Sensing cytoplasmic danger signals by the inflammasome

Abstract

Introduction: The innate immune system depends on molecules collectively known as pattern recognition receptors (PRRs) to survey the extracellular space and the cytoplasm for the presence of dangerous pathogens, pathogen-derived molecules, or even self-derived molecular danger signals, which arise from tissue damage. Absent in melanoma 2 (AIM2) is a newly discovered PRR involved in the sensing of dangerous cytosolic DNA produced by infection with DNA viruses.

Discussion: Remarkably, recent studies in AIM2-deficient mice showed that AIM2 is uniquely involved in sensing infection with the intracellular bacteria Francisella tularensis and subsequently triggering caspase-1-mediated pro-inflammatory cytokine production and macrophage cell death, which activate other components of the immune system and eliminate the infected macrophages. Here, we provide an overview of our current understanding of the role of AIM2 in innate immunity against F. tularensis in particular, and how infection of macrophages with this pathogen is thought to activate AIM2.

Fig. 1

A schematic representation of the interferon-inducible HIN-200 family and the AIM2 inflammasome. a Human interferon-inducible HIN-200 family, IFI16, IFIX, MNDA, and AIM2. PYD: pyrin domain involved in protein–protein interactions. HIN-200 domain is a DNA binding domain. b The oligomerized AIM2–DNA complex forms the AIM2 inflammasome, which serves as a molecular platform to recruit ASC through protein–protein interactions between the PYDs of the AIM2 molecules and those of ASC molecules. This causes the ASC molecules to form a large supramolecular cluster called the pyroptosome. Subsequently, the ASC pyroptosome recruits pro-caspase-1 through protein-–protein interactions between the CARDs of the ASC pyroptosome and those of the monomeric pro-caspase-1 molecules. These interactions result in activation of pro-caspase-1 into the active caspase-1 protease.

Fig. 2

A schematic model depicting activation of the AIM2 inflammasome by F. tularensis infection. The bacteria enter macrophages through phagocytosis. Shortly after, the phagosome rapidly acidifies and ruptures releasing the phagocytosed bacteria and some bacterially derived DNA from lysed bacteria. This released DNA activates IRF3 by an as yet uncharacterized mechanism, which transcriptionally induces production of type I interferons. The newly synthesized type I interferons somehow enhance activation of the AIM2 inflammasome through an autocrine signaling pathway involving IFNAR1. The released DNA can also bind to the HIN-200 DNA-binding domain of AIM2. This interaction leads to oligomerization of AIM2 into a large AIM2 inflammasome cluster. The AIM2 inflammasome activates caspase-1 as described in Fig. 1, which in turn processes pro-IL-1β and pro-IL-18 to the active cytokines, IL-1β and IL-18, which induce inflammation. The activated caspase-1 also cleaves a number of cellular proteins leading to pyroptotic cell death. The nature of the caspase-1 substrates that lead to pyroptotic cell death, however, is not yet known.