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

Background: During Aspergillus fumigatus mediated lung inflammation, NLRP3 inflammasome is rapidly activated that aggravates IL-1 beta 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 beta-glucan-induced lung inflammation. Methods: We have mimicked the lung inflammation by administering intranasal beta-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-1 beta 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-beta and IL-10 compared to the T cells co-cultured with beta-glucan primed dendritic cells. Caspase-1 inhibition in BMDCs also induced IL-22 secretion from CD4(+)T cells. Caspase-1 inhibition in intranasal beta-glucan administered mice showed decreased tissue damage, immune cell infiltration and IgA secretion compared to control mice. Further, splenocytes challenged with beta-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.

Automated summary

Inhibition of caspase-1 can reduce inflammasome activation and IL-1β secretion, leading to decreased tissue damage and immune cell infiltration in β-glucan-induced lung inflammation.