Major histocompatibility complex I‐induced endoplasmic reticulum stress mediates the secretion of pro‐inflammatory muscle‐derived cytokines

Anastasia Thoma, Kate E. Earl, Katarzyna Goljanek‐Whysall, Adam P. Lightfoot

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Abstract

Major histocompatibility complex (MHC) I is an important component of intracellular antigen presentation. However, improper expression of MHC I upon the cell surface has been associated with several autoimmune diseases. Myositis is a rare acquired autoimmune disease which targets skeletal muscle, and MHC I overexpression on the surface of muscle fibres and immune cell infiltration are clinical hallmarks. MHC I overexpression may have an important pathogenic role, mediated by the activation of the endoplasmic reticulum (ER) stress response. Given the evidence that muscle is a diverse source of cytokines, we aimed to investigate whether MHC I overexpression can modify the profile of muscle‐derived cytokines and what role the ER stress pathway may play. Using C2C12 myoblasts we overexpressed MHC I with a H‐2kb vector in the presence or absence of salubrinal an ER stress pathway modifying compound. MHC I overexpression induced ER stress pathway activation and elevated cytokine gene expression. MHC I overexpression caused significant release of cytokines and chemokines, which was attenuated in the presence of salubrinal. Conditioned media from MHC I overexpressing cells induced in vitro T‐cell chemotaxis, atrophy of healthy myotubes and modified mitochondrial function, features which were attenuated in the presence of salubrinal. Collectively, these data suggest that MHC I overexpression can induce pro‐inflammatory cytokine/chemokine release from C2C12 myoblasts, a process which appears to be mediated in‐part by the ER stress pathway.
Original languageEnglish
Number of pages10
JournalJournal of Cellular and Molecular Medicine
Early online date25 Nov 2022
DOIs
Publication statusE-pub ahead of print - 25 Nov 2022

Keywords

  • ORIGINAL ARTICLE
  • ORIGINAL ARTICLES
  • ER stress
  • major histocompatibility complex (MHC) I
  • myokines
  • skeletal muscle

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