The DOI matches its Crossref record; 35 of the 35 references it cites were found in a registry or an index.
Different tissue phagocytes sample apoptotic cells to direct distinct homeostasis programs
Open accessAbstract
Recognition and removal of apoptotic cells by professional phagocytes, including dendritic cells and macrophages, preserves immune self-tolerance and prevents chronic inflammation and autoimmune pathologies. 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 functions, are not merely extruded to maintain homeostatic cell numbers, 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 propria. 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 disease. 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.
Overview
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.
Integrity signals
Registry
Cites
Statistics
Verification
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.
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?
In the citing paper
“CD103+ DCs selectively carry apoptotic intestinal epithelial cells to mesenteric lymph nodes, which function as critical determinants to induce tolerogenic CD4+ regulatory T-cell differentiation in mice [161].”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [161]
In the citing paper
“CD24+ DCs generally exert their removal function via T-cell regulation.”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [161]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Gene Expression Omnibus: NCBI gene expression and hybridization array data repository
Edgar, R. (2002) · Nucleic Acids Research · doi:10.1093/nar/30.1.207 · Cited by 13,288
Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease
The International IBD Genetics Consortium (IIBDGC), Jostins, L., Ripke, S., Weersma, R. K., Duerr, R. H., McGovern, D. P., Hui, K. Y., Lee, J. C., Philip Schumm, L., Sharma, Y., et al. (2012) · Nature · doi:10.1038/nature11582 · Cited by 4,722
Self-citationMonocyte recruitment during infection and inflammation
Shi, C., & Pamer, E. G. (2011) · Nature Reviews Immunology · doi:10.1038/nri3070 · Cited by 3,015
Regulatory T cells: mechanisms of differentiation and function
Josefowicz, S. Z., Lu, L.-F., & Rudensky, A. Y. (2012) · Annual Review of Immunology · doi:10.1146/annurev.immunol.25.022106.141623 · Cited by 2,866
Genetics and pathogenesis of inflammatory bowel disease
Khor, B., Gardet, A., & Xavier, R. J. (2011) · Nature · doi:10.1038/nature10209 · Cited by 2,733
Jung, S., Unutmaz, D., Wong, P., Sano, G., Santos, K. D. L., Sparwasser, T., Wu, S., Vuthoori, S., Ko, K., Zavala, F., et al. (2002) · Immunity · doi:10.1016/s1074-7613(02)00365-5 · Cited by 1,953
Apoptotic cell clearance: basic biology and therapeutic potential
Poon, I. K. H., Lucas, C. D., Rossi, A. G., & Ravichandran, K. S. (2014) · Nature Reviews Immunology · doi:10.1038/nri3607 · Cited by 1,223
Immunogenic and tolerogenic cell death
Green, D. R., Ferguson, T., Zitvogel, L., & Kroemer, G. (2009) · Nature Reviews Immunology · doi:10.1038/nri2545 · Cited by 1,176
Crowding induces live cell extrusion to maintain homeostatic cell numbers in epithelia
Eisenhoffer, G. T., Loftus, P. D., Yoshigi, M., Otsuna, H., Chien, C.-B., Morcos, P. A., & Rosenblatt, J. (2012) · Nature · doi:10.1038/nature10999 · Cited by 891
Schlitzer, A., McGovern, N. N., Teo, P., Zelante, T., Atarashi, K., Low, D., Ho, A. W. S., See, P., Shin, A., Wasan, P. S., et al. (2013) · Immunity · doi:10.1016/j.immuni.2013.04.011 · Cited by 884
Origin of the Lamina Propria Dendritic Cell Network
Bogunovic, M., Ginhoux, F., Helft, J., Shang, L., Hashimoto, D., Greter, M., Liu, K., Jakubzick, C., Ingersoll, M. A., Leboeuf, M., et al. (2009) · Immunity · doi:10.1016/j.immuni.2009.08.010 · Cited by 859
Deciphering the transcriptional network of the dendritic cell lineage
