Slc6a8-Mediated Creatine Uptake and Accumulation Reprogram Macrophage Polarization via Regulating Cytokine Responses

Ji, Liangliang; Zhao, Xinbin; Zhang, Bin; Kang, Lan; Song, Wenxin; Zhao, Baohong; Xie, Wei; Chen, Ligong; Hu, Xiaoyu

doi:10.1016/j.immuni.2019.06.007

Cited by 148 publications

(119 citation statements)

References 46 publications

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“…The intracellular accumulation of (phospho)creatine has also been reported in macrophages exposed to other types of nanoparticles, namely silk, poly(lactic‐co‐glycolic acid) and silica nanoparticles,, as well as to ultrasmall superparamagnetic particles of iron oxide, and suggested to be associated with phagocytosis‐related energy demand . Furthermore, a role for creatine in the regulation of macrophage polarization has been recently proposed . Ji et al have shown that creatine, found to be actively taken up by resting macrophages, was a potent endogenous inhibitor of pro‐inflammatory IFN‐γ‐mediated polarization of mouse peritoneal macrophages, while supporting anti‐inflammatory IL4‐induced polarization.…”

Section: Discussionmentioning

confidence: 93%

Macrophage Metabolomics Reveals Differential Metabolic Responses to Subtoxic Levels of Silver Nanoparticles and Ionic Silver

et al. 2020

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This study employed NMR metabolomics to characterize macrophage responses to subtoxic concentrations of silver nanoparticles (AgNPs ca. 30 nm) and ionic silver (Ag + ), with a view to further elucidate their immunomodulatory activity at the cell metabolism level. Exposure to AgNPs caused RAW 264.7 macrophages to decrease intracellular glucose utilization, possibly due to interference with glycolytic enzymes, and to reprogram the TCA cycle towards anaplerotic fueling and production of anti-inflammatory metabolites (e.g. itaconate and creatine). Moreover, AgNPs-exposed cells were able to control the levels [a] Dr. 1867of reactive oxygen/nitrogen species (ROS/RNS), likely through upregulation of glutathione synthesis. On the other hand, macrophages exposed to Ag + at equivalent subtoxic concentrations showed reduced metabolic activity, lower ability to counterbalance ROS/RNS and alterations in membrane-related lipids. Overall, the metabolomics approach hereby employed provided novel insights into the differential effects of AgNPs and Ag + , which help explain the lower toxic potential of nanosilver than silver ions.ter. Moreover, since the release of silver ions from AgNPs has been highlighted as a main driver of AgNPs toxicity, [23] the metabolic effects of ionic silver (administered as AgNO 3 ), at inhibi-Joana Carrola graduated in Chemistry from the University of Porto, and obtained her PhD in Nanosciences and Nanotechnology, in 2017, from the University of Aveiro. Her PhD research focused on silver nanoparticles metabolism in mammalian cells. She is an expert in metabolomics, with interests in the study of drugs and nanomaterials metabolism.Verónica Bastos obtained her PhD in Biology studying nanotoxicity in in vitro cell cultures at the University of Aveiro, 2016. She is currently a Researcher in a project studying upconversion nanoparticles for multimodal therapy of melanoma at CESAM, Biology department of University of Aveiro. Her main research interests are related to nanotoxicity, nanobiomedicine and cancer therapy, ecotoxicology and human health. Ana Luísa Daniel-da-Silva graduated in Chemical Engineering by Instituto Superior Técnico (Lisbon, Portugal) in 2000 and obtained her PhD degree in Materials Science from the University of Alicante (Spain) in 2005. Since 2009 she is researcher at CICECO-Portugal. Her research focuses on the development of functional nanoparticles and nanocomposites for applications in nanomedicine, bionanotechnology and water remediation. and a member of CICECO-Aveiro Institute of Materials. Her main research interests are: 1) NMR metabolomics of biological systems (biofluids, intact tissues, tissue/material systems, cell cultures) subjected to disease, therapeutics, toxicological or environmental stresses for identification of novel biomarkers; 2) Metabolomic testing of novel biomaterials with applications in biodegradable implants, drug delivery or localized cell recognition; 3) Development of spectroscopy-based methods for food quality control.Conceição Santos is a Full Profes...

