The NLRP3 inflammasome: role in the pathobiology of chronic pain

Chronic pain is not only one of the most common health problems, it is often challenging to treat adequately. Chronic pain has a high prevalence globally, affecting approximately 20% of the adult population. Chronic inflammatory pain and neuropathic (nerve) pain conditions are areas of large unmet medical need because analgesic/adjuvant agents recommended for alleviation of these types of chronic pain often lack efficacy and/or they produce dose-limiting side effects. Recent work has implicated the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome in the pathobiology of chronic pain, especially neuropathic and inflammatory pain conditions. NLRP3 is activated by damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). This in turn leads to recruitment and activation of caspase-1 an enzyme that cleaves the inactive IL-1β and IL-18 precursors to their respective mature pro-inflammatory cytokines (IL-1β and IL-18) for release into the cellular milieu. Caspase-1 also cleaves the pyroptosis-inducing factor, gasdermin D, that leads to oligomerization of its N-terminal fragment to form pores in the host cell membrane. This then results in cellular swelling, lysis and release of cytoplasmic contents in an inflammatory form of cell death, termed pyroptosis. The ultimate outcome may lead to the development of neuropathic pain and/or chronic inflammatory pain. In this review, we address a role for NLRP3 inflammasome activation in the pathogenesis of various chronic pain conditions.