IL-5/IL-13 drive NLRP3 inflammasome-mediated, steroid-resistant AHR in a model of obesity-associated asthma

<b>Introduction:</b> Severe, steroid-resistant (SSR) asthma is the major unmet need in asthma management and obese asthmatics are more likely to have therapy-resistant disease. Recent studies strongly implicate a role for NLRP3 inflammasome responses in driving obesity-associated AHR, however, these studies did not assess its role in steroid resistance or therapeutic modulation in obesity-associated, SSR asthma. <b>Aims and Objectives:</b> To elucidate the role of NLRP3 inflammasome responses in obesity-associated, SSR asthma. <b>Methods:</b> We developed and characterised a novel murine model of high-fat diet (HFD)-induced, obesity-associated, SSR allergic airways disease (SSR AAD) and assessed the effects of steroid treatment. We also assessed the roles and potential for targeting the NLRP3 inflammasome, and IL-5/IL-13 responses, in our model of HFD-induced, obesity-associated, SSR AAD. <b>Results:</b> HFD administration results in increased weight gain and adiposity; and the development of steroid-resistant AHR. Interestingly, HFD-induced obesity results in increased levels of NLRP3 in the airways and caspase-1 activation in the lung, that are suppressed by treatment with the NLRP3 inflammasome-specific inhibitor, MCC950. Furthermore, combinatorial treatment with anti-IL-5 and anti-IL-13 neutralising antibodies suppresses airway NLRP3 inflammasome responses and steroid-resistant AHR in our model. <b>Conclusions:</b> Our study highlights an unrecognised role for HFD-induced, obesity-associated, NLRP3 inflammasome responses in steroid-resistant AHR. Furthermore, we identify a novel role for IL-5 and IL-13 responses upstream of the NLRP3 inflammasome in the development of obesity-associated, SSR asthma.