PRMT5 in T Cells Drives Th17 Responses, Mixed Granulocytic Inflammation, and Severe Allergic Airway Inflammation.

Abstract

Severe asthma is characterized by steroid insensitivity and poor symptom control and is responsible for most asthma-related hospital costs. Therapeutic options remain limited, in part due to limited understanding of mechanisms driving severe asthma. Increased arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), is increased in human asthmatic lungs. In this study, we show that PRMT5 drives allergic airway inflammation in a mouse model reproducing multiple aspects of human severe asthma. We find that PRMT5 is required in CD4+ T cells for chronic steroid-insensitive severe lung inflammation, with selective T cell deletion of PRMT5 robustly suppressing eosinophilic and neutrophilic lung inflammation, pathology, airway remodeling, and hyperresponsiveness. Mechanistically, we observed high pulmonary sterol metabolic activity, retinoic acid-related orphan receptor γt (RORγt), and Th17 responses, with PRMT5-dependent increases in RORγt's agonist desmosterol. Our work demonstrates that T cell PRMT5 drives severe allergic lung inflammation and has potential implications for the pathogenesis and therapeutic targeting of severe asthma.

• Authors: Brandon W Lewis, Stephanie A Amici, Hye-Young Kim, Emily M Shalosky, Aiman Q Khan, Joshua Walum, Kymberly M Gowdy, Joshua A Englert, Ned A Porter, Mitchell H Grayson, Rodney D Britt Jr, Mireia Guerau-de-Arellano
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 208 Issue 7 Pg. 1525-1533 (04 01 2022) ISSN: 1550-6606 [Electronic] United States
• PMID: 35288471 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 by The American Association of Immunologists, Inc.

Topics

• Animals
• Asthma (metabolism)
• Granulocytes (metabolism)
• Hypersensitivity (metabolism)
• Inflammation (metabolism)
• Mice
• Th17 Cells (metabolism)