Background: The Nucleotide-binding oligomerization domain-Like Receptor family CARD domain-containing 4 (NLRC4) inflammasome is a critical component of innate immunity. As an intracellular pattern recognition receptor, NLRC4 contributes to host defence by responding to diverse microbial ligands through interactions with Neuronal Apoptosis Inhibitory Proteins (NAIPs), leading to inflammasome assembly, caspase-1 activation, secretion of interleukins IL-1? and IL-18 and the induction of pyroptosis.
Objective: This narrative critical review aims to provide the comprehensive overview of the structural organisation, functional domains, and signalling mechanisms of NLRC4 with emphasis on its involvement in infectious as well as non-infectious inflammatory disorders.
Methods: A comprehensive literature review of peer-reviewed publications from 1995 to 2025 was conducted to evaluate the molecular and disease specific role of NLRC4 inflammasome signalling.
Results: Available literature review indicates that NLRC4 contributes to the pathophysiology of a broad spectrum of infectious, metabolic, inflammatory, and neurodegenerative diseases. Genetic mutations in NLRC4 have been identified in several auto inflammatory diseases, and emerging findings suggests a potential association between NLRC4 activation and trained innate immunity, thereby influencing immune memory and disease modulation.
Conclusion: Beyond its role in antimicrobial defence, NLRC4 is increasingly recognised as context dependent regulator of inflammatory responses across infectious and non-infectious diseases. Further investigation is required to elucidate its disease-specific regulatory mechanism and to better understand its role in inflammatory pathophysiology.