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

Thoma, Anastasia, Earl, Kate E, Goljanek-Whysall, Katarzyna ORCID: 0000-0001-8166-8800 and Lightfoot, Adam P ORCID: 0000-0003-1501-7879 (2022) Major histocompatibility complex I-induced endoplasmic reticulum stress mediates the secretion of pro-inflammatory muscle-derived cytokines. JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, 26 (24). pp. 6032-6041.

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Official URL: http://dx.doi.org/10.1111/jcmm.17621

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-2k<sup>b</sup> 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.

Item Type:	Article
Uncontrolled Keywords:	ER stress, major histocompatibility complex (MHC) I, myokines, skeletal muscle
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences
Depositing User:	Symplectic Admin
Date Deposited:	03 Feb 2023 10:29
Last Modified:	03 Feb 2023 10:29
DOI:	10.1111/jcmm.17621
Open Access URL:	https://doi.org/10.1111/jcmm.17621
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3168135