Caspase-1 inhibits IFN-β production via cleavage of cGAS during M. bovis infection.

Mycobacterium bovis (M. bovis) infection triggers cytokine production via pattern recognition receptors. These cytokines include type I interferons (IFNs) and interleukin-1β (IL-1β). Excessive type I IFN levels impair host resistance to M. bovis infection. Therefore, strict control of type I IFN production is helpful to reduce pathological damage and bacterial burden. Here, we found that a deficiency in caspase-1, which is the critical component of the inflammasome responsible for IL-1β production, resulted in increased IFN-β production upon M. bovis infection. Subsequent experiments demonstrated that caspase-1 activation reduced cyclic GMP-AMP synthase (cGAS) expression, thereby inhibiting downstream TANK-binding kinase 1 (TBK1)- interferon regulatory factor 3 (IRF3) signaling and ultimately reducing IFN production. A deficiency in caspase-1 activation enhanced the bacterial burden during M. bovis infection in vitro and in vivo and aggravated pathological lesion formation. Thus, caspase-1 activation reduced IFN-β production upon M. bovis infection by dampening cGAS-TBK1-IRF3 signaling, suggesting that the inflammasome protects hosts by negatively regulating harmful cytokines.