Recent Advances in NLRP3 Inflammasome in Corneal Diseases: Preclinical Insights and Therapeutic Implications

Ocul Surf. 2024 Sep 30:S1542-0124(24)00103-4. doi: 10.1016/j.jtos.2024.09.007. Online ahead of print.

ABSTRACT

NLRP3 inflammasome is a cytosolic multiprotein complex formed in response to exogenous environmental stress and cellular damage. The three major components of the NLRP3 inflammasome are the innate immunoreceptor protein NLRP3, the adapter protein apoptosis-associated speck-like protein containing a C-terminal caspase activation and recruitment domain, and the inflammatory protease enzyme caspase-1. The integrated NLRP3 inflammasome triggers the activation of caspase-1, leading to GSDMD-dependent pyroptosis and facilitating the maturation and release of inflammatory cytokines, namely interleukin (IL)-18 and IL-1β. However, the inflammatory responses mediated by the NLRP3 inflammasome exhibit dual functions in innate immune defense and cellular homeostasis. Aberrant activation of the NLRP3 inflammasome matters in the etiology and pathophysiology of various corneal diseases. Corneal alkali burn can induce pyroptosis, neutrophil infiltration, and corneal angiogenesis via the activation of NLRP3 inflammasome. When various pathogens invade the cornea, NLRP3 inflammasome recognizes pathogen-associated molecular patterns or damage-associated molecular patterns to engage in pro-inflammatory and anti-inflammatory mechanisms. Moreover, chronic inflammation and proinflammatory cascades mediated by the NLRP3 inflammasome contribute to the pathogenesis of diabetic keratopathy. Furthermore, overproduction of reactive oxygen species, mitochondrial dysfunction, and toll-like receptor-mediated activation of nuclear factor kappa B drive the stimulation of NLRP3 inflammasome and participate in the progression of dry eye disease. However, there still exist controversies regarding the regulatory pathways of the NLRP3 inflammasome. In this review, we provide a comprehensive overview of recent advancements in the function of NLRP3 inflammasome in corneal diseases and its regulatory pathways primarily through studies using animal models. Furthermore, we explore prospects for pharmacologically targeting pathways associated with NLRP3.

PMID:39357820 | DOI:10.1016/j.jtos.2024.09.007