Attenuated heme oxygenase-1 responses predispose the elderly to pulmonary nontuberculous mycobacterial infections
Ranu Surolia1, Suman Karki1, Zheng Wang1
1Department of Medicine, Division of Pulmonary, Allergy and Critical Care, University of Alabama at Birmingham, Birmingham, Alabama.
Abstract:
Pulmonary infections with nontuberculous mycobacteria (P-NTM), such as by Mycobacterium avium complex (M. avium), are increasingly found in the elderly, but the underlying mechanisms are unclear. Recent studies suggest that adaptive immunity is necessary, but not sufficient, for host defense against mycobacteria. Heme oxygenase-1 (HO-1) has been recognized as a critical modulator of granuloma formation and programmed cell death in mycobacterial infections. Old mice (18-21 mo) infected with M. avium had attenuated HO-1 response with diffuse inflammation, high burden of mycobacteria, poor granuloma formation, and decreased survival (45%), while young mice (4-6 mo) showed tight, well-defined granuloma, increased HO-1 expression, and increased survival (95%). To further test the role of HO-1 in increased susceptibility to P-NTM infections in the elderly, we used old and young HO-1+/+ and HO-1-/- mice. The transcriptional modulation of the JAK/STAT signaling pathway in HO-1-/- mice due to M. avium infection demonstrated similarities to infected wild-type old mice with upregulation of SOCS3 and inhibition of Bcl2. Higher expression of SOCS3 with downregulation of Bcl2 resulted in higher macrophage death via cellular necrosis. Finally, peripheral blood monocytes (PBMCs) from elderly patients with P-NTM also demonstrated attenuated HO-1 responses after M. avium stimulation and increased cell death due to cellular necrosis (9.69% ± 2.02) compared with apoptosis (4.75% ± 0.98). The augmented risk for P-NTM in the elderly is due, in part, to attenuated HO-1 responses, subsequent upregulation of SOCS3, and inhibition of Bcl2, leading to programmed cell death of macrophages, and sustained infection.
Insights
Elderly individuals with pulmonary nontuberculous mycobacteria (P-NTM) infections show weakened Heme oxygenase-1 (HO-1) responses, leading to increased macrophage death and higher infection risk. This study reveals HO-1
Area of Science:
- Immunology
- Aging Research
- Infectious Diseases
Background:
- Pulmonary nontuberculous mycobacteria (P-NTM) infections are rising in the elderly, with unclear underlying mechanisms.
- Heme oxygenase-1 (HO-1) is crucial for controlling mycobacterial infections by modulating granuloma formation and programmed cell death.
- Adaptive immunity is necessary but insufficient for effective host defense against mycobacteria.
Purpose of the Study:
- To investigate the role of Heme oxygenase-1 (HO-1) in the increased susceptibility to pulmonary nontuberculous mycobacteria (P-NTM) infections observed in the elderly.
- To elucidate the molecular mechanisms, including the JAK/STAT pathway, involved in HO-1's impact on macrophage survival and P-NTM infection outcomes.
Main Methods:
- Comparative analysis of HO-1 responses and infection outcomes in young and old HO-1 wild-type and knockout mice infected with Mycobacterium avium.
- Transcriptional analysis of the JAK/STAT signaling pathway, including SOCS3 and Bcl2 expression, in infected mice.
- Assessment of HO-1 response, cell death mechanisms (necrosis vs. apoptosis), and M. avium burden in peripheral blood monocytes (PBMCs) from elderly P-NTM patients.
Main Results:
- Old mice infected with M. avium exhibited attenuated HO-1 responses, diffuse inflammation, poor granuloma formation, and significantly reduced survival (45%) compared to young mice (95%).
- HO-1 knockout mice and old wild-type mice showed similar JAK/STAT pathway dysregulation, including SOCS3 upregulation and Bcl2 inhibition, leading to increased macrophage necrosis.
- Elderly P-NTM patients' PBMCs displayed attenuated HO-1 responses and a higher rate of macrophage necrosis upon M. avium stimulation.
Conclusions:
- Attenuated HO-1 responses contribute to the increased risk of P-NTM infections in the elderly.
- Upregulation of SOCS3 and inhibition of Bcl2, driven by diminished HO-1 activity, promote macrophage necrosis and sustain mycobacterial infections.
- Restoring HO-1 function may represent a therapeutic strategy to improve host defense against P-NTM in aging populations.
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