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

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

doi:10.1371/journal.ppat.1005783

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TPL-2 Regulates Macrophage Lipid Metabolism and M2 Differentiation to Control T_H2-Mediated Immunopathology

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Pearce, Edward J.
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1005783
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Citation

Kannan, Y., Perez-Lloret, J., Li, Y., Entwistle, L. J., Khoury, H., Papoutsopoulou, S., et al. (2016). TPL-2 Regulates Macrophage Lipid Metabolism and M2 Differentiation to Control T_H2-Mediated Immunopathology. PLoS Pathogens, 12, e1005783. doi:10.1371/journal.ppat.1005783.

Cite as: https://hdl.handle.net/21.11116/0000-0006-AAC7-A

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.