Attenuated heme oxygenase-1 responses predispose the elderly to pulmonary nontuberculous mycobacterial infections

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.

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

“…Beside killing bacilli, macrophages play an important role in granuloma formation during mycobacterial infection. HO-1 is an inducible, cytoprotective protein that can be transactivated by Nrf2 in many inflammatory conditions, including mycobacterial infection (36)(37)(38)(39). It was demonstrated that HO-1 plays an important role in granuloma formation and maturation and in prevention of dissemination of MAC infection in a mouse model by regulating MCP-1 and CCR2 expression in monocytes/macrophages (37).…”

Heme Oxygenase-1 as a Pharmacological Target for Host-Directed Therapy to Limit Tuberculosis Associated Immunopathology

“…Similar to Mtb, Mav presents as a pulmonary infection and promotes granuloma formation within the host. To date, several studies identified HO-1 as an essential component in forming the granuloma in mice infected with Mav [21,22,106]. The first of these studies demonstrated that HO-1 is induced in the normal course of Mav infection and is observed within the granuloma in wild type mice, whereas HO-1-deficient mice fail to form organized granulomas [21].…”

Lady Windermere syndrome

“…16 A recent study showed that elderly individuals' peripheral blood cells have decreased heme oxygenase-1 expression after M. avium stimulation. 65 Heme oxygenase-1 is an important modulator in granuloma formation; decreased expression in elderly individuals may lead to poor granuloma formation and a higher disease burden. 66 This could help explain the predilection on LWS for older individuals.…”