journal.ppat.1005783.PDF (7.47 MB)

TPL-2 regulates macrophage lipid metabolism and M2 differentiation to control TH2-mediated immunopathology

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journal contribution
posted on 05.08.2020 by Yashaswini Kannan, Jimena Perez-Lloret, Yanda Li, Lewis J Entwistle, Hania Khouri, Stamatia Papoutsopoulou, Radma Mahmood, Nuha R Mansour, Stanley Ching-Cheng Huang, Edward J Pearce, Luiz Pedro S de Carvalho, Steven C Ley, Mark S Wilson
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.