TPL-2;ERK1/2 signaling promotes host resistance against intracellular bacterial infection by negative regulation of type I interferon production [Set 2]
Analysis of Mtb infected murine macrophages derived from C57Bl/6 WT, TPL2KO, IFNARKO & TPL2IFNAR DKO mice [Set 2]
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of mortality and morbidity worldwide, causing approximately 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 interferon 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 Mtb in murine models through the negative regulation of key pro-inflammatory cytokines and the subsequent Th1 response. We show here, 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 interferon production. The TPL-2-ERK1/2 signalling pathway regulated production by macrophages of several cytokines important in the immune response to Mtb 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 interferon promoted IL-10 production and exacerbated disease. These findings describe an important regulatory mechanism for controlling tuberculosis and reveal mechanisms by which type I interferon may promote susceptibility to this important disease.
Overall design
Macrophages were derived from C57Bl/6 WT, TPL2KO, IFNARKO & TPL2IFNARKO bone marrow, plated and infected with Mtb H37Rv (or not) in triplicate wells. The indicated samples were also treated with 5ng/ml IFNgamma at the time of infection. Samples were then harvested for RNA at time 0, 1hr and 6hr.
Please note that *Sample and *Medium control samples (e.g. '0hr TPL2-/-IFNabR-/- Sample' vs '0hr TPL2-/-IFNabR-/- Medium Control Sample') are the same sample group (i.e. uninfected) with one group being a repeat re-run of the other (indicated in the correponding SAMPLE description field).
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