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Serine metabolism orchestrates macrophage polarization by regulating the IGF1–p38 axis


Serine metabolism is reportedly involved in immune cell functions, but whether and how serine metabolism regulates macrophage polarization remain largely unknown. Here, we show that suppressing serine metabolism, either by inhibiting the activity of the key enzyme phosphoglycerate dehydrogenase in the serine biosynthesis pathway or by exogenous serine and glycine restriction, robustly enhances the polarization of interferon-γ-activated macrophages (M(IFN-γ)) but suppresses that of interleukin-4-activated macrophages (M(IL-4)) both in vitro and in vivo. Mechanistically, serine metabolism deficiency increases the expression of IGF1 by reducing the promoter abundance of S-adenosyl methionine-dependent histone H3 lysine 27 trimethylation. IGF1 then activates the p38-dependent JAK–STAT1 axis to promote M(IFN-γ) polarization and suppress STAT6-mediated M(IL-4) activation. This study reveals a new mechanism by which serine metabolism orchestrates macrophage polarization and suggests the manipulation of serine metabolism as a therapeutic strategy for macrophage-mediated immune diseases.

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  1. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Investig. 2012;122:787–95.

  2. Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141:39–51.

  3. Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41:14–20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Langston PK, Shibata M, Horng T. Metabolism supports macrophage activation. Front Immunol. 2017;8:61.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Van den Bossche J, O’Neill LA, Menon D. Macrophage immunometabolism: where are we (going)? Trends Immunol. 2017;38:395–406.

    Article  PubMed  Google Scholar 

  6. Stienstra R, Netea-Maier RT, Riksen NP, Joosten LAB, Netea MG. Specific and complex reprogramming of cellular metabolism in myeloid cells during innate immune responses. Cell Metab. 2017;26:142–56.

    Article  PubMed  CAS  Google Scholar 

  7. Munder M, Eichmann K, Modolell M. Alternative metabolic states in murine macrophages reflected by the nitric oxide synthase/arginase balance: competitive regulation by CD4+ T cells correlates with Th1/Th2 phenotype. J Immunol. 1998;160:5347–54.

    PubMed  CAS  Google Scholar 

  8. Rath M, Muller I, Kropf P, Closs EI, Munder M. Metabolism via arginase or nitric oxide synthase: two competing arginine pathways in macrophages. Front Immunol. 2014;5:532.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Bronte V, Zanovello P. Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol. 2005;5:641–54.

    Article  PubMed  CAS  Google Scholar 

  10. Liu PS, Wang H, Li X, Chao T, Teav T, Christen S, et al. alpha-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat Immunol. 2017;18:985–94.

    Article  PubMed  CAS  Google Scholar 

  11. Rodriguez AE, Ducker GS, Billingham LK, Martinez CA, Mainolfi N, Suri V, et al. Serine metabolism supports macrophage IL-1beta production. Cell Metab. 2019;29:1003–11.e4.

  12. Yu W, Wang Z, Zhang K, Chi Z, Xu T, Jiang D, et al. One-carbon metabolism supports S-adenosylmethionine and histone methylation to drive inflammatory macrophages. Mol Cell. 2019;75:1147–60.e5.

    Article  PubMed  CAS  Google Scholar 

  13. Chen S, Xia Y, He F, Fu J, Xin Z, Deng B, et al. Serine supports IL-1beta production in macrophages through mTOR signaling. Front Immunol. 2020;11:1866.

  14. Wilson JL, Nagele T, Linke M, Demel F, Fritsch SD, Mayr HK, et al. Inverse data-driven modeling and multiomics analysis reveals Phgdh as a metabolic checkpoint of macrophage polarization and proliferation. Cell Rep. 2020;30:1542–52.e7.

    Article  PubMed  CAS  Google Scholar 

  15. Ivashkiv LB. IFNγ: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy. Nat Rev Immunol. 2018;18:545–58.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Hakuno F, Takahashi SI. IGF1 receptor signaling pathways. J Mol Endocrinol. 2018;61:T69–86.

