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

Yuejin Liang, Panpan Yi, Denley Ming Kee Yuan, Zuliang Jie, Zakari Kwota, Lynn Soong, Yingzi Cong, Jiaren Sun

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)126-137
Number of pages12
JournalCellular and Molecular Immunology
Volume16
Issue number2
DOIs
StatePublished - Feb 1 2019

Fingerprint

STAT6 Transcription Factor
Lymphocytic choriomeningitis virus
Interleukin-13
Virus Diseases
Immunosuppressive Agents
Hepatitis
Neutrophils
Transcription Factors
Lymphocytes
Arginase
Liver
Wounds and Injuries
T-Lymphocytes
Neutrophil Infiltration
CXC Chemokines
Interleukin-33
Nitric Oxide Synthase Type II
Neutralizing Antibodies
Interleukin-10
Public Health

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

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. / Liang, Yuejin; Yi, Panpan; Yuan, Denley Ming Kee; Jie, Zuliang; Kwota, Zakari; Soong, Lynn; Cong, Yingzi; Sun, Jiaren.

In: Cellular and Molecular Immunology, Vol. 16, No. 2, 01.02.2019, p. 126-137.

Research output: Contribution to journalArticle

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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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