Different tissue phagocytes sample apoptotic cells to direct distinct homeostasis programs

• Published in: Nature (London) Vol. 539; no. 7630; pp. 565 - 569
• Main Authors: Cummings, Ryan J., Barbet, Gaetan, Bongers, Gerold, Hartmann, Boris M., Gettler, Kyle, Muniz, Luciana, Furtado, Glaucia C., Cho, Judy, Lira, Sergio A., Blander, J. Magarian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.11.2016; Nature Publishing Group
• Subjects: 631/250/1933; 631/250/347; Amino acids; Amino Acids - metabolism; Animals; Antigens, CD - metabolism; Apoptosis; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; Cell Differentiation; Cell Movement; Cytological research; Dendritic cells; Dendritic Cells - cytology; Dendritic Cells - immunology; Dendritic Cells - metabolism; Diphtheria; Epithelial Cells - cytology; Epithelial Cells - immunology; Female; Gene expression; Homeostasis; Humanities and Social Sciences; Inflammation; Inflammation - genetics; Inflammation - immunology; Inflammation - pathology; Inflammatory bowel disease; Inflammatory Bowel Diseases - immunology; Inflammatory Bowel Diseases - pathology; Integrin alpha Chains - metabolism; Intestinal Mucosa - cytology; Intestinal Mucosa - immunology; letter; Lipid Metabolism; Lymph nodes; Lymph Nodes - immunology; Lymphocyte Activation; Macrophages - cytology; Macrophages - immunology; Macrophages - metabolism; Male; Mice; multidisciplinary; Phagocytes; Phagocytes - cytology; Phagocytes - immunology; Phagocytes - metabolism; Physiological aspects; Rodents; Science; Small intestine; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; Transcription, Genetic
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature20138

Apoptotic intestinal epithelial cells can be sampled by lamina propria phagocytes, leading to distinct phagocyte-type-specific anti-inflammatory gene signatures and dendritic-cell-mediated induction of regulatory T cells. Apoptotic cell phagocytosis in intestinal mucosa Rapid clearance of apoptotic cells can reduce inflammatory and autoimmune consequences of their disintegration. Its disruption can trigger immune responses against molecular components and self-antigens released from degenerating apoptotic cells. Magarian Blander and colleagues show here in a mouse model that clearance of apoptotic epithelial cells by intestinal phagocytes (dendritic cells and two types of macrophages) results in the upregulation of distinct cell-type-specific anti-inflammatory gene signatures, and dendritic-cell-mediated induction of regulatory T cells. Some of the induced genes overlap with susceptibility genes for inflammatory bowel disease. 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 1 , 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 functions 3 , are not merely extruded to maintain homeostatic cell numbers 4 , 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 5 , 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 disease 7 . 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.