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

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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-1β 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.

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Acknowledgments

We thank Drs Junying Yuan (Harvard University) for anti-mouse caspase-1 antibody, Junji Sagara for antibody to mouse ASC, Eicke Latz for the immortalized NLRP3-KO, NLRC4-KO, and ASC-KO macrophages, Daniel Portnoy for Listeria strains, Howard Young for the J2 retrovirus-producing ψCREJ2 cell line and Maria Covarrubias for technical assistance with confocal microscopy and Charles Scott for critical reading of the manuscript. This work is supported by grants from the National Institute of Health (AG14357 and AR055398 to E.S.A.) and a grant from GlaxoSmithKline.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA

    Jianghong Wu, Teresa Fernandes-Alnemri & Emad S. Alnemri

  2. Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA

    Jianghong Wu, Teresa Fernandes-Alnemri & Emad S. Alnemri

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  1. Jianghong Wu
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Correspondence to Emad S. Alnemri.

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Wu, J., Fernandes-Alnemri, T. & Alnemri, E.S. Involvement of the AIM2, NLRC4, and NLRP3 Inflammasomes in Caspase-1 Activation by Listeria monocytogenes . J Clin Immunol 30, 693–702 (2010). https://doi.org/10.1007/s10875-010-9425-2

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