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Gasdermin D Promotes AIM2 Inflammasome Activation and Is Required for Host Protection against Francisella novicida.


ABSTRACT: The DNA sensor absent in melanoma 2 (AIM2) forms an inflammasome complex with ASC and caspase-1 in response to Francisella tularensis subspecies novicida infection, leading to maturation of IL-1? and IL-18 and pyroptosis. AIM2 is critical for host protection against F. novicida infection in vivo; however, the role of pyroptosis downstream of the AIM2 inflammasome is unknown. Recent studies have identified gasdermin D (GSDMD) as the molecule executing pyroptosis by forming pores on the plasma membrane following activation by inflammatory caspase-1 and -11. In this study, we report that GSDMD-deficient mice were susceptible to F. novicida infection compared with wild type mice. Interestingly, we observed that GSDMD is required for optimal caspase-1 activation and pyroptotic cell death in F. novicida-infected bone marrow-derived macrophages. Furthermore, caspase-1 activation was compromised in bone marrow-derived macrophages lacking GSDMD stimulated with other AIM2 inflammasome triggers, including poly(dA:dT) transfection and mouse CMV infection. Overall, our study highlights a function, to our knowledge previously unknown, for GSDMD in promoting caspase-1 activation by AIM2 inflammasome.

SUBMITTER: Zhu Q 

PROVIDER: S-EPMC6317867 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Gasdermin D Promotes AIM2 Inflammasome Activation and Is Required for Host Protection against <i>Francisella novicida</i>.

Zhu Qifan Q   Zheng Min M   Zheng Min M   Balakrishnan Arjun A   Karki Rajendra R   Kanneganti Thirumala-Devi TD  

Journal of immunology (Baltimore, Md. : 1950) 20181107 12


The DNA sensor absent in melanoma 2 (AIM2) forms an inflammasome complex with ASC and caspase-1 in response to <i>Francisella tularensis</i> subspecies <i>novicida</i> infection, leading to maturation of IL-1β and IL-18 and pyroptosis. AIM2 is critical for host protection against <i>F. novicida</i> infection in vivo; however, the role of pyroptosis downstream of the AIM2 inflammasome is unknown. Recent studies have identified gasdermin D (GSDMD) as the molecule executing pyroptosis by forming po  ...[more]

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