Abstract
Nrf2 is a redox-sensitive transcription factor that is thought to be important in protection against intracellular pathogens. To determine the protective role of Nrf2 in the host defense against Mycobacterium avium complex (MAC), both wild-type and Nrf2-deficient mice were intranasally infected with MAC bacteria. Nrf2-deficient mice were highly susceptible to MAC bacteria compared with wild-type mice. There were no significant changes in the levels of oxidative stress and Th1 cytokine production between genotypes. Comprehensive transcriptome analysis showed that the expressions of Nramp1 and HO-1 were much lower in the infected lungs, and the expression of Nramp1 was especially lower in alveolar macrophages of Nrf2-deficient mice than of wild-type mice. Electron microscopy showed that many infected alveolar macrophages from Nrf2-deficient mice contained a large number of intracellular MAC bacteria with little formation of phagolysosomes, compared with those from wild-type mice. Treatment with sulforaphane, an activator of Nrf2, increased resistance to MAC with increased lung expression of Nramp1 and HO-1 in wild-type mice. These results indicate that Nramp1 and HO-1, regulated by Nrf2, are essential in defending against MAC infection due to the promotion of phagolysosome fusion and granuloma formation, respectively. Thus, Nrf2 is thought to be a critical determinant of host resistance to MAC infection.IMPORTANCE Nontuberculous mycobacteria (NTM) are an important cause of morbidity and mortality in pulmonary infections. Among them, Mycobacterium avium complex (MAC) is the most common cause of pulmonary NTM disease worldwide. It is thought that both environmental exposure and host susceptibility are required for the establishment of pulmonary MAC disease, because pulmonary MAC diseases are most commonly observed in slender, postmenopausal women without a clearly recognized immunodeficiency. However, host factors that regulate MAC susceptibility have not been elucidated until now. This study shows that Nrf2 is a critical regulator of host susceptibility to pulmonary MAC disease by promoting phagolysosome fusion and granuloma formation via activating Nramp1 and HO-1 genes, respectively. The Nrf2 system is activated in alveolar macrophages, the most important cells during MAC infection, as both the main reservoir of infection and bacillus-killing cells. Thus, augmentation of Nrf2 might be a useful therapeutic approach for protection against pulmonary MAC disease.
Highlights
Nrf2 is a redox-sensitive transcription factor that is thought to be important in protection against intracellular pathogens
Organ CFU measurement showed elevated mycobacterial counts in lungs, livers, and spleens of Nrf22/2 mice relative to those in wild-type mice 2 months after Mycobacterium avium complex (MAC) infection (Fig. 1C). These results indicate that mice lacking Nrf2 are highly susceptible to MAC infection
The present study demonstrates that Nrf2 plays an important role in protection against pulmonary MAC infection
Summary
Nrf is a redox-sensitive transcription factor that is thought to be important in protection against intracellular pathogens. Electron microscopy showed that many infected alveolar macrophages from Nrf2-deficient mice contained a large number of intracellular MAC bacteria with little formation of phagolysosomes, compared with those from wild-type mice. An activator of Nrf, increased resistance to MAC with increased lung expression of Nramp and HO-1 in wild-type mice These results indicate that Nramp and HO-1, regulated by Nrf, are essential in defending against MAC infection due to the promotion of phagolysosome fusion and granuloma formation, respectively. This study shows that Nrf is a critical regulator of host susceptibility to pulmonary MAC disease by promoting phagolysosome fusion and granuloma formation via activating Nramp and HO-1 genes, respectively. Aging is related to PNTM disease regardless of sex [7] These findings suggest that host factors are associated with the development and progression of pulmonary MAC disease. Unlike the IL-12/ IFN-g axis in disseminated MAC disease, host susceptibility factors have not been explained in pulmonary MAC disease
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