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.
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
HIGHLIGHTS
Acknowledgment
The authors acknowledge Dr. Ruma Bakshi, B. V. Patel PERD Centre for assistance with the animal experiments. The authors acknowledge Ms. Kavya Thanki for language-editing of the manuscript.
Disclosure statement
The authors declare no conflicts of interest.