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Targeting the RhoA-ROCK pathway to reverse T-cell dysfunction in SLE
  1. Cristina Rozo1,
  2. Yurii Chinenov2,3,
  3. Reena Khianey Maharaj1,
  4. Sanjay Gupta1,
  5. Laura Leuenberger1,
  6. Kyriakos A Kirou4,
  7. Vivian P Bykerk4,5,
  8. Susan M Goodman4,5,
  9. Jane E Salmon1,4,5,
  10. Alessandra B Pernis1,3,5
  1. 1Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, New York, USA
  2. 2Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York, USA
  3. 3David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York, USA
  4. 4Department of Rheumatology, Hospital for Special Surgery, New York, New York, USA
  5. 5Department of Medicine, Weill Cornell Medical College, Cornell University, New York, New York, USA
  1. Correspondence to Dr Alessandra B Pernis, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021, USA; pernisa{at}hss.edu

Abstract

Objectives 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.

  • Systemic Lupus Erythematosus
  • T Cells
  • Autoimmunity
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Footnotes

  • Handling editor Tore K Kvien

  • JES and ABP contributed equally.

  • Contributors ABP was involved in overall study conception and design as well as providing critical input on data interpretation and drafting of the manuscript. JES was also involved in study concept and design, data interpretation and drafting of the manuscript. CR was involved in experimental design, carrying out experiments, data acquisition and analysis, and drafting of the manuscript. YC performed NanoString analysis, contributed to the statistical analysis and was involved in the drafting of the manuscript. RKM recruited patients with RA and HCs, performed PBMC isolations and was involved in data interpretation. SG performed ROCK assays and western blots. LL recruited patients with SLE. KAK provided patients with SLE. VPB and SMG provided critical input on data interpretation. All authors helped to critically revise the intellectual content of the manuscript and approved the final submission.

  • Funding The research was supported by a grant from the NIH to JES and ABP (5R21AR62252-2), a grant from the NIH to ABP (1R01AI083440, 5R01AR064883), a NIH Research Rheumatology Training grant to CR (T32AR007517), a American Heart Association grant to YC (11SDG5160006) and the Peter Jay Sharp Foundation and the David Z. Rosensweig Genomics Research Center.

  • Competing interests ABP and JES received an investigator-initiated grant from Kadmon Corporation.

  • Ethics approval HSS IRB.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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