Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Defining newly formed and tissue-resident bone marrow-derived macrophages in adult mice based on lysozyme expression

Cellular & Molecular Immunology volume 19, pages 1333–1346 (2022)Cite this article

Subjects

Abstract

Tissue-resident macrophages are derived from different precursor cells and display different phenotypes. Reconstitution of the tissue-resident macrophages of inflamed or damaged tissues in adults can be achieved by bone marrow-derived monocytes/macrophages. Using lysozyme (Lysm)-GFP-reporter mice, we found that alveolar macrophages (AMs), Kupffer cells, red pulp macrophages (RpMacs), and kidney-resident macrophages were Lysm-GFP−, whereas all monocytes in the fetal liver, adult bone marrow, and blood were Lysm-GFP+. Donor-derived Lysm-GFP+ resident macrophages gradually became Lysm-GFP− in recipients and developed gene expression profiles characteristic of tissue-resident macrophages. Thus, Lysm may be used to distinguish newly formed and long-term surviving tissue-resident macrophages that were derived from bone marrow precursor cells in adult mice under pathological conditions. Furthermore, we found that Irf4 might be essential for resident macrophage differentiation in all tissues, while cytokine and receptor pathways, mTOR signaling pathways, and fatty acid metabolic processes predominantly regulated the differentiation of RpMacs, Kupffer cells, and kidney macrophages, respectively. Deficiencies in ST2, mechanistic target of rapamycin (mTOR) and fatty acid-binding protein 5 (FABP5) differentially impaired the differentiation of tissue-resident macrophages from bone marrow-derived monocytes/macrophages in the lungs, liver, and kidneys. These results indicate that a combination of shared and unique signaling pathways coordinately shape tissue-resident macrophage differentiation in various tissues.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data availability

We downloaded the microarray GM-CSF data and M-CSF-induced bone marrow-derived macrophage data from E-MTAB-791 [29]. The raw RNA-seq data generated in our study were deposited in the National Genomics Data Center (NCDC): BioProject PRJCA008365.

Material availability

Methods, including statements of data availability and any further information, are available in the online version of this paper.

References

  1. Bleriot C, Chakarov S, Ginhoux F. Determinants of resident tissue macrophage identity and function. Immunity. 2020;52:957–70.

    Article  CAS  PubMed  Google Scholar 

  2. Knipper JA, Ding X, Eming SA. Diabetes impedes the epigenetic switch of macrophages into repair mode. Immunity. 2019;51:199–201.

    Article  CAS  PubMed  Google Scholar 

  3. Ginhoux F, Guilliams M. Tissue-resident macrophage ontogeny and homeostasis. Immunity. 2016;44:439–49.

    Article  CAS  PubMed  Google Scholar 

  4. Gomez Perdiguero E, Klapproth K, Schulz C, Busch K, Azzoni E, Crozet L, et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature. 2015;518:547–51.

    Article  PubMed  Google Scholar 

  5. Zhao Y, Zou W, Du J, Zhao Y. The origins and homeostasis of monocytes and tissue-resident macrophages in physiological situation. J Cell Physiol. 2018;233:6425–39.

    Article  CAS  PubMed  Google Scholar 

  6. Scott CL, Zheng F, De Baetselier P, Martens L, Saeys Y, De Prijck S, et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat Commun. 2016;7:10321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wynn TA, Vannella KM. Macrophages in tissue repair, regeneration, and fibrosis. Immunity. 2016;44:450–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. van de Laar L, Saelens W, De Prijck S, Martens L, Scott CL, Van Isterdael G, et al. Yolk Sac macrophages, fetal liver, and adult monocytes can colonize an empty niche and develop into functional tissue-resident macrophages. Immunity. 2016;44:755–68.

