CoChat
Sign Up
Cited by 527Immune cells in cancerPhagocytosis and Immune RegulationNeuroinflammation and Neurodegeneration Mechanisms

Long-lived self-renewing bone marrow-derived macrophages displace embryo-derived cells to inhabit adult serous cavities

Open access
Bain, Calum C., Hawley, Catherine A., Garner, Hannah, Scott, Charlotte L., Schridde, Anika, Steers, Nicholas J., Mack, Matthias, Joshi, Anagha +4 more·2016·Nature Communications
DOI 10.1038/ncomms11852PMC PMC4910019
Open this paper in CoChat — free accountOpen PDF

Abstract

Peritoneal macrophages are one of the most studied macrophage populations in the body, yet the composition, developmental origin and mechanisms governing the maintenance of this compartment are controversial. Here we show resident F4/80 hi GATA6 + macrophages are long-lived, undergo non-stochastic self-renewal and retain cells of embryonic origin for at least 4 months in mice. However, Ly6C + monocytes constitutively enter the peritoneal cavity in a CCR2-dependent manner, where they mature into short-lived F4/80 lo MHCII + cells that act, in part, as precursors of F4/80 hi GATA6 + macrophages. Notably, monocyte-derived F4/80 hi macrophages eventually displace the embryonic population with age in a process that is highly gender dependent and not due to proliferative exhaustion of the incumbent embryonic population, despite the greater proliferative activity of newly recruited cells. Furthermore, although monocyte-derived cells acquire key characteristics of the embryonic population, expression of Tim4 was impaired, leading to cumulative changes in the population with age.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/ncomms11852

Cites

14 of 14 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • SPMs do so more readily in males.

    “but they actually do so more readily in males [30, 40].”

    From Alzheimer’s disease-associated protective variant Plcg2-P522R modulates peripheral macrophage function in a sex-dimorphic manner (2024) · cites this paper as [30]

    The Results section on F4/80loCSF1R+ precursors identifies small peritoneal macrophage–like cells as intermediates in replenishing resident F4/80hi macrophages. The Results section on gradual replenishment reports more than sixfold greater replacement of peritoneal F4/80hi macrophages in male mice. It does not separately establish that SPMs themselves differentiate more readily in males; the measured sex difference is in replacement of the resident population. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Recent studies have shown that SPMs can continue to alter their functional and transcriptional profiles to look more like LPMs, and even occupy that same niche over time.

    “recent studies have shown that not only can SPMs continue to alter their functional and transcriptional profiles to look more like LPMs, and even occupy that same niche over time”

    From Alzheimer’s disease-associated protective variant Plcg2-P522R modulates peripheral macrophage function in a sex-dimorphic manner (2024) · cites this paper as [30]

    The Results section, “F4/80loCSF1R+ cells are precursors of F4/80hi macrophages” (page unavailable), supports maturation of cells in the SPM-like population into F4/80hi resident macrophages over time. The Results section, “BM-derived macrophages largely phenocopy embryo macrophages” (page unavailable), shows acquisition of LPM-associated markers including GATA6 and CD102. The copy does not establish that SPMs broadly acquire LPM functional and transcriptional profiles; the Discussion says whether origin affects resident macrophage function remains to be fully determined. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Recruited monocytes can, over time, differentiate into macrophages that closely mimic resident LPMs.

    “Recent studies have shown that these recruited monocytes can, over time, differentiate into macrophages that closely mimic the resident LPMs [30].”

    From Alzheimer’s disease-associated protective variant Plcg2-P522R modulates peripheral macrophage function in a sex-dimorphic manner (2024) · cites this paper as [30]

  • pMac sub-populations are not static.

    “as these sub-populations are not static regardless.”

