Spred2 controls the severity of Concanavalin A-induced liver damage by limiting interferon-gamma production by CD4+ and CD8+ T cells
| Autor: | Toshiaki Ohara, Steven L. Kunkel, Teizo Yoshimura, Akihiro Matsukawa, Masayoshi Fujisawa, Chen Cao, Xu Yang, Qiuying Liu, Cuiming Sun |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
CD4-Positive T-Lymphocytes
Liver damage MAPK/ERK pathway Medicine (General) Science (General) T cell CD8-Positive T-Lymphocytes Signal transduction and regulation Interferon-gamma Mice Q1-390 R5-920 Interferon Concanavalin A medicine Animals Cytotoxic T cell CXCL10 Spred2 ComputingMethodologies_COMPUTERGRAPHICS Multidisciplinary Gene-modified mice Interferon-gamma production Chemistry MAPK Molecular biology Repressor Proteins Transplantation medicine.anatomical_structure Liver Medicine CD8 medicine.drug |
| Zdroj: | Journal of Advanced Research, Vol 35, Iss, Pp 71-86 (2022) Journal of Advanced Research |
| ISSN: | 2090-1232 |
| DOI: | 10.1016/j.jare.2021.03.014 |
| Popis: | Graphical abstract Highlights • Spred2-/- mice developed exacerbated Con A-induced liver damage with increased IFNγ production. • MEK/ERK inhibitor U0126 markedly inhibited the damage and reduced IFNγ production. • Neutralization of IFNγ abolished the damage with down-regulated hepatic STAT1 activation. • Depletion of CD4+/CD8+ T cells improved the damage with decreased IFNγ production. • Transplantation of CD4+/CD8+ T cells into RAG1-/- mice reproduced severe liver damage. • Liver damage and IFNγ production were significantly lower in Spred2 transgenic mice. Introduction Mitogen-activated protein kinases (MAPKs) are involved in T cell-mediated liver damage. However, the inhibitory mechanism(s) that controls T cell-mediated liver damage remains unknown. Objectives We investigated whether Spred2 (Sprouty-related, EVH1 domain-containing protein 2) that negatively regulates ERK-MAPK pathway has a biological impact on T cell-mediated liver damage by using a murine model. Methods We induced hepatotoxicity in genetically engineered mice by intravenously injecting Concanavalin A (Con A) and analyzed the mechanisms using serum chemistry, histology, ELISA, qRT-PCR, Western blotting and flow cytometry. Results Spred2-deficient mice (Spred2-/-) developed more sever liver damage than wild-type (WT) mice with increased interferon-γ (IFNγ) production. Hepatic ERK phosphorylation was enhanced in Spred2-/- mice, and pretreatment of Spred2-/- mice with the MAPK/ERK inhibitor U0126 markedly inhibited the liver damage and reduced IFNγ production. Neutralization of IFNγ abolished the damage with decreased hepatic Stat1 activation in Spred2-/- mice. IFNγ was mainly produced from CD4+ and CD8+ T cells, and their depletion decreased liver damage and IFNγ production. Transplantation of CD4+ and/or CD8+ T cells from Spred2-/- mice into RAG1-/- mice deficient in both T and B cells caused more severe liver damage than those from WT mice. Hepatic expression of T cell attractants, CXCL9 and CXCL10, was augmented in Spred2-/- mice as compared to WT mice. Conversely, liver damage, IFNγ production and the recruitment of CD4+ and CD8+ T cells in livers after Con A challenge were lower in Spred2 transgenic mice, and Spred2-overexpressing CD4+ and CD8+ T cells produced lower levels of IFNγ than WT cells upon stimulation with Con A in vitro. Conclusion We demonstrated, for the first time, that Spred2 functions as an endogenous regulator of T cell IFNγ production and Spred2-mediated inhibition of ERK-MAPK pathway may be an effective remedy for T cell-dependent liver damage. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|