Comparative Effects of Tamoxifen on NLRP3 Inflammasome Activation and IL-1β Secretion in Obese and Non-Obese Horses with Asthma

Equine asthma is a chronic neutrophilic airway disease that can be exacerbated by obesity, an immunometabolic condition increasingly linked to activation of the NLRP3 inflammasome and the release of interleukin-1 beta (IL-1β). Tamoxifen, a selective oestrogen receptor modulator with immunomodulatory properties independent of its hormonal action, has previously been shown to reduce neutrophilic airway inflammation in horses, although its effect on NLRP3 inflammasome activation remains unknown. This study aimed to determine whether tamoxifen modulates NLRP3, ASC and caspase-1 gene expression, and IL-1β production, in neutrophils isolated from obese and non-obese asthmatic horses in clinical remission (n = 3 per group), using an in vitro model of inflammasome activation induced with lipopolysaccharide (LPS) and nigericin. Gene expression was assessed by RT-qPCR and IL-1β secretion by ELISA. LPS–nigericin stimulation markedly increased NLRP3 and IL-1β expression in both groups; co-treatment with tamoxifen (5 µM) significantly attenuated the LPS–nigericin-induced increase in NLRP3 expression irrespective of body condition, without affecting ASC or caspase-1. By contrast, tamoxifen significantly reduced IL-1β gene expression and secretion specifically in neutrophils from obese horses, whereas non-obese horses showed little or no response. Obese horses also exhibited higher basal IL-1β gene expression and serum concentrations than non-obese horses. These findings indicate that tamoxifen modulates NLRP3 inflammasome activation and that its effect on IL-1β is body condition-dependent, supporting its potential as an immunomodulatory agent for neutrophilic, obesity-associated equine asthma.