Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS

Zhang, Weina; Wang, Guihua; Xu, Zhigang; Tu, Hai-Qing; Hu, Fang; Dai, Jiang; Chang, Yan; Chen, Yaqi; Lu, Yanjun; Zeng, Hao‐Long; Zhang, Cai; Han, Fei; Xu, Chuan; Jin, Guoxiang; Sun, Li; Pan, Bo-Syong; Lai, Shiue‐Wei; Hsu, Che-Chia; Xu, Jia; Chen, Zhongzhu; Li, Hongyu; Seth, Pankaj; Hu, Junbo; Zhang, Xuemin; Li, Yong; Lin, Hui-Kuan

doi:10.1016/j.cell.2019.05.003

Cited by 413 publications

(381 citation statements)

References 53 publications

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“…Lactate has long been known as a negative regulator of antitumor immunity. 31,32 For example, lactate can induce TAMs to differentiate into an M2-like phenotype by activating HIF-1α, thus promoting tumor development. 31 Here, we found that lactate could stimulate the translocation of Ap-2α from the cytoplasm to the nucleus, thus potentiating the Elk-1/Sirpα axis-mediated "don't eat me" signal.…”

Section: Discussionmentioning

confidence: 99%

The Ap-2α/Elk-1 axis regulates Sirpα-dependent tumor phagocytosis by tumor-associated macrophages in colorectal cancer

Wang

Luo

Chen

et al. 2020

Sig Transduct Target Ther

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The inhibitory receptor signal regulatory protein-α (Sirpα) is a myeloid-specific immune checkpoint that engages the "don't eat me" signal CD47, which is expressed on tumor and normal tissue cells. However, the profile and regulatory mechanism of Sirpα expression in tumor-associated macrophages (TAMs) are still not clear. Here, we found that the expression of Sirpα in TAMs increased dynamically with colorectal cancer (CRC) progression. Mechanistically, CRC cell-derived lactate induced the nuclear translocation of the transcription factor Ap-2α from the cytoplasm in TAMs. Ap-2α functioned as a transcription factor for Elk-1 by binding to the conserved element GCCTGC located at −1396/−1391 in the mouse Elk-1 promoter. Subsequently, the Elk-1 protein bound to two conserved sites, CTTCCTACA (located at −229/−221) and CTTCCTCTC (located at −190/−182), in the mouse Sirpα promoter and promoted Sirpα expression in TAMs. Functionally, the macrophage-specific knockout of Ap-2α notably promoted the phagocytic activity of TAMs and suppressed CRC progression, whereas these effects were prevented by the transgenic macrophage-specific expression of Elk-1, which regulated TAM phagocytosis and CRC development in a Sirpα-dependent manner. Furthermore, we showed that Elk-1 expression was positively correlated with Sirpα expression in TAMs and was associated with poor survival in CRC patients. Taken together, our findings revealed a novel mechanism through which CRC evades innate immune surveillance and provided potential targets for macrophage-based immunotherapy for CRC patients.Signal Transduction and Targeted Therapy (2020) 5:35; https://doi.

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Section: Discussionmentioning

confidence: 99%

The Ap-2α/Elk-1 axis regulates Sirpα-dependent tumor phagocytosis by tumor-associated macrophages in colorectal cancer

Wang

Luo

Chen

et al. 2020

Sig Transduct Target Ther

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“…Patients with influenza recruited in the present study were confirmed as being infected with H1N1 virus by qPCR. PBMCs were isolated using standard Ficoll gradient centrifugation from the peripheral blood of either infected C labeling of UDP-GlcNAc from U-13 C 6 -glucose was detected from cell lysates using nuclear magnetic resonance (NMR) spectroscopybased metabolomics analysis (16,17). Briefly, samples were dried and on September 1, 2020 http://advances.sciencemag.org/ Downloaded from then reconstituted using phosphate buffer in 100% D 2 O with 500 mM TMSP as a chemical shift reference.…”

Section: Clinical Samplesmentioning

confidence: 99%

“…Reprogramming cellular metabolic activities has recently been demonstrated to play a critical role in the activation of the immune system and hyperinflammation (15). A widely accepted concept is that embedded in immune cell physiology are metabolic pathways and metabolites that not only provide energy and substrates for growth and survival but also direct effector functions, differentiation, and gene expression (16,17). Previous studies reported increased glucose uptake and utilization in immune cells, serving as a hallmark feature of acute inflammation (18).…”

Section: Introductionmentioning

confidence: 99%

O -GlcNAc transferase promotes influenza A virus–induced cytokine storm by targeting interferon regulatory factor–5

et al. 2020

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In this study, we demonstrated an essential function of the hexosamine biosynthesis pathway (HBP)–associated O-linked β-N-acetylglucosamine (O-GlcNAc) signaling in influenza A virus (IAV)–induced cytokine storm. O-GlcNAc transferase (OGT), a key enzyme for protein O-GlcNAcylation, mediated IAV-induced cytokine production. Upon investigating the mechanisms driving this event, we determined that IAV induced OGT to bind to interferon regulatory factor–5 (IRF5), leading to O-GlcNAcylation of IRF5 on serine-430. O-GlcNAcylation of IRF5 is required for K63-linked ubiquitination of IRF5 and subsequent cytokine production. Analysis of clinical samples revealed that IRF5 is O-GlcNAcylated, and higher levels of proinflammatory cytokines correlated with higher levels of blood glucose in IAV-infected patients. We identified a molecular mechanism by which HBP-mediated O-GlcNAcylation regulates IRF5 function during IAV infection, highlighting the importance of glucose metabolism in IAV-induced cytokine storm.

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“…Notably, lactate restoration reverses increased IFN production caused by lactate deficiency. LDHA inactivation and subsequent lactate reduction, using pharmacological and genetic approaches, increases type I IFN production and protects mice from viral infection (W. Zhang et al, ).…”

Section: Lactate Modulates Immune Cell Functionsmentioning

confidence: 99%

Lactate: Fueling the fire starter

Certo

Marone

Paulis

et al. 2019

WIREs Mechanisms of Disease

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It is becoming increasingly appreciated that intermediates of metabolic pathways, besides their anabolic and catabolic functions, can act as signaling molecules and influence the outcome of immune responses. Although lactate was previously considered as a waste product of glucose metabolism, accumulating evidence has highlighted its pivotal role in regulating diverse biological processes, including immune cell polarization, differentiation and effector functions. In addition, lactate is a key player in modulating tumor immune surveillance. Hence, targeting lactate‐induced signaling pathways is a promising tool to reduce inflammation, to prevent autoimmunity and to restore anti‐tumor immune response. This article is characterized under: Biological Mechanisms > Metabolism

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Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS

Cited by 413 publications

References 53 publications

The Ap-2α/Elk-1 axis regulates Sirpα-dependent tumor phagocytosis by tumor-associated macrophages in colorectal cancer

The Ap-2α/Elk-1 axis regulates Sirpα-dependent tumor phagocytosis by tumor-associated macrophages in colorectal cancer

O -GlcNAc transferase promotes influenza A virus–induced cytokine storm by targeting interferon regulatory factor–5

Lactate: Fueling the fire starter

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