    Article  PubMed  Google Scholar 

  9. Bonnardel J, T'Jonck W, Gaublomme D, Browaeys R, Scott CL, Martens L, et al. Stellate cells, hepatocytes, and endothelial cells imprint the Kupffer cell identity on monocytes colonizing the liver macrophage niche. Immunity. 2019;51:638–54.e9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Seidman JS, Troutman TD, Sakai M, Gola A, Spann NJ, Bennett H, et al. Niche-specific reprogramming of epigenetic landscapes drives myeloid cell diversity in nonalcoholic steatohepatitis. Immunity. 2020;52:1057–74.e.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Woo YD, Jeong D, Chung DH. Development and functions of alveolar macrophages. Mol Cells. 2021;44:292–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cheah FC, Presicce P, Tan TL, Carey BC, Kallapur SG. Studying the effects of granulocyte-macrophage colony-stimulating factor on fetal lung macrophages during the perinatal period using the mouse model. Front Pediatr. 2021;9:614209.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Lambrecht BN. TGF-beta gives an air of exclusivity to alveolar macrophages. Immunity. 2017;47:807–9.

    Article  CAS  PubMed  Google Scholar 

  14. Yu X, Buttgereit A, Lelios I, Utz SG, Cansever D, Becher B, et al. The cytokine TGF-beta promotes the development and homeostasis of alveolar macrophages. Immunity. 2017;47:903–12.e4.

    Article  CAS  PubMed  Google Scholar 

  15. Kucharova K, Stallcup WB. Distinct NG2 proteoglycan-dependent roles of resident microglia and bone marrow-derived macrophages during myelin damage and repair. PLoS ONE. 2017;12:e0187530.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Zilionis R, Engblom C, Pfirschke C, Savova V, Zemmour D, Saatcioglu HD, et al. Single-cell transcriptomics of human and mouse lung cancers reveals conserved myeloid populations across individuals and species. Immunity. 2019;50:1317–34.e0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gibbings SL, Thomas SM, Atif SM, McCubbrey AL, Desch AN, Danhorn T, et al. Three unique interstitial macrophages in the murine lung at steady state. Am J Respir Cell Mol Biol. 2017;57:66–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Devisscher L, Scott CL, Lefere S, Raevens S, Bogaerts E, Paridaens A, et al. Non-alcoholic steatohepatitis induces transient changes within the liver macrophage pool. Cell Immunol. 2017;322:74–83.

    Article  CAS  Google Scholar 

  19. Miyanishi M, Tada K, Koike M, Uchiyama Y, Kitamura T, Nagata S. Identification of Tim4 as a phosphatidylserine receptor. Nature. 2007;450:435–9.

    Article  CAS  PubMed  Google Scholar 

  20. Lu Y, Basatemur G, Scott IC, Chiarugi D, Clement M, Harrison J, et al. Interleukin-33 signaling controls the development of iron-recycling macrophages. Immunity. 2020;52:782–93.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sheng J, Ruedl C, Karjalainen K. Most tissue-resident macrophages except microglia are derived from fetal hematopoietic stem cells. Immunity. 2015;43:382–93.

    Article  CAS  PubMed  Google Scholar 

  22. Gautier EL, Shay T, Miller J, Greter M, Jakubzick C, Ivanov S, et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol. 2012;13:1118–28.

    Article  CAS  PubMed  Google Scholar 

  23. Zhu L, Zhao Q, Yang T, Ding W, Zhao Y. Cellular metabolism and macrophage functional polarization. Int Rev Immunol. 2015;34:82–100.

    Article  PubMed  Google Scholar 

  24. Xu D, Huang SK. IL-33: a key player in the development of iron-recycling red pulp macrophages. Cell Mol Immunol. 2020;17:1218–9.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Umbarawan Y, Enoura A, Ogura H, Sato T, Horikawa M, Ishii T, et al. FABP5 is a sensitive marker for lipid-rich macrophages in the luminal side of atherosclerotic lesions. Int Heart J. 2021;62:666–76.

    Article  CAS  PubMed  Google Scholar 

  26. Moore SM, Holt VV, Malpass LR, Hines IN, Wheeler MD. Fatty acid-binding protein 5 limits the anti-inflammatory response in murine macrophages. Mol Immunol. 2015;67:265–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Guo Y, Liu Y, Zhao S, Xu W, Li Y, Zhao P, et al. Oxidative stress-induced FABP5 S-glutathionylation protects against acute lung injury by suppressing inflammation in macrophages. Nat Commun. 2021;12:7094.

