A recent study published in Clinical Rheumatology demonstrated that NLRC4 inflammasome activation may contribute to ankylosing spondylitis (AS) pathogenesis by targeting caspase-1 and regulating monocyte pyroptosis. The investigation included peripheral blood samples from 50 AS patients and 50 matched controls, with mRNA expression levels of NLRC4, CASP1, and GSDMD-N quantified in peripheral blood mononuclear cells, alongside inflammatory cytokine profiling in plasma.
The study revealed significantly elevated mRNA levels of NLRC4, CASP1, and GSDMD-N in AS patients. ROC curve analysis indicated their potential diagnostic utility. Positive correlations were observed between NLRC4/CASP1 expression and both ESR and ASDAS scores, with higher expression levels noted in patients with ASDAS ≥ 2.1. Bioinformatics data confirmed NLRC4 upregulation and its association with pyroptosis-related pathways, including REACTOME and GOBP. Transduced THP-1 cells showed marked increase in both mRNA and protein levels of NLRC4, CASP1, and GSDMD-N.
Inflammasomes are intracellular multiprotein complexes that play a critical role in coordinating anti-pathogenic host defenses during inflammatory responses, particularly in myeloid cells such as macrophages. Upon activation, inflammasomes initiate a cascade that activates caspase-1, leading to pyroptosis, an inflammatory form of programmed cell death, and the release of key pro-inflammatory cytokines, including interleukin (IL)-1β and IL-18. While these responses are essential components of the innate immune defense, persistent or dysregulated inflammation is a major driver of rheumatic diseases such as rheumatoid arthritis, systemic lupus erythematosus, AS, and Sjögren’s syndrome. Given the inflammatory and autoimmune nature of these disorders, it is plausible that inflammasome activation plays a central role in their initiation and progression.
Among the key innate immune sensors, nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are responsible for detecting cytosolic pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Certain NLRs assemble into cytosolic inflammasome complexes that activate caspase-1. Activated caspase-1 cleaves the pore-forming protein gasdermin D (GSDMD), triggering pyroptosis, and simultaneously processes the inactive precursors of IL-1β and IL-18 into their mature, bioactive forms. These cytokines are then released through GSDMD-formed membrane pores, amplifying the inflammatory response. The NAIP (NLR family apoptosis inhibitory proteins)-NLRC4 (NLR family caspase-associated recruitment domain-containing protein 4) inflammasome plays a critical role in the immune response against Gram-negative bacteria. Activation of NLRC4 is initiated by NAIPs recognizing components of the type III secretion system (T3SS) used by pathogens such as Salmonella Typhimurium. Genetic mutations in NAIPs or NLRC4 have been associated with autoinflammatory disorders in humans, highlighting their significance in immune regulation.
The study provided the first evidence establishing the association between pyroptosis and ankylosing spondylitis pathogenesis. The elevated expression patterns of NLRC4, CASP1, and GSDMD-N not only demonstrated diagnostic potential but also exhibited clinically relevant correlations with disease progression parameters. The findings identified the NLRC4-CASP1-GSDMD-N signaling axis as a promising therapeutic target for preventing ankylosing spondylitis progression and intervention strategies.
References
- Lu X, Chen X, Zhao H, Yu X, Jiang M, Cheng L, Li Z, Wu H, Pan Z, Qu L, Gao M, Zhou Q, Cai G, Pan F. Association of NLRC4 inflammasome targeting Caspase1 to regulate monocyte pyroptosis involved in ankylosing spondylitis pathogenesis. Clin Rheumatol. 2025 Jul 10.
- Yi YS. Role of inflammasomes in inflammatory autoimmune rheumatic diseases. Korean J Physiol Pharmacol. 2018 Jan;22(1):1-15.
- Sundaram B, Kanneganti TD. Advances in Understanding Activation and Function of the NLRC4 Inflammasome. Int J Mol Sci. 2021 Jan 21;22(3):1048.