    From Alzheimer’s disease-associated protective variant Plcg2-P522R modulates peripheral macrophage function in a sex-dimorphic manner (2024) · cites this paper as [30]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 54

  1. Virolainen M. Hematopoietic origin of macrophages as studied by chromosome markers in mice. J. Exp. Med. 127, 943– 952 (1968). 5655103 PMC2138492
  2. Ghigo C. et al. Multicolor fate mapping of Langerhans cell homeostasis. J. Exp. Med. 210, 1657– 1664 (2013). 23940255 PMC3754858
  3. Molawi K. et al. Progressive replacement of embryo-derived cardiac macrophages with age. J. Exp. Med. 211, 2151– 2158 (2014). 25245760 PMC4203946
  4. Okabe Y. & Medzhitov R. Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell 157, 832– 844 (2014). 24792964 PMC4137874
  5. Rosas M. et al. The transcription factor Gata6 links tissue macrophage phenotype and proliferative renewal. Science 344, 645– 648 (2014). 24762537 PMC4185421
  6. Gautier E. L. et al. Gata6 regulates aspartoacylase expression in resident peritoneal macrophages and controls their survival. J. Exp. Med. 211, 1525– 1531 (2014). 25024137 PMC4113942
  7. Nguyen H. H., Tran B. T., Muller W. & Jack R. S. IL-10 acts as a developmental switch guiding monocyte differentiation to macrophages during a murine peritoneal infection. J. Immunol. 189, 3112– 3120 (2012). 22869902
  8. Cain D. W. et al. Identification of a tissue-specific, C/EBPbeta-dependent pathway of differentiation for murine peritoneal macrophages. J. Immunol. 191, 4665– 4675 (2013). 24078688 PMC3808250
  9. Louis C. et al. Specific contributions of CSF-1 and GM-CSF to the dynamics of the mononuclear phagocyte system. J. Immunol. 195, 134– 144 (2015). 26019271
  10. Gautier E. L., Ivanov S., Lesnik P. & Randolph G. J. Local apoptosis mediates clearance of macrophages from resolving inflammation in mice. Blood 122, 2714– 2722 (2013). 23974197 PMC3795463
  11. Davies L. C. et al. Distinct bone marrow-derived and tissue-resident macrophage lineages proliferate at key stages during inflammation. Nat. Commun. 4, 1886 (2013). 23695680 PMC3842019
  12. Jenkins S. J. et al. Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science 332, 1284– 1288 (2011). 21566158 PMC3128495
  13. Jenkins S. J. et al. IL-4 directly signals tissue-resident macrophages to proliferate beyond homeostatic levels controlled by CSF-1. J. Exp. Med. 210, 2477– 2491 (2013). 24101381 PMC3804948
  14. Sheng J., Ruedl C. & Karjalainen K. Most tissue-resident macrophages except microglia are derived from fetal hematopoietic stem cells. Immunity 43, 382– 393 (2015). 26287683
  15. Miller J. C. et al. Deciphering the transcriptional network of the dendritic cell lineage. Nat. Immunol. 13, 888– 899 (2012). 22797772 PMC3985403
  16. Schraml B. U. et al. Genetic tracing via DNGR-1 expression history defines dendritic cells as a hematopoietic lineage. Cell 154, 843– 858 (2013). 23953115
  17. Tagliani E. et al. Coordinate regulation of tissue macrophage and dendritic cell population dynamics by CSF-1. J. Exp. Med. 208, 1901– 1916 (2011). 21825019 PMC3171096
  18. Davies L. C. et al. A quantifiable proliferative burst of tissue macrophages restores homeostatic macrophage populations after acute inflammation. Eur. J. Immunol. 41, 2155– 2164 (2011). 21710478
  19. Foudi A. et al. Analysis of histone 2B-GFP retention reveals slowly cycling hematopoietic stem cells. Nat. Biotechnol. 27, 84– 90 (2009). 19060879 PMC2805441
  20. Mack M. et al. Expression and characterization of the chemokine receptors CCR2 and CCR5 in mice. J. Immunol. 166, 4697– 4704 (2001). 11254730
  21. Tamoutounour S. et al. CD64 distinguishes macrophages from dendritic cells in the gut and reveals the Th1-inducing role of mesenteric lymph node macrophages during colitis. Eur. J. Immunol. 42, 3150– 3166 (2012). 22936024
  22. Bain C. C. et al. Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6Chi monocyte precursors. Mucosal Immunol. 6, 498– 510 (2013). 22990622 PMC3629381
  23. Perdiguero E. G. & Geissmann F. The development and maintenance of resident macrophages. Nat. Immunol. 17, 2– 8 (2015). 26681456 PMC4950995
  24. Okabe Y. & Medzhitov R. Tissue biology perspective on macrophages. Nat. Immunol. 17, 9– 17 (2015). 26681457
  25. Stutchfield B. M. et al. CSF1 restores innate immunity after liver injury in mice and serum levels indicate outcomes of patients with acute liver failure. Gastroenterology 149, 1896– 1909e14 (2015). 26344055 PMC4672154
  26. Ensan S. et al. Self-renewing resident arterial macrophages arise from embryonic CX3CR1(+) precursors and circulating monocytes immediately after birth. Nat. Immunol. 17, 159– 168 (2016). 26642357
  27. Scott C. L. et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat. Commun. 7, 10321 (2016). 26813785 PMC4737801
