PFKFB2-mediated glycolysis promotes lactate-driven continual efferocytosis by macrophages

Schilperoort, Maaike; Ngai, David; Katerelos, Marina; Power, David; Tabas, Ira

doi:10.1038/s42255-023-00736-8

Cited by 48 publications

(46 citation statements)

References 58 publications

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“…If this pathway were relevant in our setting, EIL-induced Myc protein would require the release of lactate to the extracellular space to activate the cell-surface receptor. Indeed, partial silencing the lactate transporter, SLC16a1, which prevents the export of lactate from efferocytosing macrophages 8,9 , partially lowered Myc protein expression ( Fig. 5a and Extended Data Fig.…”

Section: Resultsmentioning

confidence: 99%

“…However, a direct, mechanistic link between EIL and pro-resolving mediators remains to be fully explored. Paracrine effects are important, as only a subset of macrophages carry out efferocytosis [8][9][10]34 , and thus EIL may be a mechanism by which the resolution-efferocytosis cycle may act more broadly.…”

Section: Discussionmentioning

confidence: 99%

“…Both inflammatory macrophages and efferocytic macrophages can undergo proliferation and increase glycolysis to enhance lactate secretion [8][9][10]26 . However, whereas inflammatory macrophages do not undergo Myc-induced EIMP 10 , they do undergo CSF-1-mediated proliferation 26 .…”

Section: Discussionmentioning

confidence: 99%

“…Macrophage functions, including those involved in efferocytosis and resolution, is profoundly affected by intracellular metabolism and metabolic by-products. For example, lactate produced by glycolytic metabolism plays an active role in pro-resolution signaling in immune cells, including macrophages [6][7][8][9] . Two recent studies have shown that efferocytosis can drive increased glycolysis to produce lactate, which stimulates macrophage secretion of pro-resolving factors and promotes continual efferocytosis 8,9 .…”

Section: Introductionmentioning

confidence: 99%

“…For example, lactate produced by glycolytic metabolism plays an active role in pro-resolution signaling in immune cells, including macrophages [6][7][8][9] . Two recent studies have shown that efferocytosis can drive increased glycolysis to produce lactate, which stimulates macrophage secretion of pro-resolving factors and promotes continual efferocytosis 8,9 . Another form of macrophage metabolism that occurs during efferocytosis is "cargo" metabolism, whereby metabolites released during phagolysosomal degradation of ACs, such as nucleic acids [10][11][12] , can trigger pro-resolving pathways and continual efferocytosis in efferocytosing macrophages.…”

Section: Introductionmentioning

confidence: 99%

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Efferocytosis-Induced Lactate Enables the Proliferation of Pro-Resolving Macrophages to Mediate Tissue Repair

Ngai

Schilperoort

Tabas

2023

Preprint

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The clearance of apoptotic cells (ACs) by macrophages (efferocytosis) promotes tissue repair by preventing necrosis and inflammation and by activating pro-resolving pathways, including continual efferocytosis. A key resolution process in vivo is efferocytosis-induced macrophage proliferation (EIMP), in which AC-derived nucleotides trigger Myc-mediated macrophage proliferation, thereby increasing the pool of efferocytosis-competent macrophages. Here we show that EIMP requires a second input that is integrated with cellular metabolism, notably, efferocytosis-induced lactate production. While the AC-nucleotide pathway leads to induction of Myc mRNA, lactate signaling is required for the stabilization of Myc protein and subsequent macrophage proliferation. Lactate, via GPR132 and protein kinase A, activates AMP kinase, which increases the NAD+:NADH ratio. This upstream pathway then activates the NAD+-dependent protein deacetylase, SIRT1, which deacetylates Myc to promote its stabilization. Inhibition or silencing of any step along this pathway prevents the increase in Myc protein and proliferation in efferocytosing macrophages despite the presence of the AC-nucleotide/Myc mRNA pathway. To test importance in vivo, we transplanted mice with bone marrow cells in which the lactate biosynthetic enzyme lactate dehydrogenase A (LDHA) was knocked down. We then subjected these mice and control bone marrow-transplanted mice to dexamethasone-induced thymocyte apoptosis, a model of high-AC burden. The thymi of the LDHA-knockdown cohort showed reduced macrophage Myc protein expression and proliferation, impaired AC clearance, and increased tissue necrosis. Thus, efferocytosis-induced macrophage proliferation, which is a key process in tissue resolution, requires inputs from two independent efferocytosis-induced processes: a signaling pathway induced by AC-derived nucleotides and a cellular metabolism pathway involving lactate production. These findings illustrate how seemingly distinct pathways in efferocytosing macrophages are integrated to carry out a key process in tissue resolution.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Efferocytosis-Induced Lactate Enables the Proliferation of Pro-Resolving Macrophages to Mediate Tissue Repair

