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Efferocytosis-induced lactate enables the proliferation of pro-resolving macrophages to mediate tissue repair

Nature Metabolism volume 5, pages 2206–2219 (2023)Cite this article

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Abstract

The clearance of apoptotic cells by macrophages (efferocytosis) prevents necrosis and inflammation and activates pro-resolving pathways, including continual efferocytosis. A key resolution process in vivo is efferocytosis-induced macrophage proliferation (EIMP), in which apoptotic cell-derived nucleotides trigger Myc-mediated proliferation of pro-resolving macrophages. Here we show that EIMP requires a second input that is integrated with cellular metabolism, notably efferocytosis-induced lactate production. Lactate signalling via GPR132 promotes Myc protein stabilization and subsequent macrophage proliferation. This mechanism is validated in vivo using a mouse model of dexamethasone-induced thymocyte apoptosis, which elevates apoptotic cell burden and requires efferocytosis to prevent inflammation and necrosis. Thus, EIMP, a key process in tissue resolution, requires inputs from two independent processes: a signalling pathway induced by apoptotic cell-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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Fig. 1: LDHA-dependent lactate production during efferocytosis increases Myc protein and promotes EIMP.
Fig. 2: EIL stabilizes AC-induced Myc protein through decreased Myc acetylation, which occurs following AC-nucleotide/DNase2a-mediated Myc transcription.
Fig. 3: EIL activates SIRT1, which stabilizes Myc by deacetylation and promotes EIMP.
Fig. 4: EIL activates AMPK, thereby increasing the NAD+ to NADH ratio, SIRT1 activity, Myc protein and EIMP.
Fig. 5: EIL activates AMPK by GPR132-PKA signalling, which increases Myc protein and EIMP.
Fig. 6: In vivo evidence that EIL promotes EIMP and tissue resolution.

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Data availability

All data supporting the present study are available within the paper and supplementary information files. Source data are provided with this paper.

References

  1. Morioka, S., Maueröder, C. & Ravichandran, K. S. Living on the edge: efferocytosis at the interface of homeostasis and pathology. Immunity 50, 1149–1162 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Doran, A. C., Yurdagul, A. & Tabas, I. Efferocytosis in health and disease. Nat. Rev. Immunol. 20, 254–267 (2020).

    Article  PubMed  CAS  Google Scholar 

  3. Arandjelovic, S. & Ravichandran, K. S. Phagocytosis of apoptotic cells in homeostasis. Nat. Immunol. 16, 907–917 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Boada-Romero, E., Martinez, J., Heckmann, B. L. & Green, D. R. The clearance of dead cells by efferocytosis. Nat. Rev. Mol. Cell Biol. 21, 398–414 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Dalli, J. & Serhan, C. N. Pro-resolving mediators in regulating and conferring macrophage function. Front. Immunol. 8, 1400 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Colegio, O. R. et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559–563 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Cai, H. et al. Moderate l-lactate administration suppresses adipose tissue macrophage M1 polarization to alleviate obesity-associated insulin resistance. J. Biol. Chem. 298, 101768 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Morioka, S. et al. Efferocytosis induces a novel SLC program to promote glucose uptake and lactate release. Nature 563, 714–718 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Schilperoort, M., Ngai, D., Katerelos, M., Power, D. A. & Tabas, I. PFKFB2-mediated glycolysis promotes lactate-driven continual efferocytosis by macrophages. Nat. Metab. 5, 431–444 (2023).

    Article  PubMed  CAS  Google Scholar 

  10. Gerlach, B. D. et al. Efferocytosis induces macrophage proliferation to help resolve tissue injury. Cell Metab. 33, 2445–2463.e2448 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Yurdagul, A. Jr et al. Macrophage metabolism of apoptotic cell-derived arginine promotes continual efferocytosis and resolution of injury. Cell Metab. 31, 518–533.e10 (2020).

  12. Zhang, S. et al. Efferocytosis fuels requirements of fatty acid oxidation and the electron transport chain to polarize macrophages for tissue repair. Cell Metab. 29, 443–456.e445 (2019).

