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Serum-circulating His-tRNA synthetase inhibits organ-targeted immune responses

Cellular & Molecular Immunology 2021年第6期18卷 1463-1475页

作者： Ryan AAdams Cátia Fernandes-Cerqueira Antonella Notarnicola Elisabeth Mertsching Zhiwen Xu Wing-Sze Lo Kathleen Ogilvie kyle pchiang Jeanette Ampudia Sanna Rosengren Andrea Cubitt David JKing John DMendlein Xiang-Lei Yang Leslie ANangle Ingrid ELundberg Per-Johan Jakobsson Paul Schimmel aTyr Pharma 3545 John Hopkins CourtSuite 250San DiegoCA92121USA Division of Rheumatology Department of MedicineSolnaKarolinska InstitutetKarolinska University HospitalSE-17176StockholmSweden IAS HKUST-Scripps R&D Laboratory Institute for Advanced StudyHong Kong University of Science and Technologyand Pangu BiopharmaHong KongChina The Scripps Laboratories for tRNA Synthetase Research 10650 North Torrey Pines RoadLa JollaCA92037USA The Scripps Laboratories for tRNA Synthetase Research Scripps Florida130 Scripps WayJupiterFL33458USA

His-tRNA synthetase (HARS) is targeted by autoantibodies in chronic and acute inflammatory anti-Jo-1-positive antisynthetase syndrome. The extensive activation and migration of immune cells into lung and muscle are associated with interstitial lung disease, myositis, and morbidity. It is unknown whether the sequestration of HARS is an epiphenomenon or plays a causal role in the disease. Here, we show that HARS circulates in healthy individuals, but it is largely undetectable in the serum of anti-Jo-1-positive antisynthetase syndrome patients. In cultured primary human skeletal muscle myoblasts (HSkMC), HARS is released in increasing amounts during their differentiation into myotubes. We further show that HARS regulates immune cell engagement and inhibits CD4+ and CD8+ T-cell activation. In mouse and rodent models of acute inflammatory diseases, HARS administration downregulates immune activation. In contrast, neutralization of extracellular HARS by high-titer antibody responses during tissue injury increases susceptibility to immune attack, similar to what is seen in humans with anti-Jo-1-positive disease. Collectively, these data suggest that extracellular HARS is homeostatic in normal subjects, and its sequestration contributes to the morbidity of the anti-Jo-1-positive antisynthetase syndrome.

关键词： Immunology Autoimmunity Synthetase tRNA HARS

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