Miller, J. C., Brown, B. D., Shay, T., Gautier, E. L., Jojic, V., Cohain, A. T., Pandey, G. S., Leboeuf, M., Elpek, K. G., Helft, J., et al. (2012) · Nature Immunology · doi:10.1038/ni.2370 · Cited by 802
Madison, B., Dunbar, L., Qiao, X. T., Braunstein, K., Braunstein, E. M., & Gumucio, D. L. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204935200 · Cited by 748
How Tolerogenic Dendritic Cells Induce Regulatory T Cells
Maldonado, R., & von Andrian, U. H. (2010) · Advances in immunology · doi:10.1016/b978-0-12-380995-7.00004-5 · Cited by 568
Dietary antigens limit mucosal immunity by inducing regulatory T cells in the small intestine
Kim, K. S., Hong, S., Han, D., Yi, J., Jung, J., Yang, B., Lee, J. Y., Lee, M., & Surh, C. D. (2016) · Science · doi:10.1126/science.aac5560 · Cited by 541
Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature
Haberman, Y., Tickle, T. L., Dexheimer, P. J., Kim, M., Tang, D., Karns, R. A., Baldassano, R. N., Noe, J. D., Rosh, J. R., Markowitz, J. F., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci75436 · Cited by 531
Diphtheria toxin receptor–mediated conditional and targeted cell ablation in transgenic mice
Saito, M., Iwawaki, T., Taya, C., Yonekawa, H., Noda, M., Inui, Y., Mekada, E., Kimata, Y., Tsuru, A., & Kohno, K. (2001) · Nature Biotechnology · doi:10.1038/90795 · Cited by 512
Ubiquitin signaling in immune responses
Hu, H., & Sun, S. (2016) · Cell Research · doi:10.1038/cr.2016.40 · Cited by 492
Tran, D. Q., Andersson, J., Wang, R., Ramsey, H. E., Unutmaz, D., & Shevach, E. M. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0901944106 · Cited by 473
Spred is a Sprouty-related suppressor of Ras signalling
Wakioka, T., Sasaki, A. T., Kato, R., Shouda, T., Matsumoto, A., Miyoshi, K., Tsuneoka, M., Komiya, S., Baron, R., & Yoshimura, A. (2001) · Nature · doi:10.1038/35088082 · Cited by 454
Death in the intestinal epithelium—basic biology and implications for inflammatory bowel disease
Blander, J. M. (2016) · FEBS Journal · doi:10.1111/febs.13771 · Cited by 197
CD205 (DEC-205): A recognition receptor for apoptotic and necrotic self
Shrimpton, R. E., Butler, M., Morel, A., Eren, E., Hue, S. S., & Ritter, M. A. (2009) · Molecular Immunology · doi:10.1016/j.molimm.2008.11.016 · Cited by 187
Intestinal dendritic cells in the regulation of mucosal immunity
Bekiaris, V., Persson, E. K., & Agace, W. W. (2014) · Immunological Reviews · doi:10.1111/imr.12194 · Cited by 165
Arbore, G., & Kemper, C. (2016) · European Journal of Immunology · doi:10.1002/eji.201546131 · Cited by 145
OASL1 inhibits translation of the type I interferon–regulating transcription factor IRF7
Lee, M. S., Kim, B., Oh, G. T., & Kim, Y.-J. (2013) · Nature Immunology · doi:10.1038/ni.2535 · Cited by 142
A long-awaited merger of the pathways mediating host defence and programmed cell death
Blander, J. M. (2014) · Nature reviews. Immunology · doi:10.1038/nri3720 · Cited by 127
Guardians of the Gut – Murine Intestinal Macrophages and Dendritic Cells
Gross, M., Salame, T., & Jung, S. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00254 · Cited by 118
PIKfyve Inhibition Interferes with Phagosome and Endosome Maturation in Macrophages
Kim, G. H. E., Dayam, R. M., Prashar, A., Terebiznik, M. R., & Botelho, R. J. (2014) · Traffic · doi:10.1111/tra.12199 · Cited by 114
The cytomegalovirus-encoded chemokine receptor US28 promotes intestinal neoplasia in transgenic mice
Bongers, G., Maussang, D., Muniz, L. R., Noriega, V. M., Fraile‐Ramos, A., Barker, N., Marchesi, F., Thirunarayanan, N., Vischer, H. F., Qin, L., et al. (2010) · Journal of Clinical Investigation · doi:10.1172/jci42563 · Cited by 111
