Association of NLRP3 rs10754558 polymorphism with inflammasome-related cytokine responses in chronic spontaneous urticaria

Abstract

Background Chronic spontaneous urticaria (CSU) is a clinically heterogeneous inflammatory condition affecting the skin, in which mechanisms beyond histamine-mediated mast cell activation are increasingly recognized. Dysregulation of innate immune pathways, including inflammasome signaling, may contribute to disease pathogenesis. Within the inflammasome family, NOD-like receptor pyrin domain–containing protein 3 (NLRP3) rs10754558 polymorphism has been implicated in altered cytokine responses in other inflammatory conditions. This study aimed to investigate the association between NLRP3 rs10754558 polymorphism and CSU susceptibility, and to examine its relationship with inflammasome-related cytokine responses (interleukin-1β [IL-1β] and IL-18). Methods Fifty-six patients with CSU and 56 age- and sex-matched healthy controls were recruited. Genotyping of NLRP3 rs10754558 was performed. Whole blood cultures were stimulated with lipopolysaccharide (LPS) to assess IL-1β and IL-18 production. Clinical and laboratory parameters, including the urticaria activity score (UAS7), autologous serum skin test (ASST) reactivity, erythrocyte sedimentation rate (ESR), and total serum IgE, were also evaluated. Results The C allele of NLRP3 rs10754558 was significantly associated with increased CSU risk across multiple genetic models. CSU patients showed higher LPS-stimulated IL-1β and IL-18 levels than controls, with C/C genotype carriers exhibiting the highest responses. IL-1β and IL-18 showed a modest positive correlation (r = 0.37), and cytokine responses showed limited associations with conventional severity measures. Conclusions The NLRP3 rs10754558 C allele is associated with heightened systemic inflammasome-related cytokine responses in CSU. These findings are associative and indicate a potential link between genetic variation and innate immune responsiveness, while direct mechanistic confirmation of NLRP3 inflammasome activation in CSU remains to be investigated.