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Review
. 2011 Jan;32(1):34-41.
doi: 10.1016/j.it.2010.11.004. Epub 2010 Dec 14.

Inflammasomes as mediators of immunity against influenza virus

Iris K Pang  1 , Akiko Iwasaki
Affiliations
Review

Inflammasomes as mediators of immunity against influenza virus

Iris K Pang et al. Trends Immunol. 2011 Jan.

Abstract

Influenza viruses infect a wide range of avian and mammalian host species including humans. Influenza viruses are a major cause of human respiratory infections and mortality. The innate immune system recognizes influenza viruses through multiple mechanisms. These include endosomal recognition through the Toll-like receptor 7 (TLR7) and cytosolic recognition through the retinoic acid inducible gene I (RIG-I). Recent studies also identified the role of nucleotide binding oligomerization domain (NOD)-like receptors (NLRs) in innate detection of influenza viruses, leading to the activation of the inflammasomes. Here, we review the cellular and molecular mechanisms by which influenza virus infection leads to inflammasome activation, and discuss the consequences of such activation in innate and adaptive immune defense against influenza viruses.

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Conflict of interest statement

Authors declare no conflicts of interest.

Figures

Figure 1
Figure 1. Innate recognition of influenza A virus
Influenza A virus is sensed by at least three different types of PRRs. First, viral single-stranded RNA is recognized by TLR7 in the endosome. Second, the cytosolic sensor RIG-I detects viral ssRNA bearing 5′ triphosphates. TLR7 signals through the adaptor protein, MyD88, which leads to the downstream activation of IRF7 and NF-κB. In contrast, RIG-I signals through the adaptor IPS-I located on the mitochondria for the activation of IRF3 and NF-kB. Activated IRF-7 and IRF-3 can translocate to the nucleus to activate the production of type I interferons while NF-κB acts as a transcription factor for the induction of a proinflammatory cytokines including IL-6, TNF-α, and the pro-form IL-1β. The TLR7 pathway is critical for the production of type I interferons in specialized sentinel cells, pDCs, while most other virally infected cells utilize the RIG-I pathway. Third, influenza A virus activates the NLRP3 inflammasome in dendritic cells and macrophages leading to the activation of caspase-1, which mediates the processing of pro-IL-1β to mature IL-1β and its subsequent release.
Figure 2
Figure 2. Proposed mechanism of NLRP3 inflammasome activation by influenza A virus
Influenza A virus can trigger both signal 1 and signal 2 for the NLRP3 inflammasome activation. Sensing of influenza ssRNA in the endosome by TLR7 induces the transcription of pro-IL-1β and NLRP3. Within the TGN, the influenza-encoded M2 ion channel protein transports protons (H+) out of the lumen, leading to the neutralization of the TGN pH. Ionic imbalance in the Golgi compartment triggers M2-mediated inflammasome activation. The P2X7 receptor, an ATP-gated ion channel that causes potassium (K+) efflux when activated, is partially required for M2-induced inflammasome activation. Lysosomal maturation and the activity of cathepsin B and ROS also play a role in influenza-induced inflammasome activation but the underlying mechanisms remain to be defined.
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