14 April, 2009

Nature review: The AIM2 inflammasome

Sensing and destroying foreign microorganisms is essential for the survival of multicellular organisms. The last decade has seen great advances in our understanding of how the body detects and eliminates invading pathogens. Central to this progress was the discovery of the Toll-like receptors (TLRs), a family of germline-encoded membrane receptors that are responsible for detecting microbes. Crucially, these receptors allow the innate immune system to discriminate between 'self' and 'non-self', an ability long known to be utilised by memory T and B cells of the adaptive immune system. The TLRs function by recognising bacterial or viral motifs, called pathogen associated molecular patterns (PAMPs). These PAMPS are essential for the structural integrity of the microbes and so are highly conserved in bacteria, viruses and other microbes. Different TLRs have evolved to detect specific PAMPs, enabling a wide range of directed immune responses to be induced.

Complementing the membrane bound TLRs are several cytoplasmic pathogen recognition receptors which have evolved to recognise intracellular microbes. For example, viral RNA can be detected by TLR3, TLR7, TLR8 and the cytoplasmic receptors RIG-I and MDA-5. Until recently, TLR9 was the sole receptor for viral DNA, however Fernandes-Alnemri et al (1) and Hornung et al (2) have independently published evidence in Nature (Vol 458, March 2009) that the cytoplasmic receptor AIM2 (absent in melanoma 2) also recognises viral DNA, leading to activation of a multi-protein complex called the inflammasome. The inflammasome is responsible for cleaving the proinflammatory cytokines pro-IL1β and pro-IL18 to their active forms, resulting in the recruitment of inflammatory cells to the site of infection. Cleavage of these pro-inflammatory precursors is achieved through the inflammasome-mediated activation of caspase-1, an enzyme that has been extensively studied in both immunology and cancer research.

Figure from Schroder et al (3).

An inflammasome-activating DNA receptor had previously been implicated in the DNA-induced interferon pathway, thus both studies initially searched databases for pyrin domain-containing receptors. The rationale for this was that the hypothetical DNA receptor would require a pyrin domain to bind the inflammasome protein ASC (apoptosis-associated speck-like protein containing a CARD), such as is the case for a family of cytoplasmic pathogen recognition receptors called the Nod-like receptors (Nods). Using this starting point, both groups of researchers identified AIM2, a member of the interferon-inducible HIN-200 family, and showed the ability of the receptor to activate the inflammasome and caspase-1 following synthetic dsDNA stimulation (1,2). Furthermore, Hornung et al also observed a role for AIM2 in innate immunity to dsDNA vaccinia virus (2). These results were corroborated in cells with decreased expression of AIM2, achieved through siRNA or shRNA. Following stimulation of AIM2-deficient cells with dsDNA, decreased caspase-1 activation and IL-1β processing were observed in comparison to AIM2-expressing cells (1,2). AIM2 was also discovered as a cytoplasmic dsDNA receptor independently in a third study by Bürckstümmer et al (4) published in Nature Immunology, in which a combination of genomic and proteomic screens were used to identify the receptor.

This combined work shows that cytoplasmic DNA binds directly to AIM2 resulting in a strong proinflammatory response. This novel mechanism by which our immune system can sense viral or bacterial infection may have therapeutic applications. For example, targeted activation of AIM2 could assist in the elimination of invading pathogens. However, this finding also has implications for autoimmunity, as AIM2 will presumably also sense 'self-DNA' released by apoptotic cells. Thus, inappropriate activation of AIM2 could lead to the overproduction of inflammatory cytokines and type I interferons known to be associated with autoimmune disorders. This makes AIM2 a potential therapeutic target, as blocking the receptor may inhibit the onset of inflammation. It will also be interesting to scan autoimmune patients for single nucleotide polymorphisms or SNPs in the AIM2 mRNA, as it has been shown that mutations in the NLRP3 inflammasome result in constitutive activation, resulting in enhanced and prolonged activation of caspase-1 and secretion of IL-1β.

1. Fernandes-Alnemri et al. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 2009 Mar 26;458(7237):509-13.
2. Hornung et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 2009 Mar 26;458(7237):514-8.
3. Schroder et al. Innate immunity: cytoplasmic DNA sensing by the AIM2 inflammasome. Curr Biol. 2009 Mar 24;19(6):R262-5
4. Bürckstümmer et al. An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nat Immunol 2009 Mar;10(3):266-72.

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