Ngai

Schilperoort

Tabas

2023

Preprint

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Promoting Diabetic Wound Healing through a Hydrogel‐Based Cascade Regulation Strategy of Fibroblast‐Macrophage

Jin,

Wang,

Tang

et al. 2024

Adv Healthcare Materials

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The management of diabetic wounds (DWs) continues to pose a significant challenge in the field of medicine. DWs are primarily prevented from healing due to damage to macrophage efferocytosis and fibroblast dysfunction. Consequently, treatment strategy that involve both immunoregulation and the promotion of extracellular matrix (ECM) formation hold promise for healing DWs. Nevertheless, existing treatment methods necessitate complex interventions and are associated with increased costs, for example, the use of cytokines and cell therapy, both of which have limited effectiveness. In this study, a new type of ruthenium (IV) oxide nanoparticles (RNPs)‐laden hybrid hydrogel dressing with a double network of Pluronic F127 and F68 has been developed. Notably, the hybrid hydrogel demonstrates remarkable thermosensitivity, injectability, immunoregulatory characteristics and healing capability. RNPs in hydrogel effectively regulate both fibroblasts and macrophages in a cascade manner, stimulating fibroblast differentiation while synergistically enhancing the efferocytosis of macrophage. The immunoregulatory character of the hydrogel aids in restoring the intrinsic stability of the immune microenvironment in the wound and facilitates essential remodeling of the ECM. This hydrogel therefore offers a novel approach for treating DWs through intercellular communication.This article is protected by copyright. All rights reserved

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Activating Macrophage Continual Efferocytosis via Microenvironment Biomimetic Short Fibers for Reversing Inflammation in Bone Repair

Wang,

Zhang,

Zhang

et al. 2024

Advanced Materials

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Efferocytosis‐mediated inflammatory reversal plays a crucial role in bone repairing process. However, in refractory bone defects, the macrophage continual efferocytosis may be suppressed due to the disrupted microenvironment homeostasis, particularly the loss of apoptotic signals and overactivation of intracellular oxidative stress. In this study, we present a polydopamine‐coated short fiber matrix containing biomimetic “apoptotic signals” to reconstruct the microenvironment and reactivate macrophage continual efferocytosis for inflammatory reversal and bone defect repair. The “apoptotic signals” (AM/CeO2) are prepared using CeO2 nanoenzymes with apoptotic neutrophil membrane coating for macrophage recognition and oxidative stress regulation. Additionally, a short fiber “biomimetic matrix” is utilized for loading AM/CeO2 signals via abundant adhesion sites involving π‐π stacking and hydrogen bonding interactions. Ultimately, the implantable apoptosis‐mimetic nanoenzyme/short‐fiber matrixes (PFS@AM/CeO2), integrating apoptotic signals and biomimetic matrixes, are constructed to facilitate inflammatory reversal and reestablish pro‐efferocytosis microenvironment. In vitro and in vivo data indicate that the microenvironment biomimetic short fibers could activate macrophage continual efferocytosis, leading to the suppression of overactivated inflammation. The enhanced repair of rat femoral defect further demonstrates the osteogenic potential of pro‐efferocytosis strategy. We believe that the regulation of macrophage efferocytosis through microenvironment biomimetic materials could provide a new perspective for tissue repair.This article is protected by copyright. All rights reserved

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PFKFB2-mediated glycolysis promotes lactate-driven continual efferocytosis by macrophages

Cited by 48 publications

References 58 publications

Efferocytosis-Induced Lactate Enables the Proliferation of Pro-Resolving Macrophages to Mediate Tissue Repair

Efferocytosis-Induced Lactate Enables the Proliferation of Pro-Resolving Macrophages to Mediate Tissue Repair

Promoting Diabetic Wound Healing through a Hydrogel‐Based Cascade Regulation Strategy of Fibroblast‐Macrophage

Activating Macrophage Continual Efferocytosis via Microenvironment Biomimetic Short Fibers for Reversing Inflammation in Bone Repair

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