Letter | Published:

Different tissue phagocytes sample apoptotic cells to direct distinct homeostasis programs

Nature volume 539, pages 565569 (24 November 2016) | Download Citation

Abstract

Recognition and removal of apoptotic cells by professional phagocytes, including dendritic cells and macrophages, preserves immune self-tolerance and prevents chronic inflammation and autoimmune pathologies1,2. The diverse array of phagocytes that reside within different tissues, combined with the necessarily prompt nature of apoptotic cell clearance, makes it difficult to study this process in situ. The full spectrum of functions executed by tissue-resident phagocytes in response to homeostatic apoptosis, therefore, remains unclear. Here we show that mouse apoptotic intestinal epithelial cells (IECs), which undergo continuous renewal to maintain optimal barrier and absorptive functions3, are not merely extruded to maintain homeostatic cell numbers4, but are also sampled by a single subset of dendritic cells and two macrophage subsets within a well-characterized network of phagocytes in the small intestinal lamina propria5,6. Characterization of the transcriptome within each subset before and after in situ sampling of apoptotic IECs revealed gene expression signatures unique to each phagocyte, including macrophage-specific lipid metabolism and amino acid catabolism, and a dendritic-cell-specific program of regulatory CD4+ T-cell activation. A common ‘suppression of inflammation’ signature was noted, although the specific genes and pathways involved varied amongst dendritic cells and macrophages, reflecting specialized functions. Apoptotic IECs were trafficked to mesenteric lymph nodes exclusively by the dendritic cell subset and served as critical determinants for the induction of tolerogenic regulatory CD4+ T-cell differentiation. Several of the genes that were differentially expressed by phagocytes bearing apoptotic IECs overlapped with susceptibility genes for inflammatory bowel disease7. Collectively, these findings provide new insights into the consequences of apoptotic cell sampling, advance our understanding of how homeostasis is maintained within the mucosa and set the stage for development of novel therapeutics to alleviate chronic inflammatory diseases such as inflammatory bowel disease.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

Primary accessions

Gene Expression Omnibus

References

  1. 1.

    , , & Apoptotic cell clearance: basic biology and therapeutic potential. Nat. Rev. Immunol. 14, 166–180 (2014)

  2. 2.

    , , & Immunogenic and tolerogenic cell death. Nat. Rev. Immunol. 9, 353–363 (2009)

  3. 3.

    Death in the intestinal epithelium—basic biology and implications for inflammatory bowel disease. FEBS J . 283, 2720–2730 (2016)

  4. 4.

    et al. Crowding induces live cell extrusion to maintain homeostatic cell numbers in epithelia. Nature 484, 546–549 (2012)

  5. 5.

    , & Intestinal dendritic cells in the regulation of mucosal immunity. Immunol. Rev. 260, 86–101 (2014)

  6. 6.

    , & Guardians of the gut – murine intestinal macrophages and dendritic cells. Front. Immunol. 6, 254 (2015)

  7. 7.

    , & Genetics and pathogenesis of inflammatory bowel disease. Nature 474, 307–317 (2011)

  8. 8.

    et al. IRF4 transcription factor-dependent CD11b+ dendritic cells in human and mouse control mucosal IL-17 cytokine responses. Immunity 38, 970–983 (2013)

  9. 9.

    et al. CD205 (DEC-205): a recognition receptor for apoptotic and necrotic self. Mol. Immunol. 46, 1229–1239 (2009)

  10. 10.

    , , , & PIKfyve inhibition interferes with phagosome and endosome maturation in macrophages. Traffic 15, 1143–1163 (2014)

  11. 11.

    et al. 5-Lipoxygenase activating protein (FLAP) dependent leukotriene biosynthesis inhibition (MK591) attenuates Lipid A endotoxin-induced inflammation. PLoS One 9, e102622 (2014)

  12. 12.

    A long-awaited merger of the pathways mediating host defence and programmed cell death. Nat. Rev. Immunol. 14, 601–618 (2014)

  13. 13.

    & A novel “complement–metabolism–inflammasome axis” as a key regulator of immune cell effector function. Eur. J. Immunol. 46, 1563–1573 (2016)

  14. 14.

    & Ubiquitin signaling in immune responses. Cell Res . 26, 457–483 (2016)

  15. 15.

    , , & OASL1 inhibits translation of the type I interferon-regulating transcription factor IRF7. Nat. Immunol. 14, 346–355 (2013)

  16. 16.

    et al. Spred is a Sprouty-related suppressor of Ras signalling. Nature 412, 647–651 (2001)

  17. 17.

    et al. CD4+CD25+ regulatory T cells in the small intestinal lamina propria show an effector/memory phenotype. Int. Immunol. 20, 307–315 (2008)

  18. 18.

    et al. GARP (LRRC32) is essential for the surface expression of latent TGFβ on platelets and activated FOXP3+ regulatory T cells. Proc. Natl Acad. Sci. USA 106, 13445–13450 (2009)

  19. 19.

    , & Regulatory T cells: mechanisms of differentiation and function. Annu. Rev. Immunol. 30, 531–564 (2012)

  20. 20.