    Article  CAS  PubMed  Google Scholar 

  28. Lee MC, Lacey DC, Fleetwood AJ, Achuthan A, Hamilton JA, Cook AD. GM-CSF- and IRF4-dependent signaling can regulate myeloid cell numbers and the macrophage phenotype during inflammation. J Immunol. 2019;202:3033–40.

    Article  CAS  PubMed  Google Scholar 

  29. Lacey DC, Achuthan A, Fleetwood AJ, Dinh H, Roiniotis J, Scholz MG, et al. Defining GM-CSF—and macrophage-CSF-dependent macrophage responses by in vitro models. J Immunol. 2012;188:5752–65.

    Article  CAS  PubMed  Google Scholar 

  30. Harjes U. Home advantage for tissue-resident macrophages. Nat Rev Cancer. 2021;21:539.

    Article  CAS  PubMed  Google Scholar 

  31. Ma D, Doi Y, Jin S, Li E, Sonobe Y, Takeuchi H, et al. TGF-beta induced by interleukin-34-stimulated microglia regulates microglial proliferation and attenuates oligomeric amyloid beta neurotoxicity. Neurosci Lett. 2012;529:86–91.

    Article  CAS  Google Scholar 

  32. Sakai M, Troutman TD, Seidman JS, Ouyang Z, Spann NJ, Abe Y, et al. Liver-derived signals sequentially reprogram myeloid enhancers to initiate and maintain Kupffer cell identity. Immunity. 2019;51:655–70.e8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Dahik VD, Frisdal E, Le Goff W. Rewiring of lipid metabolism in adipose tissue macrophages in obesity: impact on insulin resistance and type 2 diabetes. Int J Mol Sci. 2020;21:5505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhao Y, Zou W, Du J, Zhao Y. mTOR masters monocyte development in bone marrow by decreasing the inhibition of STAT5 on IRF8. Blood. 2018;131:1587–99.

    Article  CAS  PubMed  Google Scholar 

  35. Tian Q, Zhang Z, Tan L, Yang F, Xu Y, Guo Y, et al. Skin and heart allograft rejection solely by long-lived alloreactive TRM cells in skin of severe combined immunodeficient mice. Sci Adv. 2022;8:eabk0270.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Otogawa K, Kinoshita K, Fujii H, Sakabe M, Shiga R, Nakatani K, et al. Erythrophagocytosis by liver macrophages (Kupffer cells) promotes oxidative stress, inflammation, and fibrosis in a rabbit model of steatohepatitis: implications for the pathogenesis of human nonalcoholic steatohepatitis. Am J Pathol. 2007;170:967–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Klei TR, Meinderts SM, van den Berg TK, van Bruggen R. From the cradle to the grave: the role of macrophages in erythropoiesis and erythrophagocytosis. Front Immunol. 2017;8:73.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Shi L, Tian H, Wang P, Li L, Zhang Z, Zhang J, et al. Spaceflight and simulated microgravity suppresses macrophage development via altered RAS/ERK/NFkappaB and metabolic pathways. Cell Mol Immunol. 2021;18:1489–502.

    Article  CAS  PubMed  Google Scholar 

  39. Chu Z, Feng C, Sun C, Xu Y, Zhao Y. Primed macrophages gain long-term specific memory to reject allogeneic tissues in mice. Cell Mol Immunol. 2021;18:1079–81.

    Article  CAS  PubMed  Google Scholar 

  40. Hou Y, Zhu L, Tian H, Sun H, Wang R, Zhang L, et al. IL-23-induced macrophage polarization and its pathological roles in mice with imiquimod-induced psoriasis. Protein Cell. 2018;9:1027–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pertea M, Kim D, Pertea GM, Leek JT, Salzberg SL. Transcript-level expression analysis of RNA-seq experiments with HISAT, StringTie and Ballgown. Nat Protoc. 2016;11:1650–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Pertea M, Pertea GM, Antonescu CM, Chang TC, Mendell JT, Salzberg SL. StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. Nat Biotechnol. 2015;33:290–5.

