title: TPL-2-ERK1/2 signaling promotes host resistance against intracellular bacterial infection by negative regulation of type I IFN production.
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.
authors.affiliation: Division of Immunoregulation, Medical Research Council, National Institute for Medical Research, London NW7 1AA, United Kingdom. fmcnab@nimr.mrc.ac.uk
authors.forename: Finlay W
authors.initials: FW
authors.lastname: McNab
authors.forename: John
authors.initials: J
authors.lastname: Ewbank
authors.forename: Ricardo
authors.initials: R
authors.lastname: Rajsbaum
authors.forename: Evangelos
authors.initials: E
authors.lastname: Stavropoulos
authors.forename: Anna
authors.initials: A
authors.lastname: Martirosyan
authors.forename: Paul S
authors.initials: PS
authors.lastname: Redford
authors.forename: Xuemei
authors.initials: X
authors.lastname: Wu
authors.forename: Christine M
authors.initials: CM
authors.lastname: Graham
authors.forename: Margarida
authors.initials: M
authors.lastname: Saraiva
authors.forename: Philip
authors.initials: P
authors.lastname: Tsichlis
authors.forename: Damien
authors.initials: D
authors.lastname: Chaussabel
authors.forename: Steven C
authors.initials: SC
authors.lastname: Ley
authors.forename: Anne
authors.initials: A
authors.lastname: O'Garra
mesh_terms: D000818:Animals; D058491:Bacterial Load; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D060467:Disease Resistance; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology*; D007370:Interferon Type I / Q000096:biosynthesis* / Q000235:genetics; D016753:Interleukin-10 / Q000276:immunology; D008089:Listeria monocytogenes / Q000276:immunology / Q000302:isolation & purification; D008088:Listeriosis / Q000276:immunology; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000302:isolation & purification; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000276:immunology*; D014158:Transcription, Genetic; D014376:Tuberculosis / Q000276:immunology*
chemical_list: D016207:Cytokines; C556062:IL10 protein, mouse; D007370:Interferon Type I; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D016753:Interleukin-10; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse