Open Source ImmGen: network perspective on metabolic diversity among mononuclear phagocytes

Gainullina, Anastasiia; Huang, Li-Hao; Todorov, Helena; Yng, Lim Sheau; Kent, Andrew; Jia, Baosen; Seddu, Kumba; Krchma, Karen; Wu, Jun; Crozat, Karine; Tomasello, Elena; Narang, Vipin; Dress, Regine J.; See, Peter; Scott, Charlotte; Gibbings, Sophie L.; Bajpai, Geetika; Desai, Jigar V.; Maier, Bárbara; This, Sébastien; Aguilar, Stephanie Vargas; Poupel, Lucie; Dussaud, Sébastien; Zhou, Tyng-An; Angeli, Véronique; Blander, J. Magarian; Choi, Kyunghee; Dalod, Marc; Dzhagalov, Ivan; Gautier, Emmanuel L.; Jakubzick, Claudia; Lavine, Kory J.; Lionakis, Michail S; Païdassi, Helena; Sieweke, Michael H.; Ginhoux, Florent; Guilliams, Martin; Benoist, Christophe; Mérad, Miriam; Randolph, Gwendalyn J.; Sergushichev, Alexey; Artyomov, Maxim N.

doi:10.1101/2020.07.15.204388

Cited by 3 publications

(2 citation statements)

References 51 publications

(51 reference statements)

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“…In addition to AMPK, LKB1 phosphorylates several other downstream AMPK-related kinases including MARK1-4, SIK1-3, NUAK1-2, BRSK1-2, and SNRK (23,24). We therefore investigated which LKB1 targets may contribute to altering DC function by analyzing published data sets for their expression in hepatic cDCs, as well as mature GM-CSF-elicited BM DCs (GMDCs) (30)(31)(32). The expression profiles were almost identical between primary hepatic cDCs and GMDCs, showing that all these kinases were expressed to a significant level, with the notable exception of Mark1, Brsk2, and Prkaa2 (encoding AMPKα2), confirming that only the catalytic AMPKα1 isoform is expressed by DCs (29).…”

Section: Resultsmentioning

confidence: 99%

Dendritic cell–intrinsic LKB1-AMPK/SIK signaling controls metabolic homeostasis by limiting the hepatic Th17 response during obesity

Zande¹,

Brombacher²,

Lambooij³

et al. 2023

JCI Insight

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Obesity-associated metabolic inflammation drives the development of insulin resistance and type 2 diabetes, notably through modulating innate and adaptive immune cells in metabolic organs. The nutrient sensor liver kinase B1 (LKB1) has recently been shown to control cellular metabolism and T cell priming functions of DCs. Here, we report that hepatic DCs from high-fat diet–fed (HFD-fed) obese mice display increased LKB1 phosphorylation and that LKB1 deficiency in DCs (CD11c ΔLKB1 ) worsened HFD-driven hepatic steatosis and impaired glucose homeostasis. Loss of LKB1 in DCs was associated with increased expression of Th17-polarizing cytokines and accumulation of hepatic IL-17A + Th cells in HFD-fed mice. Importantly, IL-17A neutralization rescued metabolic perturbations in HFD-fed CD11c ΔLKB1 mice. Mechanistically, deficiency of the canonical LKB1 target AMPK in HFD-fed CD11c ΔAMPKα1 mice recapitulated neither the hepatic Th17 phenotype nor the disrupted metabolic homeostasis, suggesting the involvement of other and/or additional LKB1 downstream effectors. We indeed provide evidence that the control of Th17 responses by DCs via LKB1 is actually dependent on both AMPKα1 and salt-inducible kinase signaling. Altogether, our data reveal a key role for LKB1 signaling in DCs in protection against obesity-induced metabolic dysfunctions by limiting hepatic Th17 responses.

