The Role of CSF1R-dependent Macrophages in Control of the Intestinal Stem-cell Niche

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Mar 30

PMID 29593242

Citations 102

Authors

Anuj Sehgal

David S Donaldson

Clare Pridans

Kristin A Sauter

David A Hume

Neil A Mabbott

Affiliations

Soon will be listed here.

Abstract

Colony-stimulating factor 1 (CSF1) controls the growth and differentiation of macrophages.CSF1R signaling has been implicated in the maintenance of the intestinal stem cell niche and differentiation of Paneth cells, but evidence of expression of CSF1R within the crypt is equivocal. Here we show that CSF1R-dependent macrophages influence intestinal epithelial differentiation and homeostasis. In the intestinal lamina propria CSF1R mRNA expression is restricted to macrophages which are intimately associated with the crypt epithelium, and is undetectable in Paneth cells. Macrophage ablation following CSF1R blockade affects Paneth cell differentiation and leads to a reduction of Lgr5 intestinal stem cells. The disturbances to the crypt caused by macrophage depletion adversely affect the subsequent differentiation of intestinal epithelial cell lineages. Goblet cell density is enhanced, whereas the development of M cells in Peyer's patches is impeded. We suggest that modification of the phenotype or abundance of macrophages in the gut wall alters the development of the intestinal epithelium and the ability to sample gut antigens.

Citing Articles

A review of gut failure as a cause and consequence of critical illness.

Soranno D, Coopersmith C, Brinkworth J, Factora F, Muntean J, Mythen M Crit Care. 2025; 29(1):91.

PMID: 40011975 PMC: 11866815. DOI: 10.1186/s13054-025-05309-7.

Wild-type bone marrow cells repopulate tissue resident macrophages and reverse the impacts of homozygous CSF1R mutation.

Carter-Cusack D, Huang S, Keshvari S, Patkar O, Sehgal A, Allavena R PLoS Genet. 2025; 21(1):e1011525.

PMID: 39869647 PMC: 11785368. DOI: 10.1371/journal.pgen.1011525.

Single-cell transcriptomics identify a novel macrophage population associated with bone invasion in pituitary neuroendocrine tumors.

Wu X, Han X, Zhu H, Li M, Gong L, Jing S J Exp Clin Cancer Res. 2025; 44(1):27.

PMID: 39865310 PMC: 11770939. DOI: 10.1186/s13046-025-03296-9.

Ribosome profiling and single-cell RNA sequencing identify the unfolded protein response as a key regulator of pigeon lactation.

Liu J, Liu S, Mao H, Jiang H, Liu S, Xu X Zool Res. 2025; 46(1):54-74.

PMID: 39846187 PMC: 11890991. DOI: 10.24272/j.issn.2095-8137.2024.336.

Impact of T-2 toxin on intestinal inflammation and transcriptional regulation of inflammatory response in mouse macrophages.

Yang X, Xu X, Zhong Q, Cui H, Xu J, Wei W Biochem Biophys Rep. 2024; 40:101840.

PMID: 39483178 PMC: 11525619. DOI: 10.1016/j.bbrep.2024.101840.

References

Mabbott N, Donaldson D, Ohno H, Williams I, Mahajan A . Microfold (M) cells: important immunosurveillance posts in the intestinal epithelium. Mucosal Immunol. 2013; 6(4):666-77. PMC: 3686595. DOI: 10.1038/mi.2013.30. View

Sangiorgi E, Capecchi M . Bmi1 is expressed in vivo in intestinal stem cells. Nat Genet. 2008; 40(7):915-20. PMC: 2906135. DOI: 10.1038/ng.165. View

Sauter K, Pridans C, Sehgal A, Tsai Y, Bradford B, Raza S . Pleiotropic effects of extended blockade of CSF1R signaling in adult mice. J Leukoc Biol. 2014; 96(2):265-74. PMC: 4378363. DOI: 10.1189/jlb.2A0114-006R. View

Kobayashi A, Donaldson D, Erridge C, Kanaya T, Williams I, Ohno H . The functional maturation of M cells is dramatically reduced in the Peyer's patches of aged mice. Mucosal Immunol. 2013; 6(5):1027-37. PMC: 3747980. DOI: 10.1038/mi.2012.141. View

Hernandez L, Smirnova T, Kedrin D, Wyckoff J, Zhu L, Stanley E . The EGF/CSF-1 paracrine invasion loop can be triggered by heregulin beta1 and CXCL12. Cancer Res. 2009; 69(7):3221-7. PMC: 2820720. DOI: 10.1158/0008-5472.CAN-08-2871. View

