Abstract
Over the last decade, innate immune system receptors and sensors called inflammasomes have been identified to play key pathological roles in the development and progression of numerous diseases. Among them, the nucleotide-binding oligomerization domain (NOD-), leucine-rich repeat (LRR-) and pyrin domain-containing protein 3 (NLRP3) inflammasome is probably the best characterized. To date, NLRP3 has been extensively studied in the heart, where its effects and actions have been broadly documented in numerous cardiovascular diseases. However, little is still known about NLRP3 implications in muscle disorders affecting non-cardiac muscles. In this review, we summarize and present the current knowledge regarding the function of NLRP3 in diseased skeletal muscle, and discuss the potential therapeutic options targeting the NLRP3 inflammasome in muscle disorders.
Highlights
Sterile inflammation drives the pathogenesis of various diseases and is controlled by intracellular multiprotein inflammasome complexes
IL-1β is a key proinflammatory cytokine involved in the mediation of inflammation in almost every cell type and tissue; where its levels and activities are correlated with the pathogenesis of various autoinflammatory and autoimmune diseases
Through miR-711, could be a major repressor of the NLRP3 inflammasome by inhibiting both its priming and activation in muscle [80,82]
Summary
Activation of the NLRP3 inflammasome is regulated at both transcriptional and posttranslational levels. The noncanonical activation of the NLRP3 inflammasome, which works in a Toll-like receptor (TLR)/NF-κB pathway independent manner, is achieved via caspases 4, 5, and 11 The latter are activated after cytosolic detection of lipopolysaccharides (LPS), which will open a pannexin-1 (panx-1) transmembrane channel, leading to the release of ATP that open the ATP-gated cation channel receptor (P2 × 7R), inducing K+ outflow. This process will indirectly activate the NLRP3 inflammasome, thereby increasing the release of inflammatory cytokines and exacerbating the inflammatory response [16] This noncanonical pathway might lead to endotoxin induced sepsis [61], and is suggested to have a crucial role as a transcriptional factor in promoting Th2 cells differentiation [63] (Figure 2)
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