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TPL-2调节巨噬细胞脂质代谢和M2分化以控制TH2介导的免疫病理。

TPL-2 Regulates Macrophage Lipid Metabolism and M2 Differentiation to Control TH2-Mediated Immunopathology.

作者信息

Kannan Yashaswini, Perez-Lloret Jimena, Li Yanda, Entwistle Lewis J, Khoury Hania, Papoutsopoulou Stamatia, Mahmood Radma, Mansour Nuha R, Ching-Cheng Huang Stanley, Pearce Edward J, Pedro S de Carvalho Luiz, Ley Steven C, Wilson Mark S

机构信息

Allergy and Anti-Helminth Immunity Laboratory, The Francis Crick Institute, London, United Kingdom.

Mycobacterial Metabolism and Antibiotic Research Laboratory, The Francis Crick Institute, London, United Kingdom.

出版信息

PLoS Pathog. 2016 Aug 3;12(8):e1005783. doi: 10.1371/journal.ppat.1005783. eCollection 2016 Aug.

DOI:10.1371/journal.ppat.1005783
PMID:27487182
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4972396/
Abstract

Persistent TH2 cytokine responses following chronic helminth infections can often lead to the development of tissue pathology and fibrotic scarring. Despite a good understanding of the cellular mechanisms involved in fibrogenesis, there are very few therapeutic options available, highlighting a significant medical need and gap in our understanding of the molecular mechanisms of TH2-mediated immunopathology. In this study, we found that the Map3 kinase, TPL-2 (Map3k8; Cot) regulated TH2-mediated intestinal, hepatic and pulmonary immunopathology following Schistosoma mansoni infection or S. mansoni egg injection. Elevated inflammation, TH2 cell responses and exacerbated fibrosis in Map3k8-/-mice was observed in mice with myeloid cell-specific (LysM) deletion of Map3k8, but not CD4 cell-specific deletion of Map3k8, indicating that TPL-2 regulated myeloid cell function to limit TH2-mediated immunopathology. Transcriptional and metabolic assays of Map3k8-/-M2 macrophages identified that TPL-2 was required for lipolysis, M2 macrophage activation and the expression of a variety of genes involved in immuno-regulatory and pro-fibrotic pathways. Taken together this study identified that TPL-2 regulated TH2-mediated inflammation by supporting lipolysis and M2 macrophage activation, preventing TH2 cell expansion and downstream immunopathology and fibrosis.

摘要

慢性蠕虫感染后持续的TH2细胞因子反应通常会导致组织病理学改变和纤维化瘢痕形成。尽管对参与纤维生成的细胞机制有了较好的理解，但可用的治疗选择却非常少，这突出了巨大的医学需求以及我们对TH2介导的免疫病理学分子机制理解上的差距。在本研究中，我们发现丝裂原活化蛋白激酶3（Map3激酶）TPL-2（Map3k8；Cot）在曼氏血吸虫感染或注射曼氏血吸虫卵后调节TH2介导的肠道、肝脏和肺部免疫病理学。在髓系细胞特异性（LysM）缺失Map3k8的小鼠中观察到Map3k8-/-小鼠炎症加剧、TH2细胞反应增强和纤维化加重，但在CD4细胞特异性缺失Map3k8的小鼠中未观察到，这表明TPL-2调节髓系细胞功能以限制TH2介导的免疫病理学。对Map3k8-/- M2巨噬细胞的转录和代谢分析表明，脂解、M2巨噬细胞活化以及多种参与免疫调节和促纤维化途径的基因表达都需要TPL-2。综上所述，本研究确定TPL-2通过支持脂解和M2巨噬细胞活化来调节TH2介导的炎症，防止TH2细胞扩增以及下游免疫病理学和纤维化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3198/4972396/18a3e9319960/ppat.1005783.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3198/4972396/1a9a5db5e685/ppat.1005783.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3198/4972396/cdb5f53dd6b5/ppat.1005783.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3198/4972396/639007649d3a/ppat.1005783.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3198/4972396/9cec4b3eb9c4/ppat.1005783.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3198/4972396/1b9eae12dd76/ppat.1005783.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3198/4972396/00a3fecd9e9f/ppat.1005783.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3198/4972396/18a3e9319960/ppat.1005783.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3198/4972396/1a9a5db5e685/ppat.1005783.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3198/4972396/cdb5f53dd6b5/ppat.1005783.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3198/4972396/639007649d3a/ppat.1005783.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3198/4972396/9cec4b3eb9c4/ppat.1005783.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3198/4972396/1b9eae12dd76/ppat.1005783.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3198/4972396/00a3fecd9e9f/ppat.1005783.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3198/4972396/18a3e9319960/ppat.1005783.g007.jpg

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