Bongers, G., Pacer, M. E., Geraldino, T. H., Chen, L., He, Z., Hashimoto, D., Furtado, G. C., Ochando, J., Kelley, K. A., Clemente, J. C., et al. (2014) · The Journal of Experimental Medicine · doi:10.1084/jem.20131587 · Cited by 79
Guo, Z., Jang, M. H., Otani, K., Bai, Z., Umemoto, E. Y., Matsumoto, M., Nishiyama, M., Yamasaki, M., Ueha, S., Matsushima, K., et al. (2008) · International Immunology · doi:10.1093/intimm/dxm143 · Cited by 51
Cummings, R. J., Gerber, S. A., Judge, J., et al. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1201371 · Cited by 29
Guo, X., Li, H., Xu, H., et al. (2012) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2012.04.007 · Cited by 29
Moon, C. M., Shin, D., Son, N., Shin, E., Hong, S. P., Kim, T. I., Kim, W. H., & Cheon, J. H. (2013) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.12214 · Cited by 15
Fang, W., Douglas, I. S., Wang, C., Kao, H.-C., Chang, Y., Tseng, C., Huang, K., Chang, H., & Lin, M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0102622 · Cited by 10
Cited by
Sorted by citations
Efferocytosis in health and disease
Doran, A. C., Yurdagul, A., & Tabas, I. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-019-0240-6 · Cited by 1,066
Type 2 immunity in tissue repair and fibrosis
Gieseck, R. L., Wilson, M. S., & Wynn, T. A. (2018) · Nature Reviews Immunology · doi:10.1038/nri.2017.90 · Cited by 1,055
Macrophages in intestinal inflammation and resolution: a potential therapeutic target in IBD
Na, Y. R., Stakenborg, M., Seok, S. H., & Matteoli, G. (2019) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0172-4 · Cited by 900
The clearance of dead cells by efferocytosis
Boada-Romero, E., Martinez, J., Heckmann, B. L., & Green, D. R. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0232-1 · Cited by 924
Macrophages in health and disease
Park, M. D., Silvin, A., Ginhoux, F., & Merad, M. (2022) · Cell · doi:10.1016/j.cell.2022.10.007 · Cited by 644
Metadata
- Authors
- Cummings, R. J., Barbet, G., Bongers, G., Hartmann, B. M., Gettler, K., Muniz, L., Furtado, G. C., Cho, J., Lira, S. A., & Blander, J. M.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Yale University (US)
- Tisch Cancer Institute (US)
- Corresponding author
- Blander, J. Magarian
- Venue
- Nature
- Published
- 2016-11
- Volume
- 539
- Issue
- 7630
- Pages
- 565-569
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5807003
- OpenAlex
- W2556519132
- Cited by
- 228
- References
- 35
- Citations by year
- 2026: 23 · 2025: 20 · 2024: 22 · 2023: 21 · 2022: 26 · 2021: 25 · 2020: 32 · 2019: 21 · 2018: 17 · 2017: 21
- FWCI
- 11.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Crohn's and Colitis Foundation (294024)
- National Institutes of Health (5r01dk092235-06, 2T32A1007605-11, DK072201)
- National Cancer Institute (R01CA161373)
- National Institute of Allergy and Infectious Diseases (HHSN272201000054C, U19AI117873, R01AI095245, R01AI123284)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK092235, R01DK111862, T32DK007792, P01DK072201, U01DK062429, U01DK062422, R01DK110352)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD007149)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- efferocytosis, intestinal epithelial cells, dendritic cells, macrophage subsets, regulatory T cells, self-tolerance, mesenteric lymph nodes, tissue homeostasis, lipid metabolism, amino acid catabolism, chronic intestinal inflammation, autoimmunity
- MeSH terms
- Amino Acids, Animals, Cell Differentiation, Cell Movement, Dendritic Cells, Epithelial Cells, Female, Homeostasis, Inflammation, Intestinal Mucosa, Lymph Nodes, Lymphocyte Activation, Macrophages, Male, Phagocytes, Transcription, Genetic, Inflammatory Bowel Diseases, CD4-Positive T-Lymphocytes, Antigens, CD, Apoptosis, Integrin alpha Chains, Lipid Metabolism, T-Lymphocytes, Regulatory, Mice
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