    Article  PubMed  CAS  Google Scholar 

  17. Kineman RD, Del Rio-Moreno M, Sarmento-Cabral A. 40 years of IGF1: understanding the tissue-specific roles of IGF1/IGF1R in regulating metabolism using the Cre/loxP system. J Mol Endocrinol. 2018;61:T187–98.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Higashi Y, Sukhanov S, Shai SY, Danchuk S, Tang R, Snarski P, et al. Insulin-like growth factor-1 receptor deficiency in macrophages accelerates atherosclerosis and induces an unstable plaque phenotype in apolipoprotein E-deficient mice. Circulation. 2016;133:2263–78.

  19. Spadaro O, Camell CD, Bosurgi L, Nguyen KY, Youm YH, Rothlin CV, et al. IGF1 shapes macrophage activation in response to immunometabolic challenge. Cell Rep. 2017;19:225–34.

  20. Barrett JP, Minogue AM, Falvey A, Lynch MA. Involvement of IGF-1 and Akt in M1/M2 activation state in bone marrow-derived macrophages. Exp Cell Res. 2015;335:258–68.

    Article  PubMed  CAS  Google Scholar 

  21. Ieronymaki E, Theodorakis EM, Lyroni K, Vergadi E, Lagoudaki E, Al-Qahtani A, et al. Insulin resistance in macrophages alters their metabolism and promotes an M2-like phenotype. J Immunol. 2019;202:1786–97.

  22. Youssif C, Cubillos-Rojas M, Comalada M, Llonch E, Perna C, Djouder N, et al. Myeloid p38alpha signaling promotes intestinal IGF-1 production and inflammation-associated tumorigenesis. EMBO Mol Med. 2018;10:e8403.

  23. American Type Culture Collection Standards Development Organization Workgroup ASN. Cell line misidentification: the beginning of the end. Nat Rev Cancer. 2010;10:441–8.

    Article  Google Scholar 

  24. Mullarky E, Lucki NC, Beheshti Zavareh R, Anglin JL, Gomes AP, Nicolay BN, et al. Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers. Proc Natl Acad Sci USA. 2016;113:1778–83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Shen L, Hu P, Zhang Y, Ji Z, Shan X, Ni L, et al. Serine metabolism antagonizes antiviral innate immunity by preventing ATP6V0d2-mediated YAP lysosomal degradation. Cell Metab. 2021;33:971–87.e6.

    Article  PubMed  CAS  Google Scholar 

  26. Foster AC, Rangel-Diaz N, Staubli U, Yang JY, Penjwini M, Viswanath V, et al. Phenylglycine analogs are inhibitors of the neutral amino acid transporters ASCT1 and ASCT2 and enhance NMDA receptor-mediated LTP in rat visual cortex slices. Neuropharmacology. 2017;126:70–83.

    Article  PubMed  CAS  Google Scholar 

  27. Muthusamy T, Cordes T, Handzlik MK, You L, Lim EW, Gengatharan J, et al. Serine restriction alters sphingolipid diversity to constrain tumour growth. Nature. 2020;586:790–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Xia L, Huang W, Tian D, Zhang L, Qi X, Chen Z, et al. Forkhead box Q1 promotes hepatocellular carcinoma metastasis by transactivating ZEB2 and VersicanV1 expression. Hepatology. 2014;59:958–73.

    Article  PubMed  CAS  Google Scholar 

  29. D’Errico G, Alonso-Nocelo M, Vallespinos M, Hermann PC, Alcala S, Garcia CP, et al. Tumor-associated macrophage-secreted 14-3-3zeta signals via AXL to promote pancreatic cancer chemoresistance. Oncogene. 2019;38:5469–85.

    Article  PubMed  Google Scholar 

  30. Wang Y, Sun Q, Ye Y, Sun X, Xie S, Zhan Y, et al. FGF-2 signaling in nasopharyngeal carcinoma modulates pericyte-macrophage crosstalk and metastasis. JCI Insight. 2022;7:e157874.

