TY - JOUR
T1 - 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
AU - Liang, Yuejin
AU - Yi, Panpan
AU - Yuan, Denley Ming Kee
AU - Jie, Zuliang
AU - Kwota, Zakari
AU - Soong, Lynn
AU - Cong, Yingzi
AU - Sun, Jiaren
N1 - Funding Information:
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).
Publisher Copyright:
© 2017, The Chinese Society of Immunology and The University of Science and Technology of China, All rights reserved.
PY - 2019/2/1
Y1 - 2019/2/1
N2 - 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.
AB - 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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U2 - 10.1038/cmi.2017.147
DO - 10.1038/cmi.2017.147
M3 - Article
C2 - 29400707
AN - SCOPUS:85056655044
SN - 1672-7681
VL - 16
SP - 126
EP - 137
JO - Cellular and Molecular Immunology
JF - Cellular and Molecular Immunology
IS - 2
ER -