title: Targeting the RhoA-ROCK pathway to reverse T-cell dysfunction in SLE.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, New York, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Rozo
authors.affiliation: Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York, USA.|David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York, USA.
authors.forename: Yurii
authors.initials: Y
authors.lastname: Chinenov
authors.affiliation: Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, New York, USA.
authors.forename: Reena Khianey
authors.initials: RK
authors.lastname: Maharaj
authors.affiliation: Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, New York, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, New York, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Leuenberger
authors.affiliation: Department of Rheumatology, Hospital for Special Surgery, New York, New York, USA.
authors.forename: Kyriakos A
authors.initials: KA
authors.lastname: Kirou
authors.affiliation: Department of Rheumatology, Hospital for Special Surgery, New York, New York, USA.|Department of Medicine, Weill Cornell Medical College, Cornell University, New York, New York, USA.
authors.forename: Vivian P
authors.initials: VP
authors.lastname: Bykerk
authors.affiliation: Department of Rheumatology, Hospital for Special Surgery, New York, New York, USA.|Department of Medicine, Weill Cornell Medical College, Cornell University, New York, New York, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Goodman
authors.affiliation: Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, New York, USA.|Department of Rheumatology, Hospital for Special Surgery, New York, New York, USA.|Department of Medicine, Weill Cornell Medical College, Cornell University, New York, New York, USA.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Salmon
authors.affiliation: Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, New York, USA.|David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York, USA.|Department of Medicine, Weill Cornell Medical College, Cornell University, New York, New York, USA.
authors.forename: Alessandra B
authors.initials: AB
authors.lastname: Pernis
mesh_terms: D000328:Adult; D000368:Aged; D000577:Amides / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000235:genetics / Q000276:immunology; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D020381:Interleukin-17 / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000097:blood* / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D019821:Simvastatin / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D058504:Th17 Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D000098546:Interleukin-21
chemical_list: D000577:Amides; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020381:Interleukin-17; D007378:Interleukins; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C108830:Y 27632; D019821:Simvastatin; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; D000098546:Interleukin-21
keywords: Autoimmunity; Systemic Lupus Erythematosus; T Cells