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Section: Resultsmentioning

confidence: 99%

Dendritic cell–intrinsic LKB1-AMPK/SIK signaling controls metabolic homeostasis by limiting the hepatic Th17 response during obesity

Zande¹,

Brombacher²,

Lambooij³

et al. 2023

JCI Insight

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“…Upregulated cholesterol is naturally expected under the high-cholesterol diet and might be considered as a positive control. As many other macrophages, peritoneal macrophages have high levels of base metabolism of phospholipids, comparing to other myeloid cells (monocytes and dendritic cells) ( 36 ), thus glycerophospholipid deregulation on high-fat diet might reflect the response to maintain phospholipid homeostasis. Interestingly, arachidonoyl-CoA (labeled as ‘(5Z,8Z,11Z,14Z)-eicosatetraenoyl-CoA’ in the module) appears in the module surrounded by changing phospholipids, without being measured.…”

Section: Resultsmentioning

confidence: 99%

Shiny GATOM: omics-based identification of regulated metabolic modules in atom transition networks

Emelianova

Gainullina

Poperechnyi

et al. 2022

Nucleic Acids Research

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Multiple high-throughput omics techniques provide different angles on systematically quantifying and studying metabolic regulation of cellular processes. However, an unbiased analysis of such data and, in particular, integration of multiple types of data remains a challenge. Previously, for this purpose we developed GAM web-service for integrative metabolic network analysis. Here we describe an updated pipeline GATOM and the corresponding web-service Shiny GATOM, which takes as input transcriptional and/or metabolomic data and finds a metabolic subnetwork most regulated between the two conditions of interest. GATOM features a new metabolic network topology based on atom transition, which significantly improves interpretability of the analysis results. To address computational challenges arising with the new network topology, we introduce a new variant of the maximum weight connected subgraph problem and provide a corresponding exact solver. To make the used networks up-to-date we upgraded the KEGG-based network construction pipeline and developed one based on the Rhea database, which allows analysis of lipidomics data. Finally, we simplified local installation, providing R package mwcsr for solving relevant graph optimization problems and R package gatom, which implements the GATOM pipeline. The web-service is available at https://ctlab.itmo.ru/shiny/gatom and https://artyomovlab.wustl.edu/shiny/gatom.

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Integrated multi-omics analysis of adverse cardiac remodeling and metabolic inflexibility upon ErbB2 and ERRα deficiency

et al. 2022

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Functional oncogenic links between ErbB2 and ERRα in HER2+ breast cancer patients support a therapeutic benefit of co-targeted therapies. However, ErbB2 and ERRα also play key roles in heart physiology, and this approach could pose a potential liability to cardiovascular health. Herein, using integrated phosphoproteomic, transcriptomic and metabolic profiling, we uncovered molecular mechanisms associated with the adverse remodeling of cardiac functions in mice with combined attenuation of ErbB2 and ERRα activity. Genetic disruption of both effectors results in profound effects on cardiomyocyte architecture, inflammatory response and metabolism, the latter leading to a decrease in fatty acyl-carnitine species further increasing the reliance on glucose as a metabolic fuel, a hallmark of failing hearts. Furthermore, integrated omics signatures of ERRα loss-of-function and doxorubicin treatment exhibit common features of chemotherapeutic cardiotoxicity. These findings thus reveal potential cardiovascular risks in discrete combination therapies in the treatment of breast and other cancers.

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Open Source ImmGen: network perspective on metabolic diversity among mononuclear phagocytes

Cited by 3 publications

References 51 publications

Dendritic cell–intrinsic LKB1-AMPK/SIK signaling controls metabolic homeostasis by limiting the hepatic Th17 response during obesity

Dendritic cell–intrinsic LKB1-AMPK/SIK signaling controls metabolic homeostasis by limiting the hepatic Th17 response during obesity

Shiny GATOM: omics-based identification of regulated metabolic modules in atom transition networks

Integrated multi-omics analysis of adverse cardiac remodeling and metabolic inflexibility upon ErbB2 and ERRα deficiency

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