  31. Tan HY, Wang N, Man K, Tsao SW, Che CM, Feng Y. Autophagy-induced RelB/p52 activation mediates tumour-associated macrophage repolarisation and suppression of hepatocellular carcinoma by natural compound baicalin. Cell Death Dis. 2015;6:e1942.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Pesce JT, Ramalingam TR, Mentink-Kane MM, Wilson MS, El Kasmi KC, Smith AM, et al. Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis. PLoS Pathog. 2009;5:e1000371.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Ji L, Zhao X, Zhang B, Kang L, Song W, Zhao B, et al. Slc6a8-mediated creatine uptake and accumulation reprogram macrophage polarization via regulating cytokine responses. Immunity. 2019;51:272–84.e7.

    Article  PubMed  CAS  Google Scholar 

  34. Ducker GS, Ghergurovich JM, Mainolfi N, Suri V, Jeong SK, Hsin-Jung Li S, et al. Human SHMT inhibitors reveal defective glycine import as a targetable metabolic vulnerability of diffuse large B-cell lymphoma. Proc Natl Acad Sci USA. 2017;114:11404–9.

  35. Ma EH, Bantug G, Griss T, Condotta S, Johnson RM, Samborska B, et al. Serine is an essential metabolite for effector T cell expansion. Cell Metab. 2017;25:345–57.

    Article  PubMed  CAS  Google Scholar 

  36. Ron-Harel N, Santos D, Ghergurovich JM, Sage PT, Reddy A, Lovitch SB, et al. Mitochondrial biogenesis and proteome remodeling promote one-carbon metabolism for T cell activation. Cell Metab. 2016;24:104–17.

  37. Gao X, Locasale JW. Serine metabolism links tumor suppression to the epigenetic landscape. Cell Metab. 2016;24:777–9.

    Article  PubMed  CAS  Google Scholar 

  38. Li S, Swanson SK, Gogol M, Florens L, Washburn MP, Workman JL, et al. Serine and SAM responsive complex SESAME regulates histone modification crosstalk by sensing cellular metabolism. Mol Cell. 2015;60:408–21.

    Article  PubMed  CAS  Google Scholar 

  39. Mentch SJ, Mehrmohamadi M, Huang L, Liu X, Gupta D, Mattocks D, et al. Histone methylation dynamics and gene regulation occur through the sensing of one-carbon metabolism. Cell Metab. 2015;22:861–73.

  40. Shilatifard A. Chromatin modifications by methylation and ubiquitination: implications in the regulation of gene expression. Annu Rev Biochem. 2006;75:243–69.

    Article  PubMed  CAS  Google Scholar 

  41. Iwabata H, Yoshida M, Komatsu Y. Proteomic analysis of organ-specific post-translational lysine-acetylation and -methylation in mice by use of anti-acetyllysine and -methyllysine mouse monoclonal antibodies. Proteomics. 2005;5:4653–64.

    Article  PubMed  CAS  Google Scholar 

  42. Giambra V, Gusscott S, Gracias D, Song R, Lam SH, Panelli P, et al. Epigenetic restoration of fetal-like IGF1 signaling inhibits leukemia stem cell activity. Cell Stem Cell. 2018;23:714–26.e7.

    Article  PubMed  CAS  Google Scholar 

  43. Galvis LA, Holik AZ, Short KM, Pasquet J, Lun AT, Blewitt ME, et al. Repression of Igf1 expression by Ezh2 prevents basal cell differentiation in the developing lung. Development. 2015;142:1458–69.