    & How tolerogenic dendritic cells induce regulatory T cells. Adv. Immunol . 108, 111–165 (2010)

  21. 21.

    et al. Dietary antigens limit mucosal immunity by inducing regulatory T cells in the small intestine. Science 351, 858–863 (2016)

  22. 22.

    et al. Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012)

  23. 23.

    et al. Genetic variants in the IL12B gene are associated with inflammatory bowel diseases in the Korean population. J. Gastroenterol. Hepatol. 28, 1588–1594 (2013)

  24. 24.

    et al. Disruption of inducible 6-phosphofructo-2-kinase impairs the suppressive effect of PPARγ activation on diet-induced intestine inflammatory response. J. Nutr. Biochem. 24, 770–775 (2013)

  25. 25.

    et al. Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature. J. Clin. Invest. 124, 3617–3633 (2014)

  26. 26.

    et al. The cytomegalovirus-encoded chemokine receptor US28 promotes intestinal neoplasia in transgenic mice. J. Clin. Invest. 120, 3969–3978 (2010)

  27. 27.

    et al. Cis elements of the villin gene control expression in restricted domains of the vertical (crypt) and horizontal (duodenum, cecum) axes of the intestine. J. Biol. Chem . 277, 33275–33283 (2002)

  28. 28.

    et al. In vivo depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by exogenous cell-associated antigens. Immunity 17, 211–220 (2002)

  29. 29.

    et al. Diphtheria toxin receptor-mediated conditional and targeted cell ablation in transgenic mice. Nat. Biotechnol. 19, 746–750 (2001)

  30. 30.

    et al. Origin of the lamina propria dendritic cell network. Immunity 31, 513–525 (2009)

  31. 31.

    et al. Deciphering the transcriptional network of the dendritic cell lineage. Nat. Immunol. 13, 888–899 (2012)

  32. 32.

    , & Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res . 30, 207–210 (2002)

  33. 33.

    et al. Interplay of host microbiota, genetic perturbations, and inflammation promotes local development of intestinal neoplasms in mice. J. Exp. Med. 211, 457–472 (2014)

  34. 34.

    et al. Exposure to ionizing radiation induces the migration of cutaneous dendritic cells by a CCR7-dependent mechanism. J. Immunol. 189, 4247–4257 (2012)

  35. 35.

    & Monocyte recruitment during infection and inflammation. Nat. Rev. Immunol. 11, 762–774 (2011)

Download references

Acknowledgements

We are grateful to S. V. Chittur and M. Kuentzel, SUNY at the Albany Center for Functional Genomics. We thank M. Bogunovic at Pennsylvania State University, S. Jung at the Weizmann Institute of Science, Blander Laboratory members, J. Ochando and C. Bare at the Icahn School of Medicine Flow Cytometry Core, and M. A. Blander and S. J. Blander for discussions, help, and support. This work was supported by institutional seed funds to J.M.B. J.M.B. and her laboratory were supported by NIH grants AI095245, AI123284, DK072201, the Burroughs Wellcome Fund, and the Leukemia and Lymphoma Society. R.J.C. was supported by NIH training grants 2T32A1007605-11 and 5T32DK007792-12. G.Ba. was supported by the Crohn’s and Colitis Foundation of America (CCFA) Research Fellowship Award. B.M.H: NIAID contract HHSN272201000054C and U19 AI117873. J.C.: R01 DK092235, U01 DK62429, U01 DK062422, philanthropic SUCCESS, Sanford J. Grossman Charitable Trust. S.A.L. and G.C.F.: NIH 5P01DK072201-09 and 5R01CA161373-04, CCFA 330239, and SUCCESS. G.Bo.: Jenna and Paul Segal grant.

Author information

Author notes

    • J. Magarian Blander

    Present address: The Jill Roberts Institute of Inflammatory Bowel Disease, Division of Gastroenterology, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, New York 10021, USA.

Affiliations

  1. Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA

    • Ryan J. Cummings
    • , Gaetan Barbet
    • , Gerold Bongers
    • , Luciana Muniz
    • , Glaucia C. Furtado
    • , Judy Cho
    • , Sergio A. Lira
    •  & J. Magarian Blander
  2. Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA

    • Ryan J. Cummings
    • , Gaetan Barbet
    • , Gerold Bongers
    • , Luciana Muniz
    • , Glaucia C. Furtado
    • , Judy Cho
    • , Sergio A. Lira
    •  & J. Magarian Blander
  3. Department of Neurology, Center for Translational Systems Biology, Icahn School of Medicine at Mount Sinai, New York 10029, USA

    • Boris M. Hartmann
  4. Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06520, USA

    • Kyle Gettler
  5. Graduate School of Biological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA

    • Luciana Muniz
    •  & J. Magarian Blander
  6. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA

    • Judy Cho
  7. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA

    • Sergio A. Lira
    •  & J. Magarian Blander
  8. Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA

    • J. Magarian Blander

Authors

  1. Search for Ryan J. Cummings in:

  2. Search for Gaetan Barbet in:

  3. Search for Gerold Bongers in:

  4. Search for Boris M. Hartmann in:

  5. Search for Kyle Gettler in:

  6. Search for Luciana Muniz in:

  7. Search for Glaucia C. Furtado in:

  8. Search for Judy Cho in:

  9. Search for Sergio A. Lira in:

  10. Search for J. Magarian Blander in:

Contributions

R.J.C. and J.M.B: designed the study and wrote the manuscript. R.J.C. conducted most experiments; G.Ba. performed the initial set-up, protocol optimization and provided sorting expertise; L.M. performed initial VDTR characterizations; G.Bo. provided microarray and statistical analysis expertise; B.M.H. performed ImageStream acquisition and analyses; J.C. and K.G. performed IBD GWAS data comparison with differentially expressed phagocyte genes; G.C.F. and S.A.L.: VDTR strain derivation and data discussions. J.M.B. conceived the study.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Sergio A. Lira or J. Magarian Blander.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains a glossary of gene names in alphabetical order.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature20138

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.