Receptor interacting protein kinase 2–mediated mitophagy regulates inflammasome activation during virus infection

Lupfer et al. Nat. Immunol. 14: 480-490, 2013

Speaker: Chung-Tend Wang (王崇騰)                                                       Time: 14:00~15:00, April 16, 2014

Commentator: Dr. Hsiao-Sheng Liu (劉校生老師)        )            Place: Room 601

Abstract:

Influenza A virus (IAV) usually causes airway disease, resulting in pulmonary dysfunction and death.¹ The 1918 H1N1 pandemic was characterized by an unusually high incidence of rapid lethality in healthy young adults. Recent studies suggest that infections with highly pathogenic IAV strains were characterized by rapid onset of a proinflammatory “cytokine storm” mediated acute lung injury.² NOD2 receptor and receptor interacting protein kinase 2 (RIPK2) regulate NF-kB and MAP kinase signaling during bacterial infections; however, the role of this immune axis during viral infections has not been addressed.³ In this study, the authors found that Nod2^−/− and Ripk2^−/− mice are hypersusceptible to infection with IAV. Ripk2^−/− cells exhibited defective autophagy of mitochondria (mitophagy), leading to enhanced mitochondrial production of superoxide and accumulation of damaged mitochondria, which resulted in greater activation of the NLRP3inflammasome and production of IL-18. The authors hypothesized that the higher production of IL-18 was responsi­ble for increased inflammation and mortality during IAV infection of Ripk2^−/−mice. In support of this idea, they further showed that neutraliza­tion of IL-18 dampened virus-induced lung pathology and airway neutrophilia, and significantly improved survival. RIPK2 regulatedmitophagy in a kinase-dependent manner by phosphorylating the mitophagy inducer ULK1. Accordingly, Ulk1^−/− cells exhibited enhanced mitochondrial production of superoxide and activation of caspase-1. Taken together, these results demonstrate a role for NOD2-RIPK2 signaling in the protection against virally triggered immunopathology by negatively regulating activation of the NLRP3 inflammasome and production of IL-18 via ULK1-dependent mitophagy.

References

1.     Kilbourne, E.D. Influenza pandemics of the 20th century. Emerg. Infect. Dis. 12, 9–14 (2006).

2.     Kobasa, D. et al. Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. Nature 445, 319–323 (2007).

3.     Cooney, R. et al. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat. Med. 16, 90–97 (2010).