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IL-4Rα-dependent alternative activation of macrophages is not decisive for Mycobacterium tuberculosis pathology and bacterial burden in mice.

ABSTRACT: Classical activation of macrophages (caMph or M1) is crucial for host protection against Mycobacterium tuberculosis (Mtb) infection. Evidence suggests that IL-4/IL-13 alternatively activated macrophages (aaMph or M2) are exploited by Mtb to divert microbicidal functions of caMph. To define the functions of M2 macrophages during tuberculosis (TB), we infected mice deficient for IL-4 receptor α on macrophages (LysMcreIL-4Rα-/lox) with Mtb. We show that absence of IL-4Rα on macrophages does not play a major role during infection with Mtb H37Rv, or the clinical Beijing strain HN878. This was demonstrated by similar mortality, bacterial burden, histopathology and T cell proliferation between infected wild-type (WT) and LysMcreIL-4Rα-/lox mice. Interestingly, we observed no differences in the lung expression of inducible nitric oxide synthase (iNOS) and Arginase 1 (Arg1), well-established markers for M1/M2 macrophages among the Mtb-infected groups. Kinetic expression studies of IL-4/IL-13 activated bone marrow-derived macrophages (BMDM) infected with HN878, followed by gene set enrichment analysis, revealed that the MyD88 and IL-6, IL-10, G-CSF pathways are significantly enriched, but not the IL-4Rα driven pathway. Together, these results suggest that IL-4Rα-macrophages do not play a central role in TB disease progression.

SUBMITTER: Guler R

PROVIDER: S-EPMC4366092 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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IL-4Rα-dependent alternative activation of macrophages is not decisive for Mycobacterium tuberculosis pathology and bacterial burden in mice.

Guler Reto R Parihar Suraj P SP Savvi Suzana S Logan Erin E Schwegmann Anita A Roy Sugata S Nieuwenhuizen Natalie E NE Ozturk Mumin M Schmeier Sebastian S Suzuki Harukazu H Brombacher Frank F

PloS one 20150319 3

Classical activation of macrophages (caMph or M1) is crucial for host protection against Mycobacterium tuberculosis (Mtb) infection. Evidence suggests that IL-4/IL-13 alternatively activated macrophages (aaMph or M2) are exploited by Mtb to divert microbicidal functions of caMph. To define the functions of M2 macrophages during tuberculosis (TB), we infected mice deficient for IL-4 receptor α on macrophages (LysMcreIL-4Rα-/lox) with Mtb. We show that absence of IL-4Rα on macrophages does not pla ...[more]

PMID: 25790379

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Project description:Tuberculosis results from an interaction between a chronically persistent pathogen counteracted by IFN-g-mediated immune responses. Modulation of IFN-g signaling could therefore constitute a major immune evasion mechanism for M. tuberculosis. SOCS1 plays a major role in the inhibition of IFN-g-mediated responses. We found that M. tuberculosis infection stimulates SOCS1 expression in mouse and human myeloid cells. Significantly higher levels of SOCS1 were induced after in vitro or in vivo infection with virulent M. tuberculosis-than with attenuated M. bovis BCG. Different innate and adaptive immune mechanisms participated in infection-induced SOCS1 expression. SOCS1 hampered M. tuberculosis clearance both in macrophages and during murine infection in vivo. On the other hand, SOCS1 protected the host from an infection-induced inflammation. Despite SOCS1 expression, mycobacteria-infected macrophages were not tolerant to IFN-g. Instead, an impaired IFN-g secretion by macrophages, associated to lower responses to IL-12, accounted for the increased mycobacterial intracellular growth in presence of SOCS1. SOCS1 attenuated the expression of the majority of genes modulated by infection of macrophages (6,1% of the transcriptome), indicating the relevance of the molecule in the outcome of infection with M. tuberculosis. We suggest that SOCS1 is expressed during M. tuberculosis infection to establish a successful chronic infection, and dampen inflammatory damage. Difference in genotype and TB infection comparison Relative gene expressions were determined by normalized intensity values. GeneSpring analysis was performed using the Treg transcriptome data with following comparisons: no GvHD d90 versus no GvHD d150, no GvHD d90 versus acute GvHD, no GvHD d150 versus chronic GvHD, acute GvHD versus chronic GvHD, acute GvHD versus GvHD d90 and chronic GvHD versus GvHD d150 (Figure 2). Cut-off was a transcript fold change of +2 or -2 in at least one comparison. Student´s t-test was used to identify significant expression changes.

Dataset Information

IL-4Rα-dependent alternative activation of macrophages is not decisive for Mycobacterium tuberculosis pathology and bacterial burden in mice.

Publications

IL-4Rα-dependent alternative activation of macrophages is not decisive for Mycobacterium tuberculosis pathology and bacterial burden in mice.

Similar Datasets

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