Different tissue phagocytes sample apoptotic cells to direct distinct homeostasis programs.
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.
Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Ryan J
RJ
Cummings
Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Gaetan
G
Barbet
Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Gerold
G
Bongers
Department of Neurology, Center for Translational Systems Biology, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
Boris M
BM
Hartmann
Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06520, USA.
Kyle
K
Gettler
Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Graduate School of Biological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Luciana
L
Muniz
Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Glaucia C
GC
Furtado
Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Judy
J
Cho
Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Sergio A
SA
Lira
Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Graduate School of Biological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
J Magarian
JM
Blander
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation; D002465:Cell Movement; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology* / Q000276:immunology*; D005260:Female; D006706:Homeostasis; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015212:Inflammatory Bowel Diseases / Q000276:immunology / Q000473:pathology; D039001:Integrin alpha Chains / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology* / Q000276:immunology*; D050356:Lipid Metabolism; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D010586:Phagocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology; D014158:Transcription, Genetic
D000596:Amino Acids; D015703:Antigens, CD; D039001:Integrin alpha Chains; C091367:alpha E integrins