    Article  CAS  PubMed Central  Google Scholar 

  43. Wang L, Feng Z, Wang X, Wang X, Zhang X. DEGseq: an R package for identifying differentially expressed genes from RNA-seq data. Bioinformatics. 2010;26:136–8.

    Article  PubMed  Google Scholar 

  44. Bu D, Luo H, Huo P, Wang Z, Zhang S, He Z, et al. KOBAS-i: intelligent prioritization and exploratory visualization of biological functions for gene enrichment analysis. Nucleic Acids Res. 2021;49:W317–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Subramanian A, Kuehn H, Gould J, Tamayo P, Mesirov JP. GSEA-P: a desktop application for Gene Set Enrichment Analysis. Bioinformatics. 2007;23:3251–3.

    Article  CAS  PubMed  Google Scholar 

  46. Ferreira MR, Santos GA, Biagi CA, Silva Junior WA, Zambuzzi WF. GSVA score reveals molecular signatures from transcriptomes for biomaterials comparison. J Biomed Mater Res A. 2021;109:1004–14.

    Article  CAS  PubMed  Google Scholar 

  47. Sergushichev AA, Loboda AA, Jha AK, Vincent EE, Driggers EM, Jones RG, et al. GAM: a web-service for integrated transcriptional and metabolic network analysis. Nucleic Acids Res. 2016;44:W194–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhou G, Soufan O, Ewald J, Hancock R, Basu N, Xia J. NetworkAnalyst 3.0: a visual analytics platform for comprehensive gene expression profiling and meta-analysis. Nucleic Acids Res. 2019;47:W234–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Demchak B, Hull T, Reich M, Liefeld T, Smoot M, Ideker T, et al. Cytoscape: the network visualization tool for GenomeSpace workflows. F1000Res. 2014;3:151.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge Mrs. Qing Meng and Mrs. Xiaoqiu Liu for their expert technical assistance, Mrs. Ling Li for her excellent laboratory management, and Mr. Yiming Jin for his assistance with the animal and cellular experiments. This work was supported by grants from the National Natural Science Foundation for Key Programs (31930041, Y.Z.), National Key Research and Development Program of China (2017YFA0105002, 2017YFA0104402, Y.Z.), and Knowledge Innovation Program of the Chinese Academy of Sciences (XDA16030301, Y.Z.).

Author information

Author notes

  1. These authors contributed equally: Tong Lei, Jiayu Zhang, Qian Zhang.

Authors and Affiliations

  1. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China

    Tong Lei, Jiayu Zhang, Qian Zhang, Xinran Ma, Yanan Xu, Yang Zhao & Yong Zhao

  2. College of Life Science, University of Chinese Academy of Sciences, Beijing, China

    Tong Lei, Xinran Ma & Zhongbing Lu

  3. Cunji Medical School, University of Chinese Academy of Sciences, Beijing, China

    Jiayu Zhang, Qian Zhang & Yong Zhao

  4. Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China

    Lianfeng Zhang

  5. Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China

    Yong Zhao

Authors
  1. Tong Lei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jiayu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xinran Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yanan Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yang Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lianfeng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zhongbing Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yong Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

T.L. and Y.Z. designed the methodology and investigation. T.L. and Q.Z. conducted experiments, collected results, and performed analyses. J.Y.Z. performed bioinformatic analysis. T.L., X.R.M., Y.N.X., and Y.Z. performed animal husbandry. T.L., J.Y.Z., and Y.Z. wrote the paper. Y.Z. supervised, directed, performed project administration, and acquired funding.

Corresponding authors

Correspondence to Lianfeng Zhang, Zhongbing Lu or Yong Zhao.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lei, T., Zhang, J., Zhang, Q. et al. Defining newly formed and tissue-resident bone marrow-derived macrophages in adult mice based on lysozyme expression. Cell Mol Immunol 19, 1333–1346 (2022). https://doi.org/10.1038/s41423-022-00936-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-022-00936-4

Keywords

This article is cited by

Search

Advanced search

Quick links