TPL-2-ERK1/2 signaling promotes host resistance against intracellular bacterial infection by negative regulation of type I IFN production

Finlay W. McNab, John Ewbank, Ricardo Rajsbaum, Evangelos Stavropoulos, Anna Martirosyan, Paul S. Redford, Xuemei Wu, Christine M. Graham, Margarida Saraiva, Philip Tsichlis, Damien J. Chaussabel, Steven C. Ley, Anne O'Garra

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51 Citations (Scopus)

Abstract

Tuberculosis, caused by Mycobacterium tuberculosis, remains a leading cause of mortality and morbidity worldwide, causing ~1.4 million deaths per year. Key immune components for host protection during tuberculosis include the cytokines IL-12, IL-1, and TNF-α, as well as IFN-γ and CD4+ Th1 cells. However, immune factors determining whether individuals control infection or progress to active tuberculosis are incompletely understood. Excess amounts of type I IFN have been linked to exacerbated disease during tuberculosis in mouse models and to active disease in patients, suggesting tight regulation of this family of cytokines is critical to host resistance. In addition, the immunosuppressive cytokine IL-10 is known to inhibit the immune response to M. tuberculosis in murine models through the negative regulation of key proinflammatory cytokines and the subsequent Th1 response. We show in this study, using a combination of transcriptomic analysis, genetics, and pharmacological inhibitors, that the TPL-2-ERK1/2 signaling pathway is important in mediating host resistance to tuberculosis through negative regulation of type I IFN production. The TPL-2-ERK1/2 signaling pathway regulated production by macrophages of several cytokines important in the immune response to M. tuberculosis as well as regulating induction of a large number of additional genes, many in a type I IFN-dependent manner. In the absence of TPL-2 in vivo, excess type I IFN promoted IL-10 production and exacerbated disease. These findings describe an important regulatory mechanism for controlling tuberculosis and reveal mechanisms by which type I IFN may promote susceptibility to this important disease.

Original languageEnglish
Pages (from-to)1732-1743
Number of pages12
JournalJournal of Immunology
Volume191
Issue number4
DOIs
Publication statusPublished - 15 Aug 2013
Externally publishedYes

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ASJC Scopus subject areas

  • Immunology

Cite this

McNab, F. W., Ewbank, J., Rajsbaum, R., Stavropoulos, E., Martirosyan, A., Redford, P. S., Wu, X., Graham, C. M., Saraiva, M., Tsichlis, P., Chaussabel, D. J., Ley, S. C., & O'Garra, A. (2013). TPL-2-ERK1/2 signaling promotes host resistance against intracellular bacterial infection by negative regulation of type I IFN production. Journal of Immunology, 191(4), 1732-1743. https://doi.org/10.4049/jimmunol.1300146