  28. Guilliams M. et al. Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF. J. Exp. Med. 210, 1977– 1992 (2013). 24043763 PMC3782041
  29. Takizawa H. & Manz M. G. In vivo divisional tracking of hematopoietic stem cells. Ann. N. Y. Acad. Sci. 1266, 40– 46 (2012). 22901254
  30. Melnicoff M. J., Horan P. K., Breslin E. W. & Morahan P. S. Maintenance of peritoneal macrophages in the steady state. J. Leukoc. Biol. 44, 367– 375 (1988). 2460572
  31. Hashimoto D., Miller J. & Merad M. Dendritic cell and macrophage heterogeneity in vivo. Immunity 35, 323– 335 (2011). 21943488 PMC4520532
  32. Jenkins S. J. & Hume D. A. Homeostasis in the mononuclear phagocyte system. Trends Immunol. 35, 358– 367 (2014). 25047416
  33. Liu K. et al. Origin of dendritic cells in peripheral lymphoid organs of mice. Nat. Immunol. 8, 578– 583 (2007). 17450143
  34. Scotland R. S., Stables M. J., Madalli S., Watson P. & Gilroy D. W. Sex differences in resident immune cell phenotype underlie more efficient acute inflammatory responses in female mice. Blood 118, 5918– 5927 (2011). 21911834 PMC5363818
  35. Lambert K. C., Curran E. M., Judy B. M., Lubahn D. B. & Estes D. M. Estrogen receptor-alpha deficiency promotes increased TNF-alpha secretion and bacterial killing by murine macrophages in response to microbial stimuli in vitro. J. Leukoc. Biol. 75, 1166– 1172 (2011). 15020652
  36. Campbell L. et al. Estrogen receptor-alpha promotes alternative macrophage activation during cutaneous repair. J. Invest. Dermatol. 134, 2447– 2457 (2014). 24769859
  37. Barnes M. A., Carson M. J. & Nair M. G. Non-traditional cytokines: how catecholamines and adipokines influence macrophages in immunity, metabolism and the central nervous system. Cytokine 72, 210– 219 (2015). 25703786 PMC4590987
  38. Gui Y., Silha J. V. & Murphy L. J. Sexual dimorphism and regulation of resistin, adiponectin, and leptin expression in the mouse. Obes. Res. 12, 1481– 1491 (2004). 15483213
  39. Newson J. et al. Resolution of acute inflammation bridges the gap between innate and adaptive immunity. Blood 124, 1748– 1764 (2014). 25006125 PMC4383794
  40. Plantinga M. et al. Conventional and monocyte-derived CD11b(+) dendritic cells initiate and maintain T helper 2 cell-mediated immunity to house dust mite allergen. Immunity 38, 322– 335 (2013). 23352232
  41. Griffith J. W., Sokol C. L. & Luster A. D. Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu. Rev. Immunol. 32, 659– 702 (2014). 24655300
  42. Serbina N. V. & Pamer E. G. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat. Immunol. 7, 311– 317 (2006). 16462739
  43. Gosselin D. et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159, 1327– 1340 (2014). 25480297 PMC4364385
  44. Lavin Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312– 1326 (2014). 25480296 PMC4437213
  45. Wong K. et al. Phosphatidylserine receptor Tim-4 is essential for the maintenance of the homeostatic state of resident peritoneal macrophages. Proc. Natl Acad. Sci. USA 107, 8712– 8717 (2010). 20421466 PMC2889355
  46. Zhu H. et al. Macrophage differentiation and expression of macrophage colony-stimulating factor in murine milky spots and omentum after macrophage elimination. J. Leukoc. Biol. 61, 436– 444 (1997). 9103230
  47. Boring L. et al. Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C-C chemokine receptor 2 knockout mice. J. Clin. Invest. 100, 2552– 2561 (1997). 9366570 PMC508456
  48. Caton M. L., Smith-Raska M. R. & Reizis B. Notch-RBP-J signaling controls the homeostasis of CD8- dendritic cells in the spleen. J. Exp. Med. 204, 1653– 1664 (2007). 17591855 PMC2118632
  49. McKenna H. J. et al. Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells. Blood 95, 3489– 3497 (2000). 10828034
  50. Benz C., Martins V. C., Radtke F. & Bleul C. C. The stream of precursors that colonizes the thymus proceeds selectively through the early T lineage precursor stage of T cell development. J. Exp. Med. 205, 1187– 1199 (2008). 18458114 PMC2373849
  51. Bain C. C. & Mowat A. M. CD200 receptor and macrophage function in the intestine. Immunobiology 217, 643– 651 (2012). 22204814
  52. Henri S., Poulin L. F., Tamoutounour S., Ardouin L. & Guilliams M. CD207+ CD103+ dermal dendritic cells cross-present keratinocyte-derived antigens irrespective of the presence of Langerhans cells. J. Exp. Med. 207, 189– 206 (2010). 20038600 PMC2812532
  53. Gautier L., Cope L., Bolstad B. M. & Irizarry R. A. affy--analysis of Affymetrix GeneChip data at the probe level. Bioinformatics 20, 307– 315 (2004). 14960456
  54. Smyth G. K., Michaud J. & Scott H. S. Use of within-array replicate spots for assessing differential expression in microarray experiments. Bioinformatics 21, 2067– 2075 (2005). 15657102

