Nrf2 Regulates Granuloma Formation and Macrophage Activation during Mycobacterium avium Infection via Mediating Nramp1 and HO-1 Expressions

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.

Druggable redox pathways against M. abscessus in cystic fibrosis patient-derived airway organoids

“…By contrast, an oxidative environment has been shown to favour Mabs growth in macrophages (66,67). Moreover, activation of Nrf2 reduces the bacterial burden both in vitro and in vivo (47,48,50,68).…”

MicroRNA-155 Modulates Macrophages’ Response to Non-Tuberculous Mycobacteria through COX-2/PGE2 Signaling

“…The Mycobacterium avium -intracellulare complex strain is a clinical isolate from patients at Emory University Hospital and was kindly provided by Dr. Eileen M Burd. The strain was cultured in Middlebrook 7H9 broth (BD-Difco, Franklin Lakes, NJ, USA), as previously described [ 63 ]. Colony-forming units (CFUs) were determined on Middlebrook 7H11agar plates (BD-Difco).…”

The Role of NRF2 in Mycobacterial Infection

“…Recently, Nakajima et al reported that NRF2-deficient mice were highly susceptible to M. avium bacteria compared to wild-type mice [ 81 ]. Surprisingly, NRF2 did not affect the level of oxidative stress or Th1 cytokine production in this M. avium -infection model.…”

“…Taken together, higher susceptibility of the elderly to pulmonary NTM infection is partly caused by attenuated HO-1 responses, subsequent upregulation of SOCS3 , and inhibition of Bcl2 , leading to programmed cell death of macrophages and sustained infection. Since HO-1 is induced under the influence of NRF2 in young mice in response to NTM infection [ 81 ], it is likely that increased susceptibility to mycobacterial infection in the elderly is related to the decline of NRF2 functions with advancing age.…”

“…These cells showed restored macrophage phagocytosis function and improved bacterial clearance due to the upregulation of the scavenger macrophage receptor with collagenous structure (MARCO) by NRF2 [ 103 ]. Although there are no reports regarding the efficacy of SFN in TB infection, the usefulness of SFN against M. abscessus and M. avium infections has been reported [ 75 , 81 ]. Thus, control of oxidative stress and activation of NRF2 might become novel therapeutic options for treatment of NTM and TB infections.…”