1. Lack of IL-1 Receptor-Associated Kinase-4 Leads to Defective Th1 Cell Responses and Renders Mice Susceptible to Mycobacterial Infection.
- Author
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Marinho FV, Fahel JS, Scanga CA, Gomes MT, Guimarães G, Carvalho GR, Morales SV, Báfica A, and Oliveira SC
- Subjects
- Adaptive Immunity, Animals, Bacterial Load, Caspase 1 genetics, Caspase 1 metabolism, Cell Line, Dendritic Cells immunology, Dendritic Cells microbiology, Humans, Immunity, Innate, Interleukin-12 metabolism, Interleukin-1beta metabolism, Liver microbiology, Liver pathology, Lung microbiology, Macrophages immunology, Macrophages pathology, Mice, Mitogen-Activated Protein Kinase Kinases immunology, Mitogen-Activated Protein Kinase Kinases metabolism, Monocytes drug effects, Monocytes microbiology, Mycobacterium bovis growth & development, Mycobacterium bovis immunology, Mycobacterium bovis pathogenicity, NF-kappa B metabolism, Signal Transduction, Spleen microbiology, Th1 Cells immunology, Tuberculin immunology, Tuberculosis metabolism, Tumor Necrosis Factor-alpha metabolism, Interleukin-1 Receptor-Associated Kinases deficiency, Interleukin-1 Receptor-Associated Kinases metabolism, Macrophages metabolism, Macrophages microbiology, Th1 Cells pathology, Tuberculosis immunology
- Abstract
The Toll-like and IL-1 family receptors play critical roles in innate and adaptive immunity against intracellular pathogens. Although previous data demonstrated the importance of TLRs and IL-1R signaling events for the establishment of an effective immune response to mycobacteria, the possible function of the adaptor molecule IL-1R-associated kinase (IRAK)-4 against this pathogen has not been addressed. In this study, we determined the role of IRAK-4 in signaling pathways responsible for controlling mycobacterial infections. This kinase is important for the production of IL-12 and TNF-α by macrophages and dendritic cells exposed to mycobacteria. Moreover, Mycobacterium bovis-infected IRAK-4-knockout macrophages displayed impaired MAPK and NF-κB activation. IL-1β secretion and caspase-1 activation were also dependent on IRAK-4 signaling. Mice lacking IRAK-4 showed increased M. bovis burden in spleen, liver, and lungs and smaller liver granulomas during 60 d of infection compared with wild-type mice. Furthermore, 80% of IRAK-4(-/-) mice succumbed to virulent M. tuberculosis within 100 d following low-dose infection. This increased susceptibility to mycobacteria correlated with reduced IFN-γ/TNF-α recall responses by splenocytes, as well as fewer IL-12p70-producing APCs. Additionally, we observed that IRAK-4 is also important for the production of IFN-γ by CD4(+) T cells from infected mice. Finally, THP-1 cells treated with an IRAK-4 inhibitor and exposed to M. bovis showed reduced TNF-α and IL-12, suggesting that the results found in mice can be extended to humans. In summary, these data demonstrate that IRAK-4 is essential for innate and adaptive immunity and necessary for efficient control of mycobacterial infections., (Copyright © 2016 by The American Association of Immunologists, Inc.)
- Published
- 2016
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