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

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.Cellular and Molecular Immunology advance online publication, 5 February 2018; doi:10.1038/cmi.2017.147.

Neutrophils in liver diseases: pathogenesis and therapeutic targets

“…18 Meanwhile, the higher neutrophil-to-lymphocyte ratio (NLR) at the 24th week after the onset of interferon treatment predicted the elimination of the replicative HCV-RNA strand in the liver during the antiviral treatment of patients with chronic hepatitis C. 19 In a viral hepatitis model induced by lymphocytic choriomeningitis virus infection, deletion of neutrophils increased the viral load, aggravated the T-cell response, and increased liver injury, while IL-33 treatment contributed to reducing liver inflammation by promoting the aggregation and immunosuppressive phenotype transformation of neutrophils within the liver. 20 In acute murine viral hepatitis, increased infiltration of neutrophils into liver tissue is also exacerbated by endogenous IL-33 deficiency. 21 These data indicated that IL-33 might be a target for reducing neutrophil infiltration in hepatitis, and IL-33 targeting therapy might benefit the outcome of viral hepatitis.…”

Mechanisms of action of ruxolitinib in murine models of hemophagocytic lymphohistiocytosis

“…8,16 However, studies using WT mice reveal that neutrophils are also recruited to sites of LCMV infection. [31][32][33][34] Based on this information, we next sought to investigate the contribution of T cells and neutrophils during primary HLH and the effects of ruxolitinib treatment upon them. Therefore, we quantified these lineages in the organs of LCMV-infected Prf1 2/2 mice that had been treated or not with ruxolitinib or aIFN-g.…”

The Pleiotropic Immunomodulatory Functions of IL-33 and Its Implications in Tumor Immunity

“…In a mouse model of choriomeningitis virus-induced hepatitis, IL-33 promoted neutrophil recruitment in the liver and dampened liver injury by limiting T-cell activation. Liver neutrophils displayed an immunosuppressive phenotype, characterized by high levels of arginase-1, iNOS and IL-10 ( 87 ). Thus, IL-33 may promote inflammatory or regulatory neutrophils, depending on the pathological condition.…”