Ryan G, Dai X, Dominguez M, Tong W, Chuan F, Chisholm O . Rescue of the colony-stimulating factor 1 (CSF-1)-nullizygous mouse (Csf1(op)/Csf1(op)) phenotype with a CSF-1 transgene and identification of sites of local CSF-1 synthesis. Blood. 2001; 98(1):74-84. DOI: 10.1182/blood.v98.1.74. View

Alexander K, Chang M, Maylin E, Kohler T, Muller R, Wu A . Osteal macrophages promote in vivo intramembranous bone healing in a mouse tibial injury model. J Bone Miner Res. 2011; 26(7):1517-32. DOI: 10.1002/jbmr.354. View

Forrest A, Kawaji H, Rehli M, Baillie J, de Hoon M, Haberle V . A promoter-level mammalian expression atlas. Nature. 2014; 507(7493):462-70. PMC: 4529748. DOI: 10.1038/nature13182. View

MacDonald K, Palmer J, Cronau S, Seppanen E, Olver S, Raffelt N . An antibody against the colony-stimulating factor 1 receptor depletes the resident subset of monocytes and tissue- and tumor-associated macrophages but does not inhibit inflammation. Blood. 2010; 116(19):3955-63. DOI: 10.1182/blood-2010-02-266296. View

10.

Bain C, Bravo-Blas A, Scott C, Gomez Perdiguero E, Geissmann F, Henri S . Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice. Nat Immunol. 2014; 15(10):929-937. PMC: 4169290. DOI: 10.1038/ni.2967. View

11.

Kim T, Escudero S, Shivdasani R . Intact function of Lgr5 receptor-expressing intestinal stem cells in the absence of Paneth cells. Proc Natl Acad Sci U S A. 2012; 109(10):3932-7. PMC: 3309789. DOI: 10.1073/pnas.1113890109. View

12.

Alikhan M, Jones C, Williams T, Beckhouse A, Fletcher A, Kett M . Colony-stimulating factor-1 promotes kidney growth and repair via alteration of macrophage responses. Am J Pathol. 2011; 179(3):1243-56. PMC: 3157188. DOI: 10.1016/j.ajpath.2011.05.037. View

13.

Farin H, van Es J, Clevers H . Redundant sources of Wnt regulate intestinal stem cells and promote formation of Paneth cells. Gastroenterology. 2012; 143(6):1518-1529.e7. DOI: 10.1053/j.gastro.2012.08.031. View

14.

Cosin-Roger J, Ortiz-Masia D, Calatayud S, Hernandez C, Esplugues J, Barrachina M . The activation of Wnt signaling by a STAT6-dependent macrophage phenotype promotes mucosal repair in murine IBD. Mucosal Immunol. 2015; 9(4):986-98. DOI: 10.1038/mi.2015.123. View

15.

Stutchfield B, Antoine D, MacKinnon A, Gow D, Bain C, Hawley C . CSF1 Restores Innate Immunity After Liver Injury in Mice and Serum Levels Indicate Outcomes of Patients With Acute Liver Failure. Gastroenterology. 2015; 149(7):1896-1909.e14. PMC: 4672154. DOI: 10.1053/j.gastro.2015.08.053. View

16.

Inman C, Rees L, Barker E, Haverson K, Stokes C, Bailey M . Validation of computer-assisted, pixel-based analysis of multiple-colour immunofluorescence histology. J Immunol Methods. 2005; 302(1-2):156-67. DOI: 10.1016/j.jim.2005.05.005. View

17.

Gow D, Sauter K, Pridans C, Moffat L, Sehgal A, Stutchfield B . Characterisation of a novel Fc conjugate of macrophage colony-stimulating factor. Mol Ther. 2014; 22(9):1580-92. PMC: 4435485. DOI: 10.1038/mt.2014.112. View

18.

Tian H, Biehs B, Warming S, Leong K, Rangell L, Klein O . A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature. 2011; 478(7368):255-9. PMC: 4251967. DOI: 10.1038/nature10408. View

19.

Sasaki N, Sachs N, Wiebrands K, Ellenbroek S, Fumagalli A, Lyubimova A . Reg4+ deep crypt secretory cells function as epithelial niche for Lgr5+ stem cells in colon. Proc Natl Acad Sci U S A. 2016; 113(37):E5399-407. PMC: 5027439. DOI: 10.1073/pnas.1607327113. View

20.

Muller P, Koscso B, Rajani G, Stevanovic K, Berres M, Hashimoto D . Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility. Cell. 2014; 158(2):300-313. PMC: 4149228. DOI: 10.1016/j.cell.2014.04.050. View