EPMC5839171 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Rozo Cristina C Chinenov Yurii Y Maharaj Reena Khianey RK Gupta Sanjay S Leuenberger Laura L Kirou Kyriakos A KA Bykerk Vivian P VP Goodman Susan M SM Salmon Jane E JE Pernis Alessandra B AB

Annals of the rheumatic diseases 20161109 4

<h4>Objectives</h4>Deregulated production of interleukin (IL)-17 and IL-21 contributes to the pathogenesis of autoimmune disorders such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Production of IL-17 and IL-21 can be regulated by ROCK2, one of the two Rho kinases. Increased ROCK activation was previously observed in an SLE cohort. Here, we evaluated ROCK activity in a new SLE cohort, and an RA cohort, and assessed the ability of distinct inhibitors of the ROCK pathway to ...[more]

PMID: 28283529

Similar Datasets

Project description:Background:Erectile dysfunction (ED) occurs more frequently and causes a worse response to the first-line therapies in diabetics compared with nondiabetic men. Corpus cavernosum vascular dysfunction plays a pivotal role in the occurrence of diabetes mellitus ED (DMED). The aim of this study was to investigate the protective effects of glucagon-like peptide-1 (GLP-1) analog liraglutide on ED and explore the underlying mechanisms in vivo and in vitro. Methods:Type 1 diabetes was induced in rats by streptozotocin, and the apomorphine test was for screening the DMED model in diabetic rats. Then they were randomly treated with subcutaneous injections of liraglutide (0.3 mg/kg/12 h) for 4 weeks. Erectile function was assessed by cavernous nerve electrostimulation. The corpus cavernosum was used for further study. In vitro, effects of liraglutide were evaluated by primary corpus cavernosum smooth muscle cells (CCSMCs) exposed to low or high glucose (HG)-containing medium with or without liraglutide and GLP-1 receptor (GLP-1R) inhibitor. Western blotting, fluorescent probe, immunohistochemistry, and relevant assay kits were performed to measure the levels of target proteins. Results:Administration of liraglutide did not significantly affect plasma glucose and body weights in diabetic rats, but improved erectile function, reduced levels of NADPH oxidases and ROS production, downregulated expression of Ras homolog gene family (RhoA) and Rho-associated protein kinase (ROCK) 2 in the DMED group dramatically. The liraglutide treatment promoted autophagy further and restored expression of GLP-1R in the DMED group. Besides, cultured CCSMCs with liraglutide exhibited a lower level of oxidative stress accompanied by inhibition of the RhoA/ROCK pathway and a higher level of autophagy compared with HG treatment. These beneficial effects of liraglutide effectively reversed by GLP-1R inhibitor. Conclusion:Liraglutide exerts protective effects on ED associated with the regulation of smooth muscle dysfunction, oxidative stress and autophagy, independently of a glucose- lowering effect. It provides new insight into the extrapancreatic actions of liraglutide and preclinical evidence for a potential treatment for DMED.

Project description:Abstract Background Melatonin (MEL), an endogenous hormone, has been widely investigated in neurological diseases. Microglia (MG), a resident immunocyte localizing in central nervous system is reported to play important functions in the animal model of temporal lobe epilepsy (TLE). Some evidence showed that MEL influenced activation of MG, but the detailed model of action that MEL plays in remains uncertain. Methods In this study, we established a model of TLE in mice by stereotactic injection of kainic acid (KA). We treated the mice with MEL. Lipopolysaccharide, ROCK2‐knockdown (ROCK‐KD) and ‐overexpression (ROCK‐OE) of lentivirus‐treated cells were used in cell experiments to simulate an in vitro inflammatory model. Results The results of electrophysiological tests showed that MEL reduced frequency and severity of seizure. The results of behavioral tests indicated MEL improved cognition, learning, and memory ability. Histological evidences demonstrated a significant reduction of neuronal death in the hippocampus. In vivo study showed that MEL changed the polarization status of MG from a proinflammatory M1 phenotype to an anti‐inflammatory M2 phenotype by inversely regulating the RhoA/ROCK signaling pathway. In cytological study, we found that MEL had a significant protective effect in LPS‐treated BV‐2 cells and ROCK‐KD cells, while the protective effect of MEL was significantly attenuated in ROCK‐OE cells. Conclusion MEL played an antiepileptic role in the KA‐induced TLE modeling mice both in behavioral and histological levels, and changed MG polarization status by regulating the RhoA/ROCK signaling pathway. 1. Melatonin (MEL) reduces frequency and severity of seizure. 2. MEL regulates the ROCK2 signaling pathway rather than ROCK1 to promote microglial polarization toward an anti‐inflammatory direction. 3. RhoA/ROCK2 signaling pathway might be a potential mechanism in the status epilepticus modeling mice. Highlights • Melatonin (MEL) reduces frequency and severity of seizure.• MEL regulates the ROCK2 signaling pathway rather than ROCK1 to promote microglial polarization toward an anti‐inflammatory direction.• RhoA/ROCK2 signaling pathway may be important in the temporal lobe epilepsy modeling mice.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets