Lactate Inhibits the Pro-Inflammatory Response and Metabolic Reprogramming in Murine Macrophages in a GPR81-Independent Manner

Errea, Agustina Juliana; Cayet, Delphine; Marchetti, Philippe; Tang, Cong; Kluza, Jérôme; Offermanns, Stefan; Sirard, Jean‐Claude; Rumbo, Martı́n

doi:10.1371/journal.pone.0163694

Cited by 110 publications

(111 citation statements)

References 33 publications

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“…Rahman et al (24) implicated HCA2 in the differentiation of Ly6C high -positive monocytes/ macrophages into M2-like Ly6C low -positive monocytes/ macrophages in repair of ischemic damage in the brain (44). Taken together with previous results in tumor cells (41) and bone marrow-derived macrophages (40), our data suggest that lactate may promote polarization of macrophages through HCA2 activation. Interestingly, sepsis outcomes have been correlated with the M1/M2 macrophage ratio; whereas the survivors displayed a mixed M1/M2 phenotype, higher proportions of M1-macrophages or higher levels of M1-type cytokines were associated with higher mortality (45)(46)(47).…”

Section: Discussionsupporting

confidence: 82%

“…We also investigated the effect of LR treatment on inflammatory cytokine production and macrophage polarization. Lactate inhibits LPS-induced macrophage glycolysis (40) and drives tumor-associated macrophage polarization from classically activated (M1) phenotype to the alternatively activated (M2) phenotype in vivo (41). To this end, we FACS-fractionated live peritoneal cells.…”

Section: The Role Of Lactate-induced Activation Of Hca2 On Survival Imentioning

confidence: 99%

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Lactate‐induced activation of HCA2 improves survival in mice with sepsis

Takakura

Zandi‐Nejad

2019

FASEB j.

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Sepsis is characterized by systemic inflammation that is caused by infection and by activation of proinflammatory pathways, resulting in mitochondrial and cellular dysfunction leading to multiorgan failure. Here, we show the following: 1) in peritoneal immune cells, particularly macrophages, from mice that have undergone cecal ligation and puncture (CLP), hydroxycarboxylic acid receptor 2 (HCA2) expression increased in parallel with proinflammatory cytokines; 2) post‐CLP survival rates of Hca2−/− knockout mice (n = 22) were lower than those of wild‐type (WT) mice (n = 15) (P < 0.011), which is suggestive of a protective role for HCA2 in sepsis; 3) WT mice subjected to CLP‐induced sepsis and treated with lactated Ringer's solution (LR, n = 13) survived longer than those treated with normal saline (n = 14; P < 0.027); 4) LR treatment of CLP‐induced sepsis reduced proinflammatory cytokine expression in CD11b+F4/80+ macrophages and promoted M2‐like polarization; 5) HCA2 was expressed by kidney in the setting of sepsis, but not by normal kidneys; 6) LR administration attenuated sepsis‐associated acute kidney injury (AKI), partly restored expression of the key regulator of mitochondrial biogenesis, peroxisome proliferator‐activated receptor γ coactivator 1α (P < 0.03), and reduced proinflammatory cytokine production (TNF‐α, P < 0.04; IL‐1β, P < 0.006; IL‐6, P < 0.03). Our data suggest that lactate‐induced activation of HCA2 during sepsis activates a negative feedback loop to attenuate the inflammatory response. The data further suggest that fluid resuscitation with LR may benefit patients with sepsis, particularly those with sepsis‐associated AKI treated with potentially lactate‐depleting renal replacement therapies.—Takakura, A., Zandi‐Nejad, K. Lactate‐induced activation of HCA2 improves survival in mice with sepsis. FASEB J. 33, 7625–7634 (2019). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 82%

Section: The Role Of Lactate-induced Activation Of Hca2 On Survival Imentioning

confidence: 99%

Lactate‐induced activation of HCA2 improves survival in mice with sepsis

Takakura

Zandi‐Nejad

2019

FASEB j.

