title: PRMT5-Selective Inhibitors Suppress Inflammatory T Cell Responses and Experimental Autoimmune Encephalomyelitis.
abstract: In the autoimmune disease multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), expansion of pathogenic, myelin-specific Th1 cell populations drives active disease; selectively targeting this process may be the basis for a new therapeutic approach. Previous studies have hinted at a role for protein arginine methylation in immune responses, including T cell-mediated autoimmunity and EAE. However, a conclusive role for the protein arginine methyltransferase (PRMT) enzymes that catalyze these reactions has been lacking. PRMT5 is the main PRMT responsible for symmetric dimethylation of arginine residues of histones and other proteins. PRMT5 drives embryonic development and cancer, but its role in T cells, if any, has not been investigated. In this article, we show that PRMT5 is an important modulator of CD4+T cell expansion. PRMT5 was transiently upregulated during maximal proliferation of mouse and human memory Th cells. PRMT5 expression was regulated upstream by the NF-κB pathway, and it promoted IL-2 production and proliferation. Blocking PRMT5 with novel, highly selective small molecule PRMT5 inhibitors severely blunted memory Th expansion, with preferential suppression of Th1 cells over Th2 cells. In vivo, PRMT5 blockade efficiently suppressed recall T cell responses and reduced inflammation in delayed-type hypersensitivity and clinical disease in EAE mouse models. These data implicate PRMT5 in the regulation of adaptive memory Th cell responses and suggest that PRMT5 inhibitors may be a novel therapeutic approach for T cell-mediated inflammatory disease.
authors.affiliation: Division of Medical Laboratory Science, School of Health and Rehabilitation Sciences, College of Medicine, The Ohio State University, Columbus, OH 43210.|Biomedical Sciences Graduate Program, College of Medicine, The Ohio State University, Columbus, OH 43210.
authors.forename: Lindsay M
authors.identifier: 0000-0002-3204-568X
authors.initials: LM
authors.lastname: Webb
authors.affiliation: Division of Medical Laboratory Science, School of Health and Rehabilitation Sciences, College of Medicine, The Ohio State University, Columbus, OH 43210.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Amici
authors.affiliation: Division of Medical Laboratory Science, School of Health and Rehabilitation Sciences, College of Medicine, The Ohio State University, Columbus, OH 43210.
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Jablonski
authors.affiliation: Division of Medical Laboratory Science, School of Health and Rehabilitation Sciences, College of Medicine, The Ohio State University, Columbus, OH 43210.
authors.forename: Himanshu
authors.initials: H
authors.lastname: Savardekar
authors.affiliation: College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Panfil
authors.affiliation: Division of Medicinal Chemistry and Pharmacology, College of Pharmacy, The Ohio State University, Columbus OH 43210.
authors.forename: Linsen
authors.initials: L
authors.lastname: Li
authors.affiliation: Division of Medicinal Chemistry and Pharmacology, College of Pharmacy, The Ohio State University, Columbus OH 43210.
authors.forename: Wei
authors.identifier: 0000-0003-3895-1429
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599.
authors.forename: Kevin
authors.initials: K
authors.lastname: Peine
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210.
authors.forename: Vrajesh
authors.identifier: 0000-0003-2293-4499
authors.initials: V
authors.lastname: Karkhanis
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Bachelder
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599.
authors.forename: Kristy M
authors.initials: KM
authors.lastname: Ainslie
authors.affiliation: College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Green
authors.affiliation: Division of Medicinal Chemistry and Pharmacology, College of Pharmacy, The Ohio State University, Columbus OH 43210.
authors.forename: Chenglong
authors.identifier: 0000-0001-9460-3168
authors.initials: C
authors.lastname: Li
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Baiocchi
authors.affiliation: Division of Medical Laboratory Science, School of Health and Rehabilitation Sciences, College of Medicine, The Ohio State University, Columbus, OH 43210; mireia.guerau@osumc.edu.|Institute of Behavioral Medicine Research, College of Medicine, The Ohio State University, Columbus, OH 43210.|Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, OH 43210; and.|Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH 43210.
authors.forename: Mireia
authors.identifier: 0000-0002-0600-4593
authors.initials: M
authors.lastname: Guerau-de-Arellano
mesh_terms: D000818:Animals; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007156:Immunologic Memory; D007249:Inflammation; D007376:Interleukin-2 / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation; D008745:Methylation; D051379:Mice; D016328:NF-kappa B / Q000276:immunology; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D007376:Interleukin-2; D016328:NF-kappa B; C400529:PRMT5 protein, human; C498518:Prmt5 protein, mouse; D011484:Protein-Arginine N-Methyltransferases