    Article  PubMed  CAS  Google Scholar 

  13. Farrell, A. S. & Sears, R. C. MYC degradation. Cold Spring Harb. Perspect. Med. 4, a014365 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Marshall, G. M. et al. SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability. PLoS Genet. 7, e1002135 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Menssen, A. et al. The c-MYC oncoprotein, the NAMPT enzyme, the SIRT1-inhibitor DBC1, and the SIRT1 deacetylase form a positive feedback loop. Proc. Natl Acad. Sci. USA 109, E187–E196 (2012).

    Article  PubMed  CAS  Google Scholar 

  16. Li, L. et al. SIRT1 activation by a c-MYC oncogenic network promotes the maintenance and drug resistance of human FLT3-ITD acute myeloid leukemia stem cells. Cell Stem Cell 15, 431–446 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Nebbioso, A. et al. c-Myc modulation and acetylation is a key HDAC inhibitor target in cancer. Clin. Cancer Res. 23, 2542–2555 (2017).

    Article  PubMed  CAS  Google Scholar 

  18. Mao, B. et al. Sirt1 deacetylates c-Myc and promotes c-Myc/Max association. Int. J. Biochem. Cell Biol. 43, 1573–1581 (2011).

    Article  PubMed  CAS  Google Scholar 

  19. Zhang, Y. & Dong, F. Gfi1 upregulates c-Myc expression and promotes c-Myc-driven cell proliferation. Sci. Rep. 10, 17115 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Yang, L. et al. Lactate promotes synthetic phenotype in vascular smooth muscle cells. Circ. Res. 121, 1251–1262 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Watson, M. J. et al. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature 591, 645–651 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Le, A. et al. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc. Natl Acad. Sci. USA 107, 2037–2042 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. McCubbrey, A. L. et al. MicroRNA-34a negatively regulates efferocytosis by tissue macrophages in part via SIRT1. J Immunol. 196, 1366–1375 (2016).

    Article  PubMed  CAS  Google Scholar 

  24. El Hayek, L. et al. Lactate mediates the effects of exercise on learning and memory through SIRT1-dependent activation of hippocampal brain-derived neurotrophic factor (BDNF). J. Neurosci. 39, 2369–2382 (2019).

    PubMed  PubMed Central  Google Scholar 

  25. Gertz, M. et al. Ex-527 inhibits Sirtuins by exploiting their unique NAD+-dependent deacetylation mechanism. Proc. Natl Acad. Sci. USA 110, E2772–E2781 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. López-Villegas, D., Lenkinski, R. E., Wehrli, S. L., Ho, W. Z. & Douglas, S. D. Lactate production by human monocytes/macrophages determined by proton MR spectroscopy. Magn. Reson. Med. 34, 32–38 (1995).

    Article  PubMed  Google Scholar 

  27. Roussel, M. F. Signal transduction by the macrophage-colony-stimulating factor receptor (CSF-1R). J. Cell Sci. Suppl. 18, 105–108 (1994).

    Article  PubMed  CAS  Google Scholar 

  28. Stanley, E. R. & Chitu, V. CSF-1 receptor signaling in myeloid cells. Cold Spring Harb. Perspect. Biol. 6, a021857 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Cantó, C. et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458, 1056–1060 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Costford, S. R. et al. Skeletal muscle NAMPT is induced by exercise in humans. Am. J. Physiol. Endocrinol. Metab. 298, E117–E126 (2010).

    Article  PubMed  CAS  Google Scholar 

  31. Cerda-Kohler, H. et al. Lactate administration activates the ERK1/2, mTORC1, and AMPK pathways differentially according to skeletal muscle type in mouse. Physiol. Rep. 6, e13800 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Jiang, S. et al. Mitochondria and AMP-activated protein kinase-dependent mechanism of efferocytosis. J. Biol. Chem. 288, 26013–26026 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Garcia, D. & Shaw, R. J. AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Mol. Cell 66, 789–800 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Foster, J. R. et al. N-palmitoylglycine and other N-acylamides activate the lipid receptor G2A/GPR132. Pharmacol. Res. Perspect. 7, e00542 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Nii, T. et al. Imipridone ONC212 activates orphan G protein-coupled receptor GPR132 and integrated stress response in acute myeloid leukemia. Leukemia 33, 2805–2816 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Ampomah, P. B. et al. Macrophages use apoptotic cell-derived methionine and DNMT3A during efferocytosis to promote tissue resolution. Nat. Metab. 4, 444–457 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Kasikara, C. et al. Deficiency of macrophage PHACTR1 impairs efferocytosis and promotes atherosclerotic plaque necrosis. J. Clin. Invest. 131, e145275 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Park, D. et al. Continued clearance of apoptotic cells critically depends on the phagocyte Ucp2 protein. Nature 477, 220–224 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Yurdagul, A., Doran, A. C., Cai, B., Fredman, G. & Tabas, I. A. Mechanisms and consequences of defective efferocytosis in atherosclerosis. Front. Cardiovasc. Med. 4, 86 (2017).