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Section: Discussionmentioning

confidence: 93%

Macrophage Metabolomics Reveals Differential Metabolic Responses to Subtoxic Levels of Silver Nanoparticles and Ionic Silver

et al. 2020

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“…Upstream of phosphocreatine, creatine is an antioxidant that can help protect cells and tissues against oxidative damage (44). Intriguingly, creatine and the Slc6a8 creatine transporter that was strongly increased by prior pneumococcal exposures can directly influence polarized macrophage cytokine expression, favoring the "alternative" activation phenotype in bone marrow-derived macrophages, perhaps by modifying chromatin accessibility (49). The alveolar macrophages that remodeled after pneumococcal pneumonia displayed elevated creatine without a skewing toward "alternative" activation, but it is possible that creatine may influence chromatin accessibility and transcriptome changes in this setting as well.…”

Section: Discussionmentioning

confidence: 99%

Pneumonia recovery reprograms the alveolar macrophage pool

et al. 2020

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“…However, an intrinsic downside of depleting TAMs is the loss of their innate immunostimulatory role as the primary phagocytes and professional antigen-presenting cells (APCs) in solid tumours. Reprogramming or repolarizing immunosuppressive TAMs towards an immunostimulatory phenotype therefore can be an attractive direction; this second category of TAM-repolarizing strategies includes those reprogramming TAMs via CD40 agonists, HDAC inhibitors, PI3Kg inhibitors, and creatine 39,40,86,87,88 . Many of these TAM reprogramming strategies are currently under active clinical evaluation 39 .…”

Section: Discussionmentioning

confidence: 99%

“…Many of these TAM reprogramming strategies are currently under active clinical evaluation 39 . Notably, CD40 agonists work through activating CD40L-downstream NF-kB pathway 87,89 ; HDAC inhibitors work through altering histone modi cations 86,90,91 ; PI3Kγ inhibitors work through stimulating NF-κB activation while inhibiting C/EBPβ activation 88,92,93 ; and creatine uptake works through regulating cytokine responses 40 . Our discovery of MAO-A as a critical regulator of TAM polarization through modulating oxidative stress provides a new drug target and a new mechanism of action (MOA) for expanding TAM-repolarizing strategies.…”

Section: Discussionmentioning

confidence: 99%

“…Preclinical and clinical studies are ongoing, evaluating TAM-repolarizing reagents (e.g., CD40 agonists, HDAC inhibitors, PI3Kγ inhibitors, creatine, etc.) for improving ICB therapy; certain e cacies have been reported 17,29,31,39,40,41,42 . Therefore, the search for new molecules regulating TAM polarization and the development of new combination treatments targeting TAM reprogramming are an active direction of current cancer immunotherapy studies.…”

Section: Introductionmentioning

confidence: 99%

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Targeting monoamine oxidase A-regulated TAM polarization for cancer immunotherapy

Wang

et al. 2020

Preprint

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Abstract Targeting tumour-associated macrophages (TAMs) is a promising strategy to modify the immunosuppressive tumour microenvironment and improve cancer immunotherapy. Monoamine oxidase A (MAO-A) is an enzyme best known for its function in the brain; small molecule MAO inhibitors (MAOIs) are clinically used for treating neurological disorders. Here we observed MAO-A induction in mouse and human TAMs. MAO-A-deficient mice exhibited decreased TAM immunosuppressive functions corresponding with enhanced antitumour immunity. MAOI treatment induced TAM reprogramming and suppressed tumour growth in preclinical mouse syngeneic and human xenograft tumour models. Combining MAOI and anti-PD-1 treatments resulted in synergistic tumour suppression. Clinical data correlation studies associated high intratumoural MAOA expression with poor patient survival in a broad range of cancers. We further demonstrated that MAO-A promotes TAM immunosuppressive polarization via upregulating oxidative stress. Together, these data identify MAO-A as a critical regulator of TAMs and support repurposing MAOIs for TAM reprogramming to improve cancer immunotherapy.

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Slc6a8-Mediated Creatine Uptake and Accumulation Reprogram Macrophage Polarization via Regulating Cytokine Responses

Cited by 148 publications

References 46 publications

Macrophage Metabolomics Reveals Differential Metabolic Responses to Subtoxic Levels of Silver Nanoparticles and Ionic Silver

Macrophage Metabolomics Reveals Differential Metabolic Responses to Subtoxic Levels of Silver Nanoparticles and Ionic Silver

Pneumonia recovery reprograms the alveolar macrophage pool

Targeting monoamine oxidase A-regulated TAM polarization for cancer immunotherapy

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