Involvement of the AIM2, NLRC4, and NLRP3 Inflammasomes in Caspase-1 Activation by Listeria monocytogenes

Abstract

Infection with Listeria monocytogenes can cause meningitis and septicemia in newborn, elderly, or immunocompromised individuals. Pregnant women are particularly susceptible to Listeria, leading to a potentially fatal infection. Cytosolic Listeria activates the proinflammatory caspase-1 and induces the processing and secretion of interleukins IL-1beta and IL-18 as well as caspase-1-dependent pyroptosis. This study elucidates the role of various inflammasome components of host macrophages in the proinflammatory response to infection with Listeria. Here, we have used macrophages from AIM2-, NLRC4-, NLRP3-, and ASC-deficient mice to demonstrate that AIM2, NLRC4, and NLRP3 inflammasomes as well as the adaptor protein ASC all contribute to activation of caspase-1 in Listeria-infected macrophages. We show that Listeria DNA, which escapes into the cytosol of infected macrophages, triggers AIM2 oligomerization, caspase-1 activation, and pyroptosis. Interestingly, we found that flagellin-deficient Listeria, like Francisella tularensis, is recognized primarily by the AIM2 inflammasome, as no caspase-1 activation or cell death was observed in AIM2-deficient macrophages infected with this Listeria mutant. We further show that prior priming of NLRC4-deficient macrophages with LPS is sufficient for Listeria-induced caspase-1 activation in these macrophages, suggesting that TLR4 signaling is important for activation of the AIM2 and NLRP3 inflammasomes by Listeria in the absence of NLRC4. Taken together, our results indicate that Listeria infection is sensed by multiple inflammasomes that collectively orchestrate a robust caspase-1 activation and proinflammatory response.