    Article  PubMed  Google Scholar 

  40. Vadevoo, S. M. P. et al. The macrophage odorant receptor Olfr78 mediates the lactate-induced M2 phenotype of tumor-associated macrophages. Proc. Natl Acad. Sci. USA 118, e2102434118 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Sag, D., Carling, D., Stout, R. D. & Suttles, J. Adenosine 5′-monophosphate-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype. J. Immunol. 181, 8633–8641 (2008).

    Article  PubMed  CAS  Google Scholar 

  42. Jha, M. K. et al. Macrophage monocarboxylate transporter 1 promotes peripheral nerve regeneration after injury in mice. J. Clin. Invest. 131, e141964 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Wang, Y. et al. Mitochondrial fission promotes the continued clearance of apoptotic cells by macrophages. Cell 171, 331–345.e322 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Li, X. et al. Lactate metabolism in human health and disease. Signal Transduct. Target. Ther. 7, 305 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Brooks, G. A. Lactate as a fulcrum of metabolism. Redox Biol. 35, 101454 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Sharma, M. et al. Regulatory T cells license macrophage pro-resolving functions during atherosclerosis regression. Circ. Res. 127, 335–353 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Newby, A. C. & Zaltsman, A. B. Fibrous cap formation or destruction–the critical importance of vascular smooth muscle cell proliferation, migration and matrix formation. Cardiovasc. Res. 41, 345–360 (1999).

    Article  PubMed  CAS  Google Scholar 

  48. Haas, R. et al. Lactate regulates metabolic and pro-inflammatory circuits in control of T cell migration and effector functions. PLoS Biol. 13, e1002202 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Skuljec, J. et al. Absence of regulatory T cells causes phenotypic and functional switch in murine peritoneal macrophages. Front. Immunol. 9, 2458 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Proto, J. D. et al. Regulatory T cells promote macrophage efferocytosis during inflammation resolution. Immunity 49, 666–677.e666 (2018).

    Article  PubMed  CAS  Google Scholar 

  51. Miao, P., Sheng, S., Sun, X., Liu, J. & Huang, G. Lactate dehydrogenase A in cancer: a promising target for diagnosis and therapy. IUBMB Life 65, 904–910 (2013).

    Article  PubMed  CAS  Google Scholar 

  52. Sinha, S. K. et al. Local M-CSF (macrophage colony-stimulating factor) expression regulates macrophage proliferation and apoptosis in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 41, 220–233 (2021).

    PubMed  CAS  Google Scholar 

  53. Shantha, G. P. et al. Association of blood lactate with carotid atherosclerosis: the Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study. Atherosclerosis 228, 249–255 (2013).

    Article  PubMed  CAS  Google Scholar 

  54. Garcia-Alvarez, M., Marik, P. & Bellomo, R. Sepsis-associated hyperlactatemia. Crit. Care 18, 503 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Tabas, I. Consequences and therapeutic implications of macrophage apoptosis in atherosclerosis: the importance of lesion stage and phagocytic efficiency. Arterioscler. Thromb. Vasc. Biol. 25, 2255–2264 (2005).

    Article  PubMed  CAS  Google Scholar 

  56. Cui, X. et al. The G2A receptor deficiency aggravates atherosclerosis in rats by regulating macrophages and lipid metabolism. Front. Physiol. 12, 659211 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Koyama, T. Lactated Ringer’s solution for preventing myocardial reperfusion injury. Int. J. Cardiol. Heart Vasc. 15, 1–8 (2017).

