Caspase-1 inhibition by YVAD generates tregs pivoting IL-17 to IL-22 response in β-glucan induced airway inflammation

Abstract

Background During Aspergillus fumigatus mediated lung inflammation, NLRP3 inflammasome is rapidly activated that aggravates IL-1β production contributing to lung inflammation. Previously, we have shown the protective role of SYK-1 inhibition in inhibiting inflammasome activation during lung inflammation. In the current manuscript, we explored the protective role of direct caspase-1 inhibition during β-glucan-induced lung inflammation. Methods We have mimicked the lung inflammation by administering intranasal β-glucan in mice model. YVAD was used for caspase-1 inhibition. Results We have shown that caspase-1 inhibition by YVAD did not alter inflammasome independent inflammatory cytokines, while it significantly reduced inflammasome activation and IL-1β secretion. Caspase-1 inhibited bone marrow derived dendritic cells (BMDCs), co-cultured with T cells showed decreased T-cell proliferation and direct them to secrete high TGF-β and IL-10 compared to the T cells co-cultured with β-glucan primed dendritic cells. Caspase-1 inhibition in BMDCs also induced IL-22 secretion from CD4+T cells. Caspase-1 inhibition in intranasal β-glucan administered mice showed decreased tissue damage, immune cell infiltration and IgA secretion compared to control mice. Further, splenocytes challenged with β-glucan show high IL-10 secretion and increased FOXp3 and Ahr indicating an increase in regulatory T cells on caspase-1 inhibition. Conclusion Caspase-1 inhibition can thus be an attractive target to prevent inflammation mediated tissue damage during Aspergillus fumigatus mouse model and can be explored as an attractive therapeutic strategy. HIGHLIGHTS Caspase-1 inhibition protects lung damage from inflammation during β-glucan exposure Caspase-1 inhibition in dendritic cells decreases IL-1β production resulting in decreased pathogenic Th17 Caspase-1 inhibition promotes regulatory T cells thereby inhibiting lung inflammation