Impaired M. tuberculosis-mediated apoptosis in alveolar macrophages from HIV+ persons: potential role of IL-10 and BCL-3

Abstract

The mechanism of increased MTb disease susceptibility in HIV+ persons remains poorly understood. Apoptosis of macrophages in response to MTb represents a critical host defense response, and decreased apoptosis may represent a mechanism of increased susceptibility to MTb in HIV. In the current study, MTb-mediated apoptosis of human AM was reduced in HIV+ subjects compared with healthy subjects in a TNF-alpha-dependent manner. IL-10 levels in BALF from HIV+ persons were significantly elevated compared with HIV- persons, and exogenous IL-10 reduced MTb-mediated apoptosis in healthy AM, suggesting that IL-10 could mediate decreased apoptosis observed in HIV. Further study showed that IL-10 reduced TNF release in response to MTb in AM through a reduction in TNF mRNA levels, and exogenous TNF could partially reverse IL-10-associated effects on AM apoptosis. IL-10 did not influence p-IRAK, IkappaB degradation, or NF-kappaB p65 nuclear translocation in response to MTb, but IL-10 did increase levels of AM BCL-3, an inhibitor of NF-kappaB nuclear activity. BCL-3 knockdown in human macrophages increased MTb-mediated TNF release. Importantly, BCL-3 levels in AM from HIV+ subjects were higher compared with healthy subjects. Taken together, these data suggest that elevated lung levels of IL-10 may impair MTb-mediated AM apoptosis in HIV through a BCL-3-dependent mechanism. BCL-3 may represent a potential therapeutic target to treat or prevent MTb disease in HIV+ persons.

Vitamin D Rescues Impaired Mycobacterium tuberculosis-Mediated Tumor Necrosis Factor Release in Macrophages of HIV-Seropositive Individuals through an Enhanced Toll-Like Receptor Signaling PathwayIn Vitro

“…Differences in the magnitude of observed biological responses in comparing HIV ϩ U1 macrophage cell lines and alveolar macrophages from HIV ϩ persons may in part reflect differences in the level of HIV infection (as 100% of U1 macrophages contain the HIV genome, whereas Ͻ10% of human alveolar macrophages contain the HIV genome) (7,28,33,34). The use of irradiated virulent M. tuberculosis may not accurately predict the influence of live M. tuberculosis on human macrophage function, although we previously observed similar human macrophage TNF responses in comparing irradiated to live M. tuberculosis H37Rv (7,8). The use of irradiated M. tuberculosis did not allow determination of the influence of 1,25D 3 on M. tuberculosis growth.…”

“…However, the underlying predisposing mechanisms, particularly in HIV ϩ persons with relatively preserved CD4 ϩ T-lymphocyte counts, remain incompletely understood (3)(4)(5). Alveolar macrophages (AMs) represent a critical cell type in the host defense response to M. tuberculosis (6), and alveolar macrophages from HIV ϩ persons demonstrate specific and targeted impairment of critical host cell responses, including impaired M. tuberculosis-mediated tumor necrosis factor (TNF) release and macrophage apoptosis (7), which may be related in part to interleukin-10 (IL-10)-mediated upregulation of BCL3 (8). Preliminary data suggest that M. tuberculosis-mediated macrophage apoptosis may be restored by exogenous TNF, suggesting that alveolar macrophages from HIV ϩ persons are not irreversibly impaired and may be responsive to immunomodulation (7).…”

HIV-1/Mycobacterium tuberculosisCoinfection Immunology: How Does HIV-1 Exacerbate Tuberculosis?

“…HIV decreases responsiveness to M. tuberculosis ex vivo. Macrophage apoptosis appears to be a critical immune response to M. tuberculosis during coinfection (61,72,73,76). Although it is not fully understood, HIV infection of alveolar macrophages from healthy adults (73) or HIV ϩ adults (72) is associated with reduced M. tuberculosis-induced apoptosis compared to that of macrophages infected with M. tuberculosis alone.…”

“…HIV appears to manipulate both apoptosis (72,73) and the ability of macrophages to acidify M. tuberculosis-infected phagosomes (22,67). These changes in macrophage function may increase the risk of developing active or reactivated TB in coinfected patients.…”

Novel Developments in the Epidemic of Human Immunodeficiency Virus and Tuberculosis Coinfection

“…Whereas asymptomatic HIV infection does not affect the intracellular growth of MTb (43,54), AMs from asymptomatic HIV-infected subjects have increased phagocytosis of MTb (54,55), decreased release of specific cytokines and chemokines (56), and similarly impaired MTb phagosomal maturation (49) compared with AMs from healthy subjects. AMs from HIV-infected subjects also have decreased apoptosis in response to MTb (55) (see Figure 2); the mechanism may involve increased lung levels of IL-10 in HIV, which up-regulates BCL-3 (B-cell lymphoma 3-encoded protein), an apoptosis inhibitor (57). HIV infection of macrophages also inhibits autophagy (58), another cellular process that may be critical for macrophage intracellular killing of MTb (59).…”