Abstract
Inflammasomes are molecular hubs that are assembled and activated by a host in response to various microbial and non-microbial stimuli and play a pivotal role in maintaining tissue homeostasis. The NLRP3 is a highly promiscuous inflammasome that is activated by a wide variety of sterile triggers, including misfolded protein aggregates, and drives chronic inflammation via caspase-1-mediated proteolytic cleavage and secretion of proinflammatory cytokines, interleukin-1β and interleukin-18. These cytokines further amplify inflammatory responses by activating various signaling cascades, leading to the recruitment of immune cells and overproduction of proinflammatory cytokines and chemokines, resulting in a vicious cycle of chronic inflammation and tissue damage. Neuromuscular diseases are a heterogeneous group of muscle disorders that involve injury or dysfunction of peripheral nerves, neuromuscular junctions and muscles. A growing body of evidence suggests that dysregulation, impairment or aberrant NLRP3 inflammasome signaling leads to the initiation and exacerbation of pathological processes associated with neuromuscular diseases. In this review, we summarize the available knowledge about the NLRP3 inflammasome in neuromuscular diseases that affect the peripheral nervous system and amyotrophic lateral sclerosis, which affects the central nervous system. In addition, we also examine whether therapeutic targeting of the NLRP3 inflammasome components is a viable approach to alleviating the detrimental phenotype of neuromuscular diseases and improving clinical outcomes.
Highlights
Neuromuscular disorders comprise of a wide range of diseases that are often classified according to the affected regions of the neuromuscular system
In ALS patients, reactive astrocytes become dysfunctional and lose their beneficial functions and interactions with motor neurons [156], thereby evoking detrimental effects on the muscles. It has been demonstrated for the first time that astrocytes carrying mutant SOD1 and cocultured with motor neurons derived either from mouse embryonic spinal cord or embryonic stem cells caused neurotoxicity [157,158]. This gain of function by astrocytes resulted in toxicity that was highly specific to motor neurons, and astrocytes expressing mutant SOD1 did not cause the death of other neuronal subtypes
Inflammation has emerged as a main culprit in the initiation and progression of neuromuscular diseases, the precise mechanisms involved are far from being fully elucidated
Summary
Neuromuscular disorders comprise of a wide range of diseases that are often classified according to the affected regions of the neuromuscular system. At the early stage of muscle regeneration, following muscle damage, infiltrating immune cells (i.e., mast cells and neutrophils) clear the damaged myofibers and secrete cytokines to recruit macrophages, to regulate the inflammatory response This cascade of events stimulates satellite cell activation, proliferation and differentiation to myotubes, resulting in mature muscle fibers [3]. The stimulation and assembly of inflammasomes induces a chain-reaction of caspase 1-dependent proteolytic cleavage, along with the maturation and secretion of proinflammatory cytokines, namely, IL-1β and IL-18, resulting in a highly inflammatory form of programmed cell death, distinct from apoptosis, called pyroptosis (further described below) This process leads to plasma membrane rupture and the release of proinflammatory intracellular contents, including inflammasome components, into the extracellular milieu to promote chemotaxis and infiltration of innate immune cells at the sites of tissue damage [9]
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