Dataset Information

An acidic microenvironment in Tuberculosis increases extracellular matrix degradation by regulating macrophage inflammatory responses.

ABSTRACT: Mycobacterium tuberculosis (M.tb) infection causes marked tissue inflammation leading to lung destruction and morbidity. The inflammatory extracellular microenvironment is acidic, however the effect of this acidosis on the immune response to M.tb is unknown. Using RNA-seq we show that acidosis produces system level transcriptional change in M.tb infected human macrophages regulating almost 4000 genes. Acidosis specifically upregulated extracellular matrix (ECM) degradation pathways with increased expression of Matrix metalloproteinases (MMPs) which mediate lung destruction in Tuberculosis. Macrophage MMP-1 and -3 secretion was increased by acidosis in a cellular model. Acidosis markedly suppresses several cytokines central to control of M.tb infection including TNF-α and IFN-γ. Murine studies demonstrated expression of known acidosis signaling G-protein coupled receptors OGR-1 and TDAG-8 in Tuberculosis which are shown to mediate the immune effects of decreased pH. Receptors were then demonstrated to be expressed in patients with TB lymphadenitis. Collectively, our findings show that an acidic microenvironment modulates immune function to reduce protective inflammatory responses and increase extracellular matrix degradation in Tuberculosis. Acidosis receptors are therefore potential targets for host directed therapy in patients.

SUBMITTER: Whittington AM

PROVIDER: S-EPMC10355421 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

An acidic microenvironment in Tuberculosis increases extracellular matrix degradation by regulating macrophage inflammatory responses.

Whittington Ashley M AM Turner Frances S FS Baark Friedrich F Templeman Sam S Kirwan Daniela E DE Roufosse Candice C Krishnan Nitya N Robertson Brian D BD Chong Deborah L W DLW Porter Joanna C JC Gilman Robert H RH Friedland Jon S JS

PLoS pathogens 20230707 7

Mycobacterium tuberculosis (M.tb) infection causes marked tissue inflammation leading to lung destruction and morbidity. The inflammatory extracellular microenvironment is acidic, however the effect of this acidosis on the immune response to M.tb is unknown. Using RNA-seq we show that acidosis produces system level transcriptional change in M.tb infected human macrophages regulating almost 4000 genes. Acidosis specifically upregulated extracellular matrix (ECM) degradation pathways with increase ...[more]

PMID: 37418488

Similar Datasets

Project description:BackgroundThe extracellular pH (pH e ) is known to be acidic. We investigated the effect of mild (pH e 6.8) and severe (pH e 5.9) acidosis on gene expression in mouse B16-BL6 melanoma cells using cDNA microarray analysis and compared them with the acidic pH e dependence of human tumors.MethodsB16-BL6 cells were treated with pH e 7.4 (control), pH e 6.8, and pH e 5.9. The mRNA expression was analyzed by using the cDNA microarray. Heat map, volcano plot, and gene ontology enrichment analysis were performed. The data were compared with the gene signatures of published data GSE52031 and GSE8401 and compared with the pathological staging by GEPIA2, and the prognostic signature of proteins was searched by the Human Protein Atlas database. If the acidic pH e -induced and -reduced genes were correlated with shortened and prolonged survival times, respectively, and also correlated with pathological staging, we defined it as "hit" and counted the sum of hit points of eight types of tumors such as breast, colorectal, prostate, gastric, liver, prostate, lung, and head and neck and melanoma.ResultsGene expression was differentially and commonly regulated by both pH e s. The number of genes upregulated fourfold or more at pH e 6.8 and 5.9 only for 25 and 131 genes, respectively, and 85 genes were common. The number of genes downregulated fourfold or less at pH e 6.8 and 5.9 only for 63 and 82 genes, respectively, and 118 genes were common. Compared with human mRNA expression data (GSE8401), there is no correlation with the overall pattern of the signature. In seven types of cancer (breast, colorectal, gastric, liver, prostate, lung, and head and neck) and melanoma, the relationship between acidic pH e -modulated gene expression and overall survival was evaluated. As a result, acidic pH e dependency contributing to prognosis was higher in colorectal, lung, and head and neck cancers and lower in prostate cancer.ConclusionTumor classification based on response to extracellular acidic pH e will provide new insights into chemotherapy strategy for patients with tumors.

Project description:BackgroundExtensive immunopathology occurs in human immunodeficiency virus (HIV)/tuberculosis (TB) coinfection, but the underlying molecular mechanisms are not well-defined. Excessive matrix metalloproteinase (MMP) activity is emerging as a key process but has not been systematically studied in HIV-associated TB.MethodsWe performed a cross-sectional study of matrix turnover in HIV type 1 (HIV-1)-infected and -uninfected TB patients and controls, and a prospective cohort study of HIV-1-infected TB patients at risk of TB immune reconstitution inflammatory syndrome (TB-IRIS), in Cape Town, South Africa. Sputum and plasma MMP concentrations were quantified by Luminex, plasma procollagen III N-terminal propeptide (PIIINP) by enzyme-linked immunosorbent assay, and urinary lipoarabinomannan (LAM) by Alere Determine TB LAM assay. Peripheral blood mononuclear cells from healthy donors were cultured with Mycobacterium tuberculosis and extracellular matrix in a 3D model of TB granuloma formation.ResultsMMP activity differed between HIV-1-infected and -uninfected TB patients and corresponded with specific TB clinical phenotypes. HIV-1-infected TB patients had reduced pulmonary MMP concentrations, associated with reduced cavitation, but increased plasma PIIINP, compared to HIV-1-uninfected TB patients. Elevated extrapulmonary extracellular matrix turnover was associated with TB-IRIS, both before and during TB-IRIS onset. The predominant collagenase was MMP-8, which was likely neutrophil derived and M. tuberculosis-antigen driven. Mycobacterium tuberculosis-induced matrix degradation was suppressed by the MMP inhibitor doxycycline in vitro.ConclusionsMMP activity in TB differs by HIV-1 status and compartment, and releases matrix degradation products. Matrix turnover in HIV-1-infected patients is increased before and during TB-IRIS, informing novel diagnostic strategies. MMP inhibition is a potential host-directed therapy strategy for prevention and treatment of TB-IRIS.

Dataset Information

An acidic microenvironment in Tuberculosis increases extracellular matrix degradation by regulating macrophage inflammatory responses.

Publications

An acidic microenvironment in Tuberculosis increases extracellular matrix degradation by regulating macrophage inflammatory responses.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets