Lack of IL-1 Receptor-Associated Kinase-4 Leads to Defective Th1 Cell Responses and Renders Mice Susceptible to Mycobacterial Infection

• Published in: The Journal of immunology (1950) Vol. 197; no. 5; pp. 1852 - 1863
• Main Authors: Marinho, Fábio V, Fahel, Júlia S, Scanga, Charles A, Gomes, Marco Tulio R, Guimarães, Gabriela, Carvalho, Gabrielle R M, Morales, Stefanny V, Báfica, André, Oliveira, Sergio Costa
• Format: Journal Article
• Language: English
• Published: United States 01.09.2016
• Subjects: Adaptive Immunity; Animals; Bacterial Load; Caspase 1 - genetics; Caspase 1 - metabolism; Cell Line; Dendritic Cells - immunology; Dendritic Cells - microbiology; Humans; Immunity, Innate; Interleukin-1 Receptor-Associated Kinases - deficiency; Interleukin-1 Receptor-Associated Kinases - metabolism; Interleukin-12 - metabolism; Interleukin-1beta - secretion; Liver - microbiology; Liver - pathology; Lung - microbiology; Macrophages - immunology; Macrophages - metabolism; Macrophages - microbiology; Macrophages - pathology; Mice; Mitogen-Activated Protein Kinase Kinases - immunology; Mitogen-Activated Protein Kinase Kinases - metabolism; Monocytes - drug effects; Monocytes - microbiology; Mycobacterium; Mycobacterium bovis - growth & development; Mycobacterium bovis - immunology; Mycobacterium bovis - pathogenicity; NF-kappa B - metabolism; Signal Transduction; Spleen - microbiology; Th1 Cells - immunology; Th1 Cells - pathology; Tuberculin - immunology; Tuberculosis - immunology; Tuberculosis - metabolism; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1502157

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.