title: ROCK2 signaling is required to induce a subset of T follicular helper cells through opposing effects on STATs in autoimmune settings.
abstract: Rho-associated kinase 2 (ROCK2) determines the balance between human T helper 17 (TH17) cells and regulatory T (Treg) cells. We investigated its role in the generation of T follicular helper (TFH) cells, which help to generate antibody-producing B cells under normal and autoimmune conditions. Inhibiting ROCK2 in normal human T cells or peripheral blood mononuclear cells from patients with active systemic lupus erythematosus (SLE) decreased the number and function of TFH cells induced by activation ex vivo. Moreover, inhibition of ROCK2 activity decreased the abundance of the transcriptional regulator Bcl6 (B cell lymphoma 6) and increased that of Blimp1 by reducing the binding of signal transducer and activator of transcription 3 (STAT3) and increasing that of STAT5 to the promoters of the genes Bcl6 and PRDM1, respectively. In the MRL/lpr murine model of SLE, oral administration of the selective ROCK2 inhibitor KD025 resulted in a twofold reduction in the numbers of TFH cells and antibody-producing plasma cells in the spleen, as well as a decrease in the size of splenic germinal centers, which are the sites of interaction between TFH cells and B cells. KD025-treated mice showed a substantial improvement in both histological and clinical scores compared to those of untreated mice and had reduced amounts of Bcl6 and phosphorylated STAT3, as well as increased STAT5 phosphorylation. Together, these data suggest that ROCK2 signaling plays a critical role in controlling the development of TFH cells induced by autoimmune conditions through reciprocal regulation of STAT3 and STAT5 activation.
authors.affiliation: Kadmon Research Institute, New York, NY 10016, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Weiss
authors.affiliation: Kadmon Research Institute, New York, NY 10016, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Kadmon Research Institute, New York, NY 10016, USA.
authors.forename: Melanie S
authors.initials: MS
authors.lastname: Nyuydzefe
authors.affiliation: Kadmon Research Institute, New York, NY 10016, USA.
authors.forename: Alissa
authors.initials: A
authors.lastname: Trzeciak
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics and Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Flynn
authors.affiliation: Kadmon Research Institute, New York, NY 10016, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Tonra
authors.affiliation: Hooke Laboratories, Lawrence, MA 01843, USA.
authors.forename: Suzana
authors.initials: S
authors.lastname: Marusic
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics and Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Kadmon Research Institute, New York, NY 10016, USA.
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Waksal
authors.affiliation: Kadmon Research Institute, New York, NY 10016, USA. alexandra.zanin-zhorov@kadmon.com.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zanin-Zhorov
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008875:Middle Aged; D010950:Plasma Cells / Q000276:immunology / Q000473:pathology; D000074462:Positive Regulatory Domain I-Binding Factor 1 / Q000235:genetics / Q000276:immunology; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology*; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000473:pathology; D054460:rho-Associated Kinases / Q000235:genetics / Q000276:immunology*
chemical_list: C084103:BCL6 protein, human; D006576:Heterocyclic Compounds, 4 or More Rings; C000619755:KD025; D051560:Proto-Oncogene Proteins c-bcl-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C494087:Stat3 protein, mouse; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1; C515852:ROCK2 protein, human; C515855:Rock2 protein, mouse; D054460:rho-Associated Kinases