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“…Cellular metabolism has emerged as a key regulator of macrophage function. Metabolic reprogramming is required to meet the bioenergetic and biosynthetic demands of the cell and to drive effector functions [8][9][10] . Alterations in metabolites and other bioactive metabolic products have also been shown to activate and regulate gene expression, signal transduction and epigenetic profiles 9,[11][12][13][14] .…”

Section: Introductionmentioning

confidence: 99%

Differential remodeling of the electron transport chain is required to support TLR3 and TLR4 signaling and cytokine production in macrophages

Ahmed

Roy

Jaworski

et al. 2019

Preprint

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Increasing evidence suggests that mitochondria play a critical role in driving innate immune responses against bacteria and viruses. However, it is unclear if differential reprogramming of mitochondrial function contributes to the fine tuning of pathogen specific immune responses. Here, we found that TLR3 and TLR4 engagement on murine bone marrow derived macrophages was associated with differential remodeling of electron transport chain complex expression. This remodeling was associated with differential accumulation of mitochondrial and cytosolic ROS, which were required to support ligand specific inflammatory and antiviral cytokine production.We also found that the magnitude of TLR3, but not TLR4, responses were modulated by glucose availability. Under conditions of low glucose conditions, TLR3 engagement was associated with increased ETC complex III expression, increased mitochondrial and cytosolic ROS and increased inflammatory and antiviral cytokine production. This amplification was selectively reversed by targeting superoxide production from the outer Q-binding site of the ETC complex III. These results suggest that ligand specific modulation of the ETC may act as a rheostat that fine-tunes innate immune responses via mitochondrial ROS production. Modulation of these processes may represent a novel mechanism to modulate the nature as well as the magnitude of antiviral versus inflammatory immune responses.3 Introduction:

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“…We have previously observed that lactate treatment abrogates enhanced glycolysis in TLR-stimulated macrophages, which correlates with its activity as modulator of innate response (22), Caco-2- CCL20:LUC reporter cell line was utilized to evaluate if the effects of lactate on epithelial cells could be related to metabolic changes.…”

Section: Resultsmentioning

confidence: 99%

“…We have recently shown that lactate impairs macrophage metabolic reprograming after LPS activation in a GPR81-independent manner (22), which has also been associated with blunting the proinflammatory cytokine response (46). In accordance with these results, Selleri et al (47) have shown that local increase of lactate in the environment of mesenchymal stromal cells shifts macrophage M1 activation toward the less inflammatory M2 (47).…”

Section: Discussionmentioning

confidence: 99%

Local Treatment with Lactate Prevents Intestinal Inflammation in the TNBS-Induced Colitis Model

et al. 2016

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Lactate has long been considered as a metabolic by-product of cells. Recently, this view has been changed by the observation that lactate can act as a signaling molecule and regulates critical functions of the immune system. We previously identified lactate as the component responsible for the modulation of innate immune epithelial response of fermented milk supernatants in vitro. We have also shown that lactate downregulates proinflammatory responses of macrophages and dendritic cells. So far, in vivo effects of lactate on intestinal inflammation have not been reported. We evaluated the effect of intrarectal administration of lactate in a murine model of colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS). The increase in lactate concentration in colon promoted protective effects against TNBS-induced colitis preventing histopathological damage, as well as bacterial translocation and rise of IL-6 levels in serum. Using intestinal epithelial reporter cells, we found that flagellin treatment induced reporter gene expression, which was abrogated by lactate treatment as well as by glycolysis inhibitors. Furthermore, lactate treatment modulated glucose uptake, indicating that high levels of extracellular lactate can impair metabolic reprograming induced by proinflammatory activation. These results suggest that lactate could be a potential beneficial microbiota metabolite and may constitute an overlooked effector with modulatory properties.

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Lactate Inhibits the Pro-Inflammatory Response and Metabolic Reprogramming in Murine Macrophages in a GPR81-Independent Manner

Cited by 110 publications

References 33 publications

Lactate‐induced activation of HCA2 improves survival in mice with sepsis

Lactate‐induced activation of HCA2 improves survival in mice with sepsis

Differential remodeling of the electron transport chain is required to support TLR3 and TLR4 signaling and cytokine production in macrophages

Local Treatment with Lactate Prevents Intestinal Inflammation in the TNBS-Induced Colitis Model

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