Cited by

Sorted by citations

Authors
Bain, C. C., Hawley, C. A., Garner, H., Scott, C. L., Schridde, A., Steers, N. J., Mack, M., Joshi, A., Guilliams, M., Mowat, A. M. I., Geissmann, F., & Jenkins, S. J.
Affiliations
  • Centre for Inflammation Research (GB)
  • King's College London (GB)
  • Ghent University (BE)
  • University of Glasgow (GB)
  • University Hospital Regensburg (DE)
  • Roslin Institute (GB)
Corresponding author
Jenkins, Stephen J.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2016-06-13
Volume
7
Issue
1
Pages
ncomms11852-ncomms11852
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms11852
PMC
PMC4910019
OpenAlex
W2443001171
Cited by
527
References
14
Citations by year
2026: 24 · 2025: 27 · 2024: 30 · 2023: 40 · 2022: 45 · 2021: 131 · 2020: 89 · 2019: 46 · 2018: 43 · 2017: 42 · 2016: 9
FWCI
28.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
  • Ghent University Academic Bibliography (Ghent University) (submittedVersion, cc-by)
  • Research Portal (King's College London) (submittedVersion, cc-by)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
  • RWTH Publications (RWTH Aachen) (submittedVersion, other-oa)
Funders
  • Wellcome Trust
  • Fonds Wetenschappelijk Onderzoek
  • Medical Research Council (MR/L008076/1)
  • Biotechnology and Biological Sciences Research Council (1168004)
  • National Cancer Institute (P30CA008748)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
peritoneal macrophages, macrophage self-renewal, embryonic macrophages, monocyte-derived macrophages, Ly6C+ monocytes, CCR2, F4/80, GATA6, TIM-4, sex differences, serous cavities, macrophage origin
MeSH terms
Cell Self Renewal, Aging, Animals, Embryo, Mammalian, Macrophages, Mice, Inbred C57BL, Peritoneum, Phenotype, Time Factors, Myeloid Cells, Cell Proliferation, Receptors, CCR2

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review