MFG-E8-mediated Uptake of Apoptotic Cells by APCs Links the Pro- and Antiinflammatory Activities of GM-CSF

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2007 Jun 9

PMID 17557120

Citations 97

Authors

Masahisa Jinushi

Yukoh Nakazaki

Michael Dougan

Daniel R Carrasco

Martin Mihm

Glenn Dranoff

Affiliations

Soon will be listed here.

Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances protection against tumors and infections, but GM-CSF-deficient mice develop inflammatory disease. Here we show that GM-CSF is required for the expression of milk fat globule EGF 8 (MFG-E8) in antigen-presenting cells, and that MFG-E8-mediated uptake of apoptotic cells is a key determinant of GM-CSF-triggered tolerance and immunity. Upon exposure to apoptotic cells, GM-CSF-deficient antigen-presenting cells (APCs) produce an altered cytokine profile that results in decreased Tregs and increased Th1 cells, whereas concurrent ablation of IFN-gamma promotes Th17 cells. In wild-type mice, MFG-E8 attenuates the vaccination activity of GM-CSF-secreting tumor cells through Treg induction, whereas a dominant-negative MFG-E8 mutant potentiates GM-CSF-stimulated tumor destruction through Treg inhibition. These findings clarify the immunoregulatory effects of apoptotic cells and suggest new therapeutic strategies to modulate CD4(+) T cell subsets in cancer and autoimmunity.

Citing Articles

Disrupting Smad3 potentiates immunostimulatory function of NK cells against lung carcinoma by promoting GM-CSF production.

Lian G, Wang Q, Mak T, Huang X, Yu X, Lan H Cell Mol Life Sci. 2024; 81(1):262.

PMID: 38878186 PMC: 11335298. DOI: 10.1007/s00018-024-05290-4.

Potent CTLs can be induced against tumor cells in an environment of lower levels of systemic MFG-E8.

Mizote Y, Inoue T, Akazawa T, Kunimasa K, Tamiya M, Kumamoto Y Cancer Sci. 2024; 115(4):1114-1128.

PMID: 38332689 PMC: 11007000. DOI: 10.1111/cas.16099.

MFG-E8 promotes M2 polarization of macrophages and is associated with poor prognosis in patients with gastric cancer.

Li Y, Qiu J, Meng Z, Yin S, Ruan M, Zhang W Heliyon. 2024; 10(1):e23917.

PMID: 38192793 PMC: 10772258. DOI: 10.1016/j.heliyon.2023.e23917.

Cellular mechanisms underlying the impairment of macrophage efferocytosis.

Ma Y, Kemp S, Yang X, Wu M, Yuan S Immunol Lett. 2023; 254:41-53.

PMID: 36740099 PMC: 9992097. DOI: 10.1016/j.imlet.2023.02.001.

Recombinant GM-CSF for diseases of GM-CSF insufficiency: Correcting dysfunctional mononuclear phagocyte disorders.

Lazarus H, Pitts K, Wang T, Lee E, Buchbinder E, Dougan M Front Immunol. 2023; 13:1069444.

PMID: 36685591 PMC: 9850113. DOI: 10.3389/fimmu.2022.1069444.

References

Mach N, Gillessen S, Wilson S, Sheehan C, Mihm M, Dranoff G . Differences in dendritic cells stimulated in vivo by tumors engineered to secrete granulocyte-macrophage colony-stimulating factor or Flt3-ligand. Cancer Res. 2000; 60(12):3239-46. View

Bettelli E, Carrier Y, Gao W, Korn T, Strom T, Oukka M . Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006; 441(7090):235-8. DOI: 10.1038/nature04753. View

Hodi F, Dranoff G . Combinatorial cancer immunotherapy. Adv Immunol. 2006; 90:341-68. DOI: 10.1016/S0065-2776(06)90009-1. View

Janssen E, Tabeta K, Barnes M, Rutschmann S, McBride S, Bahjat K . Efficient T cell activation via a Toll-Interleukin 1 Receptor-independent pathway. Immunity. 2006; 24(6):787-799. DOI: 10.1016/j.immuni.2006.03.024. View

