Aberrant NLRP3 Inflammasome Activation Ignites the Fire of Inflammation in Neuromuscular Diseases

Int J Mol Sci. 2021 Jun 4;22(11):6068. doi: 10.3390/ijms22116068.


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.

Keywords: amyotrophic lateral sclerosis; astrocytes; cytokines; immune cells; innate immune system; macrophages; microglia; muscular dystrophy; neuroinflammation; therapy.

Publication types

  • Review

MeSH terms

  • Animals
  • Humans
  • Inflammasomes / metabolism*
  • Inflammation / complications
  • Inflammation / metabolism
  • Inflammation / pathology*
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Neuromuscular Diseases / etiology
  • Neuromuscular Diseases / metabolism
  • Neuromuscular Diseases / pathology*


  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein