Metallothionein 3 Controls the Phenotype and Metabolic Programming of Alternatively Activated Macrophages

Chowdhury, Debabrata; Alrefai, Hani; Figueroa, Julio A. Landero; Candor, Kathleen; Porollo, Aleksey; Fecher, Roger; Divanovic, Senad; Deepe, George S.; Vignesh, Kavitha Subramanian

doi:10.1016/j.celrep.2019.05.093

Cited by 31 publications

(41 citation statements)

References 66 publications

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“…We found higher levels of M2 macrophage infiltration in the high immune risk groups with relatively worse prognosis. M2 macrophages, acting as anti-inflammatory and pro-tumor, are increasingly recognized as contributors to metastatic progression of breast cancer and correlated with poor prognosis (Chowdhury et al, 2019;Little et al, 2019). These are all hints of potential therapeutic opportunities by regulation of M 2 macrophage-induced migratory and invasive response in breast cancer.…”

Section: Go Termmentioning

confidence: 99%

Development of an Immune-Related Prognostic Signature in Breast Cancer

Xie

et al. 2020

Front. Genet.

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Background: Although increased early detection, diagnosis and treatment have improved the outcome of breast cancer patients, prognosis estimation still poses challenges due to the disease heterogeneity. Accumulating data indicated an evident correlation between tumor immune microenvironment and clinical outcomes. Objective: To construct an immune-related signature that can estimate disease prognosis and patient survival in breast cancer. Methods: Gene expression profiles and clinical data of breast cancer patients were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, which were further divided into a training set (n = 499), a testing set (n = 234) and a Meta-validation set (n = 519). In the training set, immune-related genes were recognized using combination of gene expression data and ESTIMATE algorithm-derived immune scores. An immune-related prognostic signature was generated with LASSO Cox regression analysis. The prognostic value of the signature was validated in the testing set and the Meta-validation set. Results: A total of 991 immune-related genes were identified. Twelve genes with nonzero coefficients in LASSO analysis were used to construct an immune-related prognostic signature. The 12-gene signature significantly stratified patients into high and low immune risk groups in terms of overall survival independent of clinical and pathologic factors. The signature also significantly stratified overall survival in clinical defined groups, including stage I/II disease. Several biological processes, such as immune response, were enriched among genes in the immune-related signature. The percentage of M 2 macrophage infiltration was significantly different between low and high immune risk groups. Timedependent ROC curves indicated good performance of our signature in predicting the 1-, 3-and 5-year overall survival for patients from the full TCGA cohort. Furthermore, the composite signature derived by integrating immune-related signature with clinical factors, provided a more accurate estimation of survival relative to molecular signature alone.

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Section: Go Termmentioning

confidence: 99%

Development of an Immune-Related Prognostic Signature in Breast Cancer

Xie

et al. 2020

Front. Genet.

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“…In aerobic glycolysis, each molecule of glucose yields only two ATP molecules and produces lactate as an end product. However, it is a rapid energy production process and supports the cell during acute inflammation at the early stages of infection (Chowdhury et al, 2019[ 10 ]; Ramond et al, 2019[ 50 ]).…”

Section: Metabolic Reprogramming Of Macrophagesmentioning

confidence: 99%

“…2) ) (Wilson et al, 2019[ 65 ]). FAO supplies energy to generate acetyl-coenzyme (CoA), which further enters the TCA cycle (Chowdhury et al, 2019[ 10 ]) to generate ATP via OXPHOS. OXPHOS produces higher amounts of ATP (30-32 from one glucose molecule) compared with glycolysis.…”

Section: Metabolic Reprogramming Of Macrophagesmentioning

confidence: 99%

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Metabolic reprogramming of macrophages and its involvement in inflammatory diseases

Guo

Islam

Zhang

et al. 2021

EXCLI Journal; 20:Doc628; ISSN 1611-2156

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“…Our functional enrichment data based on protein-protein interaction network analyses revealed a potential involvement of MT3 in LPS, TRIF, type-I IFN and IL-1 signaling (Table 1 and Extended Data Table 1, Extended Data Files 1 and 2). We further examined our published RNAseq data (NCBI SRA: PRJNA533616) to determine differentially expressed genes by comparing resting WT and Mt3 -/-BMDMϕ 19 . The derived list of differentially expressed genes significantly enriched 12 GO BP categories directly related to cytokine and chemokine signaling and regulation of inflammatory responses based on DAVID functional enrichment analysis (Fig.…”

Section: Myeloid Mt3 Orchestrates Negative Control Of the Non-canonical Inflammasomementioning

confidence: 99%

Metallothionein 3-zinc axis suppresses caspase-11 inflammasome activation and impairs antibacterial immunity

Chowdhury

Gardner

Satpati

et al. 2021

Preprint

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Non-canonical inflammasome activation by mouse caspase-11 (or human CASPASE-4/5) is crucial for the clearance of certain gram-negative bacterial infections, but can lead to severe inflammatory damage. Factors that promote non-canonical inflammasome activation are well recognized, but less is known about the mechanisms underlying its negative regulation. Herein, we identify that the caspase-11 inflammasome in mouse and human macrophages (Mϕ) is negatively controlled by the zinc (Zn2+) regulating protein, metallothionein 3 (MT3). Upon challenge with intracellular lipopolysaccharide (iLPS), Mϕ increased MT3 expression that curtailed the activation of caspase-11 and its downstream targets caspase-1 and interleukin (IL)-1β. Mechanistically, MT3 increased intramacrophage Zn2+ to downmodulate the TRIF-IRF3-STAT1 axis that is prerequisite for caspase-11 effector function. MT3 suppressed activation of the caspase-11 inflammasome, while caspase-11 and MT3 synergized in impairing antibacterial immunity. The present study identifies an important yin-yang relationship between the non-canonical inflammasome and MT3 in controlling inflammation and immunity to gram-negative bacteria.

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Metallothionein 3 Controls the Phenotype and Metabolic Programming of Alternatively Activated Macrophages

Cited by 31 publications

References 66 publications

Development of an Immune-Related Prognostic Signature in Breast Cancer

Development of an Immune-Related Prognostic Signature in Breast Cancer

Metabolic reprogramming of macrophages and its involvement in inflammatory diseases

Metallothionein 3-zinc axis suppresses caspase-11 inflammasome activation and impairs antibacterial immunity

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