Quezada S, Peggs K, Curran M, Allison J . CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J Clin Invest. 2006; 116(7):1935-45. PMC: 1479425. DOI: 10.1172/JCI27745. View

Langowski J, Zhang X, Wu L, Mattson J, Chen T, Smith K . IL-23 promotes tumour incidence and growth. Nature. 2006; 442(7101):461-5. DOI: 10.1038/nature04808. View

Gallina G, Dolcetti L, Serafini P, De Santo C, Marigo I, Colombo M . Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. J Clin Invest. 2006; 116(10):2777-90. PMC: 1578632. DOI: 10.1172/JCI28828. View

Rabinovich G, Gabrilovich D, Sotomayor E . Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol. 2006; 25:267-96. PMC: 2895922. DOI: 10.1146/annurev.immunol.25.022106.141609. View

Dalton D, Keshav S, Figari I, Bradley A, Stewart T . Multiple defects of immune cell function in mice with disrupted interferon-gamma genes. Science. 1993; 259(5102):1739-42. DOI: 10.1126/science.8456300. View

10.

Ishimoto Y, Ohashi K, Mizuno K, Nakano T . Promotion of the uptake of PS liposomes and apoptotic cells by a product of growth arrest-specific gene, gas6. J Biochem. 2000; 127(3):411-7. DOI: 10.1093/oxfordjournals.jbchem.a022622. View

11.

Scott R, McMahon E, Pop S, Reap E, Caricchio R, Cohen P . Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature. 2001; 411(6834):207-11. DOI: 10.1038/35075603. View

12.

Wiekowski M, Leach M, Evans E, Sullivan L, Chen S, Vassileva G . Ubiquitous transgenic expression of the IL-23 subunit p19 induces multiorgan inflammation, runting, infertility, and premature death. J Immunol. 2001; 166(12):7563-70. DOI: 10.4049/jimmunol.166.12.7563. View

13.

Fadok V, Bratton D, Henson P . Phagocyte receptors for apoptotic cells: recognition, uptake, and consequences. J Clin Invest. 2001; 108(7):957-62. PMC: 200959. DOI: 10.1172/JCI14122. View

14.

Shibata Y, Berclaz P, Chroneos Z, Yoshida M, Whitsett J, Trapnell B . GM-CSF regulates alveolar macrophage differentiation and innate immunity in the lung through PU.1. Immunity. 2001; 15(4):557-67. DOI: 10.1016/s1074-7613(01)00218-7. View

15.

Hanayama R, Tanaka M, Miwa K, Shinohara A, Iwamatsu A, Nagata S . Identification of a factor that links apoptotic cells to phagocytes. Nature. 2002; 417(6885):182-7. DOI: 10.1038/417182a. View

16.

Cohen P, Caricchio R, Abraham V, Camenisch T, Jennette J, Roubey R . Delayed apoptotic cell clearance and lupus-like autoimmunity in mice lacking the c-mer membrane tyrosine kinase. J Exp Med. 2002; 196(1):135-40. PMC: 2194017. DOI: 10.1084/jem.20012094. View

17.

Re F, Belyanskaya S, Riese R, Cipriani B, Fischer F, Granucci F . Granulocyte-macrophage colony-stimulating factor induces an expression program in neonatal microglia that primes them for antigen presentation. J Immunol. 2002; 169(5):2264-73. DOI: 10.4049/jimmunol.169.5.2264. View

18.

Savill J, Dransfield I, Gregory C, Haslett C . A blast from the past: clearance of apoptotic cells regulates immune responses. Nat Rev Immunol. 2002; 2(12):965-75. DOI: 10.1038/nri957. View

19.

Numasaki M, Fukushi J, Ono M, Narula S, Zavodny P, Kudo T . Interleukin-17 promotes angiogenesis and tumor growth. Blood. 2002; 101(7):2620-7. DOI: 10.1182/blood-2002-05-1461. View

20.

Hodi F, Mihm M, Soiffer R, Haluska F, Butler M, Seiden M . Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A. 2003; 100(8):4712-7. PMC: 153621. DOI: 10.1073/pnas.0830997100. View