Alternative activation deprives macrophages of a coordinated defense program to Mycobacterium tuberculosis

Abstract

A potent Th1 immune response is critical to the control of tuberculosis. The impact of an additive Th2 response on the course of disease has so far been insufficiently characterized, despite increased morbidity after co-infection with Mycobacterium tuberculosis and Th2-eliciting helminths and possible involvement of Th2 polarization in reactivation of latent tuberculosis. Here, we describe the gene expression profile of murine bone marrow-derived macrophages alternatively activated by IL-4 in response to infection with M. tuberculosis. Comparison of transcriptional profiles of infected IL-4-and IFN-c-activated macrophages revealed delayed and partially diminished responses to intracellular bacteria in alternatively activated macrophages, characterized by reduced exposure to nitrosative stress and increased iron availability, respectively. Alternative activation of host macrophages correlated with elevated expression of the M. tuberculosis iron storage protein bacterioferritin as well as reduced expression of the mycobactin synthesis genes mbtI and mbtJ. The extracellular matrix-remodeling enzyme matrix metalloproteinase (MMP)-12 was induced in alternatively activated macrophages in vitro, and MMP-12-expressing macrophages were abundant at late, but not early, stages of tuberculosis in murine lungs. Our findings emphasize that alternative activation deprives macrophages of control mechanisms that limit mycobacterial growth in vivo, thus supporting intracellular persistence of M. tuberculosis.

Differential regulation of iron homeostasis during human macrophage polarized activation

“…4A). These results are in line with the difference in TfR1 expression previously found between IFN-g-activated and IL-4-treated mouse macrophages [31].…”

“…4A). These results are in line with the difference in TfR1 expression previously found between IFN-g-activated and IL-4-treated mouse macrophages [31].We then performed RNA-bandshift assays to assess the activity of IRP, which regulate intracellular iron homeostasis by binding to iron-responsive elements (IRE) in target mRNA [30]. In comparison with M0 macrophages, the combined binding activity of IRP1 and IRP2, which co-migrate in bandshift assays, was lower in cells exposed to LPS/IFN-g (M1) (in line with previous results [17]) and slightly increased in M2 (Fig.…”

A role for IL‐18 in protective immunity against Mycobacterium tuberculosis

“…4C). AAMF have been shown to be compromised in anti-mycobacterial effector function [14,15] and promote intracellular survival and replication of M. tuberculosis.…”

“…For PMN depletion, mice were treated i.p. with anti-Gr-1 antibodies (Rb6-8C5, [14]) in PBS or with PBS alone on days 10 and 16 p.i. …”

Increased expression of host iron-binding proteins precedes iron accumulation and calcification of primary lung lesions in experimental tuberculosis in the guinea pig

“…M. tuberculosis has been shown to acquire host iron within the phagosome by the secretion and binding of iron chelating siderophores that have a higher binding capacity for iron than transferrin or lactoferrin (34,48,49). Classical activation of macrophages with IFN-gamma prevents the accumulation of iron within the phagosome and down regulates the expression of surface bound transferrin (50). The increased expression of macrophage transferrin receptor expression in vivo in our study is consistent with the phenomenon of alternative macrophage activation induced by exposure of macrophages to IL-4 in vitro (50).…”