  44. Wang Y, Hou N, Cheng X, Zhang J, Tan X, Zhang C, et al. Ezh2 acts as a tumor suppressor in Kras-driven lung adenocarcinoma. Int J Biol Sci. 2017;13:652–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Bialopiotrowicz E, Noyszewska-Kania M, Kachamakova-Trojanowska N, Loboda A, Cybulska M, Grochowska A, et al. Serine biosynthesis pathway supports MYC-miR-494-EZH2 feed-forward circuit necessary to maintain metabolic and epigenetic reprogramming of Burkitt lymphoma cells. Cancers. 2020;12:580.

  46. Kovarik P, Stoiber D, Eyers PA, Menghini R, Neininger A, Gaestel M, et al. Stress-induced phosphorylation of STAT1 at Ser727 requires p38 mitogen-activated protein kinase whereas IFN-gamma uses a different signaling pathway. Proc Natl Acad Sci USA. 1999;96:13956–61.

  47. Ramsauer K, Sadzak I, Porras A, Pilz A, Nebreda AR, Decker T, et al. p38 MAPK enhances STAT1-dependent transcription independently of Ser-727 phosphorylation. Proc Natl Acad Sci USA. 2002;99:12859–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Goh KC, Haque SJ, Williams BR. p38 MAP kinase is required for STAT1 serine phosphorylation and transcriptional activation induced by interferons. EMBO J. 1999;18:5601–8.

  49. Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol. 2010;11:889–96.

    Article  PubMed  CAS  Google Scholar 

  50. Vitale I, Manic G, Coussens LM, Kroemer G, Galluzzi L. Macrophages and metabolism in the tumor microenvironment. Cell Metab. 2019;30:36–50.

    Article  PubMed  CAS  Google Scholar 

  51. Tajan M, Hennequart M, Cheung EC, Zani F, Hock AK, Legrave N, et al. Serine synthesis pathway inhibition cooperates with dietary serine and glycine limitation for cancer therapy. Nat Commun. 2021;12:366.

  52. Yoshino H, Nohata N, Miyamoto K, Yonemori M, Sakaguchi T, Sugita S, et al. PHGDH as a key enzyme for serine biosynthesis in HIF2alpha-targeting therapy for renal cell carcinoma. Cancer Res. 2017;77:6321–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Wang Q, Liberti MV, Liu P, Deng X, Liu Y, Locasale JW, et al. Rational design of selective allosteric inhibitors of PHGDH and serine synthesis with anti-tumor activity. Cell Chem Biol. 2017;24:55–65.

    Article  PubMed  CAS  Google Scholar 

  54. Ngo B, Kim E, Osorio-Vasquez V, Doll S, Bustraan S, Liang RJ, et al. Limited environmental serine and glycine confer brain metastasis sensitivity to PHGDH inhibition. Cancer Discov. 2020;10:1352–73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Pacold ME, Brimacombe KR, Chan SH, Rohde JM, Lewis CA, Swier LJ, et al. A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate. Nat Chem Biol. 2016;12:452–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Locasale JW. Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat Rev Cancer. 2013;13:572–83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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We thank Dr. Xiaoyue Tan (Nankai University, China) for kindly providing the Lyz2-Cre mice and several cell lines. This research was supported by grants from the Tianjin Municipal Natural Science Foundation of China (20JCYBJC00220, QY) and from the National Natural Science Foundation of China: 81672710 (QY), 81872239 (QY), 82073051 (TW), 81874055 (TW), and 81902900 (LS).

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QY conceived the project and designed the experiments. QY, YW, and ZY wrote and edited the manuscript. TW, LW, and BC helped with editing the manuscript. XS, PH, LN, LS, YZ, ZJ, and YC conducted the experiments. MG, HW, LR, and KY contributed the IGF1Rfl/fl mice.

Corresponding authors

Correspondence to Zhi Yao, Yingjie Wu or Qiujing Yu.

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Shan, X., Hu, P., Ni, L. et al. Serine metabolism orchestrates macrophage polarization by regulating the IGF1–p38 axis. Cell Mol Immunol 19, 1263–1278 (2022).

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  • Serine metabolism
  • Macrophage polarization
  • SAM
  • IGF1
  • p38


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