Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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IFN-γ and IL-17 synergistic anti-mycobacterial response via coronin-1A inhibition

ABSTRACT: This study investigates the molecular mechanism underlying the synergistic anti-mycobacterial effect of IFN-γ and IL-17. We performed microarray analysis on bone marrow-derived macrophages (BMDMs) from C57BL/6J mice infected with Mycobacterium tuberculosis H37Rv and treated with infection control, IFN-γ (1, 10, 100 ng/mL), IL-17 (10, 100 ng/mL), or IFN-γ/IL-17 combination (1 ng/mL each) for 24 hours. The study identified coronin-1A as a key molecule whose retention on phagosomes is inhibited by IFN-γ/IL-17 treatment via LRG47-dependent STAT1/STAT3 pathway activation. These findings provide insights into cytokine-based adjunctive therapy for tuberculosis treatment.

ORGANISM(S): Mus musculus

SUBMITTER: Han-Gyu Choi

PROVIDER: E-MTAB-16005 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Intracellular pathogens including the apicomplexan and opportunistic parasite Toxoplasma gondii profoundly modify their host cells in order to establish infection. We have shown previously that intracellular T. gondii inhibit up-regulation of regulatory and effector functions in murine macrophages (MΦ) stimulated with interferon (IFN)-γ, which is the cytokine crucial for controlling the parasites’ replication. Using genome-wide transcriptome analysis we show herein that infection with T. gondii leads to global unresponsiveness of murine macrophages to IFN-γ. More than 61% and 89% of the transcripts, which were induced or repressed by IFN-γ in non-infected MΦ, respectively, were not altered after stimulation of T. gondii-infected cells with IFN-γ. These genes are involved in a variety of biological processes, which are mostly but not exclusively related to immune responses. Analyses of the underlying mechanisms revealed that IFN-γ-triggered nuclear translocation of STAT1 still occurred in Toxoplasma-infected MΦ. However, STAT1 bound aberrantly to oligonucleotides containing the IFN-γ-responsive gamma-activated site (GAS) consensus sequence. Conversely, IFN-γ did not induce formation of active GAS-STAT1 complexes in nuclear extracts from infected MΦ. Mass spectrometry of protein complexes bound to GAS oligonucleotides showed that T. gondii-infected MΦ are unable to recruit non-muscle actin to IFN-γ-responsive DNA sequences, which appeared to be independent of stimulation with IFN-γ and of STAT1 binding. IFN-γ-induced recruitment of BRG-1 and acetylation of core histones at the IFN-γ-regulated CIITA promoter IV, but not β-actin was diminished by >90% in Toxoplasma-infected MΦ as compared to non-infected control cells. Remarkably, treatment with histone deacetylase inhibitors restored the ability of infected macrophages to express the IFN-γ regulated genes H2-A/E and CIITA. Taken together, these results indicate that Toxoplasma-infected MΦ are unable to respond to IFN-γ due to disturbed chromatin remodelling, but can be rescued using histone deacetylase inhibitors. Comparison of 4 different RNA pools with a 2-Color-Loop Design including 10 microarrays: [1] T. gondii infected and IFN-gamma treated, [2] T. gondii infected and untreated, [3] Non-infected and IFN-gamma treated, and [4] Non-infected and untreated.

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IFN-γ and IL-17 synergistic anti-mycobacterial response via coronin-1A inhibition

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