ZBP1 governs the inflammasome-independent IL-1α and neutrophil inflammation that play a dual role in anti-influenza virus immunity

Int Immunol. 2020 Mar 7;32(3):203-212. doi: 10.1093/intimm/dxz070.

Masatoshi Momota ¹ ² ³, Patrick Lelliott ⁴, Atsuko Kubo ¹, Takato Kusakabe ¹ ² ³, Kouji Kobiyama ¹ ⁵ ⁶, Etsushi Kuroda ¹ ³ ⁷, Yumiko Imai ⁸, Shizuo Akira ⁹, Cevayir Coban ⁴ ⁶ ¹⁰, Ken J Ishii ¹ ² ³ ⁵ ⁶

Affiliations

1 Laboratory of Adjuvant Innovation, Center for Vaccine and Adjuvant Research Center (CVAR), National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan.
2 Laboratory of Mockup Vaccine, Center for Vaccine and Adjuvant Research Center (CVAR), National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan.
3 Laboratory of Vaccine Science, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan.
4 Malaria Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan.
5 Division of Vaccine Science, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
6 International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
7 Department of Immunology, Hyogo College of Medicine, Hyogo, Japan.
8 Laboratory of Regulation of Intractable Infectious Diseases, Center for Vaccine and Adjuvant Research Center (CVAR), National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan.
9 Host Defense, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan.
10 Division of Malaria Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

PMID: 31630209 DOI: 10.1093/intimm/dxz070

Abstract

Influenza A virus (IAV) triggers the infected lung to produce IL-1 and recruit neutrophils. Unlike IL-1β, however, little is known about IL-1α in terms of its mechanism of induction, action and physiological relevance to the host immunity against IAV Infection. In particular, whether Z-DNA-binding protein 1 (ZBP1), a key molecule for IAV-induced cell death, is involved in the IL-1α induction, neutrophil infiltration and the physiological outcome has not been elucidated. Here, we show in a murine model that the IAV-induced IL-1α is mediated solely by ZBP1, in an NLRP3-inflammasome-independent manner, and is required for the optimal IL-1β production followed by the formation of neutrophil extracellular traps (NETs). During IAV Infection, ZBP1 displays a dual role in anti-IAV immune responses mediated by neutrophils, resulting in either protective or pathological outcomes in vivo. Thus, ZBP1-mediated IL-1α production is the key initial step of IAV-infected NETs, regulating the duality of the consequent lung inflammation.

Keywords

IL-1; ZBP1; influenza virus; innate immunity; neutrophil.

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