    PubMed  PubMed Central  Google Scholar 

  58. Gleeson, M. et al. The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat. Rev. Immunol. 11, 607–615 (2011).

    Article  PubMed  CAS  Google Scholar 

  59. Casteels, K. M. et al. Sex difference in resistance to dexamethasone-induced apoptosis in NOD mice: treatment with 1,25(OH)2D3 restores defect. Diabetes 47, 1033–1037 (1998).

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by an American Heart Association Postdoctoral Fellowship (grant no. 900337 to M.S.); the Niels Stensen Fellowship (to M.S.) and NIH/NHLBI grant nos. R35-HL145228 and P01-HL087123 (to I.T.). We thank L. Becker (University of Chicago) for providing Ldhafl/fl and Ldhafl/fl; LysMCre+/− mouse femurs for BMDM differentiation to use in our in vitro studies. We thank X. Wang (Columbia University) for assisting with intravenous injections for BMT. We acknowledge C. Lu of the Columbia Center for Translational Immunology Core Facility for assisting in the immunofluorescent imaging experiments that were conducted in the Columbia Center for Translational Immunology Core Facility, funded by NIH grant nos. P30CA013696, S10RR027050 and S10OD020056.

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Authors and Affiliations

  1. Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA

    David Ngai, Maaike Schilperoort & Ira Tabas

  2. Departments of Physiology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA

    Ira Tabas

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Contributions

D.N. and I.T. conceived the project. D.N., M.S. and I.T. provided intellectual input to the development of the project. D.N. performed the in vitro experiments. D.N. and M.S. performed the in vivo dexamethasone-thymus experiment.

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Correspondence to David Ngai or Ira Tabas.

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Nature Metabolism thanks Roel De Maeyer, Nicholas Leeper and Feilong Wang for their contribution to the peer review of this work. Primary Handling Editor: Alfredo Giménez-Cassina, in collaboration with the Nature Metabolism team.

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Extended data

Extended Data Fig. 1 Related to Figs. 1 and 2: Controls for BMDM experiments.

a, BMDMs were incubated with or without ACs for 45 minutes before washing and chasing for 1 hour in low-serum DMEM ± 50 µM FX11. The media were assayed for lactate concentration (n = 3). b, BMDMs were transfected with scrambled (Scr) or Ldha siRNA for 72 hours and then assayed for Ldha mRNA by RT-qPCR (n = 3). c) BMDMs pre-treated with 50 µM FX11 for 1 hour were incubated for 45 minutes with PKH26-labelled ACs and quantified for % PKH26+ macrophages (n = 3). d, BMDMs were incubated with ACs for 45 minutes, chased for 3 hours ± 50 µM FX11 and ± 2/5/10 mM LA, and immunoblotted for Myc (n = 3). e, BMDMs were incubated with or without ACs for 45 minutes, chased for 3 hours ± 50 µM FX11 and ± 10 mM sodium lactate (NaLa), and immunoblotted for Myc (n = 3). f, BMDMs transfected with 50 nM scrambled or Myc siRNA for 72 hours were incubated with or without ACs for 45 minutes, chased for 3 hours, and immunoblotted for Myc (n = 3). g, BMDMs were treated ± 10 mM LA for 3 hours and immunoblotted for Myc (n = 3). h, BMDMs were treated for 24 hours ± 10 mM LA before performing a cell count (n = 3). i, BMDMs were incubated with or without ACs for 45 minutes, chased for 3 hours ± 10 mM LA, and immunoblotted for Myc (n = 3). j, BMDMs were incubated with ACs for 45 minutes, chased for 3 hours ± 50 µM FX11 and ± 10 or 25 mM LA, and immunoblotted for Myc. Similar results were obtained in a repeat experiment. k, BMDMs were incubated with or without ACs for 45 minutes, chased for 3 hours ± 10 µM MG132, and immunoblotted for Myc (n = 3). Bars represent means ± s.e.m. Statistics were performed by two-tailed student’s t-test in panels b-c, h, or one-way ANOVA in panels a, d, e, i, and k. n.s. = non-significant (P > 0.05).

