Abstract
Muscle inflammation as in idiopathic inflammatory myopathies (IIM) leads to muscle weakness, mononuclear cell infiltration, and myofiber dysfunction affecting calcium channels. The effects of interleukin-17A (IL-17) and tumor necrosis factor-α (TNFα) on inflammation and calcium changes were investigated in human myoblasts. Human myoblasts were exposed to IL-17 and/or TNFα with/without store-operated Ca2+ entry (SOCE) inhibitors (2-ABP or BTP2). For co-cultures, peripheral blood mononuclear cells (PBMC) from healthy donors activated or not with phytohemagglutinin (PHA) were added to myoblasts at a 5:1 ratio. IL-17 and TNFα induced in synergy CCL20 and IL-6 production by myoblasts (>14-fold). PBMC-myoblast co-cultures enhanced CCL20 and IL-6 production in the presence or not of PHA compared to PBMC or myoblast monocultures. Anti-IL-17 and/or anti-TNFα decreased the production of IL-6 in co-cultures (p < 0.05). Transwell system that prevents direct cell-cell contact reduced CCL20 (p < 0.01) but not IL-6 secretion. IL-17 and/or TNFα increased the level of the ER stress marker Grp78, mitochondrial ROS and promoted SOCE activation by 2-fold (p < 0.01) in isolated myoblasts. SOCE inhibitors reduced the IL-6 production induced by IL-17/TNFα. Therefore, muscle inflammation induced by IL-17 and/or TNFα may increase muscle cell dysfunction, which, in turn, increased inflammation. Such close interplay between immune and non-immune mechanisms may drive and increase muscle inflammation and weakness.
Highlights
Idiopathic Inflammatory Myopathies (IIM) such as dermatomyositis and polymyositis are chronic muscle diseases characterized by muscle inflammation, skeletal muscle weakness and early sarcopenia
Store-operate calcium entry (SOCE) interacts with immune mechanisms to further increase the myoblast inflammatory response. Both immune and non-immune mechanisms contribute to IIM pathogenesis. The interplay between these two mechanisms was studied in human myoblasts stimulated with the proinflammatory cytokines IL-17 and tumor necrosis factor-α (TNFα)
The results indicate that in addition of the inflammatory response induced by IL-17 and TNFα; IL-17 and TNFα promoted endoplasmic reticulum (ER) and mitochondrial stress and calcium dysregulation in myoblasts, leading to muscle cell dysfunction
Summary
Idiopathic Inflammatory Myopathies (IIM) such as dermatomyositis and polymyositis are chronic muscle diseases characterized by muscle inflammation, skeletal muscle weakness and early sarcopenia. Calcium (Ca2+) dysregulation contributes to muscle cell dysfunction with effects on contractibility [1]. Store-operate calcium entry (SOCE) is a SOCE Blockade Reduces Muscle Inflammation major pathway for Ca2+. SOCE is activated by Ca2+ depletion from the endoplasmic reticulum (ER) that triggers the storeoperated calcium channels (SOCs) opening through stromalinteracting molecule (STIM1) translocation to Orai channels. SOCE process is important for maintaining proper Ca2+ store filling that is crucial for muscle function [2]. Overexpression of STIM1 and Orai and the associated rapid activation and deactivation of SOCE was observed in dystrophic mouse muscles [3]. SOCE activation is essential in the induction of myoblast differentiation [4]. A tight regulation of SOCE is required for proper muscle development and contractile function [2]
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