Research Article

IL-33 induces immunosuppressive neutrophils via a type 2 innate lymphoid cell/IL-13/STAT6 axis and protects the liver against injury in LCMV infection-induced viral hepatitis

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Abstract

Viral hepatitis is still a public health problem affecting several million people around the world. Neutrophils are polymorphonuclear cells that have a critical role in antibacterial infection. However, the role of neutrophils in viral infection is not fully understood. By using a mouse model of lymphocytic choriomeningitis virus infection-induced viral hepatitis, we observed increased neutrophil recruitment in the liver accompanied by enhanced CD8+ T-cell responses. Liver neutrophils expressed high levels of immunomodulatory cytokines, such as C-X-C chemokine ligand 2, arginase-1, inducible nitric oxide synthase and interleukin (IL)-10, demonstrating immunosuppressive properties. Depletion of neutrophils in vivo by a neutralizing antibody resulted in the exacerbation of liver injury and the promotion of T-cell responses at the immune contraction stage. IL-33 significantly induced neutrophil recruitment in the liver and attenuated liver injury by limiting effector T-cell accumulation. Mechanistically, we found that IL-33 promoted the expression of arginase-1 in neutrophils through the type 2 innate lymphoid cell (ILC2)-derived IL-13. Additionally, IL-13 increased the inhibitory effect of neutrophils on CD8+ T-cell proliferation in vitro, partially through arginase-1. Finally, we found that IL-13 induced arginase-1 expression, depending on signal transducer and activator of transcription factor 6 (STAT6) signaling. Therefore, IL-33 induced immunosuppressive neutrophils via an ILC2/IL-13/STAT6 axis. Collectively, our findings shed new light on the mechanisms associated with IL-33-triggered neutrophils in the liver and suggest potential targets for therapeutic investigation in viral hepatitis.

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Acknowledgements

We thank Ms Mardelle Susman and Dr Linsey Yeager for assistance with manuscript preparation. We express our gratitude to other members of the UTMB Joint Immunology Working Group (Dr Stephens, Dr Rajsbaum and Dr Hu, as well as their trainees) for many helpful discussions. This work was supported, in part, by grants from the NIH (AI109100 and AI126371 to JS). PY was a visiting scientist partially supported by the Department of Infectious Diseases, Xiangya Hospital, China and the Natural Science Foundation of Hunan Province (no. 14JJ6003). DMKY and ZK were recipients of summer internships from an NIAID T35 training grant (AI078878, PI: LS).

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Affiliations

  1. Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1070, USA

    • Yuejin Liang
    • , Panpan Yi
    • , Denley Ming Kee Yuan
    • , Zuliang Jie
    • , Zakari Kwota
    • , Lynn Soong
    • , Yingzi Cong
    •  & Jiaren Sun
  2. Department of Infectious Diseases, Key Laboratory of Viral Hepatitis of Hunan, Xiangya Hospital, Central South University, Changsha 410008, China

    • Panpan Yi
  3. Pathology and Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555-1070, USA

    • Lynn Soong
    • , Yingzi Cong
    •  & Jiaren Sun

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The authors declare no conflict of interest.

Corresponding authors

Correspondence to Yuejin Liang or Jiaren Sun.

Supplementary information

Supplementary Information for this article can be found on the Cellular & Molecular Immunology website (http://www.nature.com/cmi)