Source data

Extended Data Fig. 2 Related to Figs. 3 and 4: Controls for BMDM experiments.

a, BMDMs were transfected with 50 nM scrambled or Sirt1 siRNA for 72 hours, incubated with PKH26-labelled ACs for 45 minutes, and quantified for the percent PKH26+ macrophages (n = 3). b, BMDMs were incubated with or without ACs for 45 minutes, chased for 3 hours ± 10 µM EX527 and ± 10 mM LA, and immunoblotted for Myc (n = 3). c, BMDMs were treated with 50 ng/mL CSF-1 for 3, 6, 12, or 24 hours and immunoblotted for Myc. The image presented is one representative replicate (n = 3). d, BMDMs were treated with or without 50 ng/mL CSF-1 + 50 µM FX11 or 10 µM EX527, and immunoblotted for Myc (n = 3). e, BMDMs were treated for 24 hours with 50 ng/mL CSF-1 + 50 μM FX11 or 10 μM EX527, and quantified for cell number (n = 3). f, BMDMs were transfected with 50 nM scrambled or Myc siRNA for 72 hours, incubated ± ACs for 45 minutes or with CSF-1, and then assayed 24 hours later for cell number and Myc protein for CSF1-treated cells (n = 3). g, BMDMs pre-treated for 1 hour with 10 µM CompC were incubated with PKH26-labelled ACs and quantified for the percent PKH26+ (n = 3). h, BMDMs were chased for 1 hour + 10 µM CompC with or without 500 µM NMN and then assayed for NAD+ to NADH ratio (n = 3). i, BMDMs were treated ± 500 µM NMN for 3 hours and then immunoblotted for Myc (n = 3). j, BMDMs transfected with scrambled or Sirt1 siRNA were chased for 3 hours ± 500 µM NMN and then immunoblotted for Myc (n = 3). Bars represent means ± s.e.m. Statistics were performed by two-tailed student’s t-test in panels a and g, or one-way ANOVA in panels b-f, h, and j. n.s. = non-significant (P > 0.05).

Source data

Extended Data Fig. 3 Related to Fig. 5: Controls for BMDM experiments.

a, BMDMs were transfected with 50 nM scrambled or Slc16a1 siRNA for 72 hours and then assayed for Slc16a1 mRNA by RT-qPCR (n = 3). b, BMDMs transfected with 50 nM scrambled or Slc16a1 siRNA for 72 hours were incubated with ACs for 45 minutes, chased for 3 hours in 1% FBS DMEM before collecting supernatants and cell lysates to measure intracellular and extracellular lactate concentrations (n = 3). c, BMDMs were transfected with 50 nM scrambled or Gpr132 siRNA for 72 hours and then assayed for Gpr132 mRNA by RT-qPCR (n = 3). d, BMDMs transfected with 50 nM scrambled or Gpr132 siRNA for 72 hours were incubated with or without ACs for 45 minutes, chased for 3 hours ± 50 µM FX11 and ± 10 mM LA, and immunoblotted for Myc. The displayed immunoblot is a representative replicate (n = 3). e, BMDMs were incubated with or without ACs for 45 minutes, chased for 3 hours ± 50 μM FX11, and assayed for Gpr132 mRNA (n = 3). Bars represent means ± s.e.m. Statistics were performed by two-tailed student’s t-test in panels a-c, one-way ANOVA in panel d, or two-way ANOVA in panel e. n.s. = non-significant (P > 0.05).

Source data

Extended Data Fig. 4 Related to Fig. 6: Controls and blood counts for the dexamethasone-thymus experiment.

a-f, Counts of blood WBCs, neutrophils, lymphocytes, monocytes, eosinophils, and basophils (n = 5). g, Plasma was measured for lactate concentration (n = 5). h, Mac2+ cells in immunostained thymus sections were counted per field of view (FOV) using images taken with a 20x objective (n = 8,6). Bars represent means ± s.e.m. Statistics were performed by two-tailed student’s t-test in panels a-e and g-h, and Mann–Whitney test for panel f. n.s. = non-significant (P > 0.05).

Supplementary information

Source data

Source Data Fig. 1–6 and Extended Data Figs. 1–3

Unprocessed western blots for Figs. 1–6 and Extended Data Figs. 1–3.

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Ngai, D., Schilperoort, M. & Tabas, I. Efferocytosis-induced lactate enables the proliferation of pro-resolving macrophages to mediate tissue repair. Nat Metab 5, 2206–2219 (2023). https://doi.org/10.1038/s42255-023-00921-9

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