Different tissue phagocytes sample apoptotic cells to direct distinct homeostasis programs

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.

Ophiocordyceps pulvinata Induces Caspase-Dependent Apoptosis through Mitochondrial Impairment in Human Leukemia Cells

“…Macrophages recognize a lipid called PS found only on the surface of apoptotic cells. Furthermore, autoimmune diseases can inhibit the ability of macrophages to process apoptotic cells (Cummings et al, 2016). In the present study, chromatin condensation, nuclear fragmentation, and increased annexin V binding were observed in leukemia cells treated with OP-He, indicating the induction of apoptosis.…”

The many ways tissue phagocytes respond to dying cells

“…Using a mouse model where expression of a transgene encoding an enhanced green fluorescent protein (eGFP) and diphtheria toxin receptor (DTR) fusion protein is directed specifically to IECs, the fate of IEC after apoptosis in situ could be visualized (39). The model is referred to as the VDTR mouse (39).…”

“…Using a mouse model where expression of a transgene encoding an enhanced green fluorescent protein (eGFP) and diphtheria toxin receptor (DTR) fusion protein is directed specifically to IECs, the fate of IEC after apoptosis in situ could be visualized (39). The model is referred to as the VDTR mouse (39). The diphtheria toxin receptor enables the experimental induction of apoptosis as was determined by administering a carefully titrated concentration of diphtheria toxin that increased the levels of apoptosis over background (39).…”

“…The transgenic VDTR mouse model enabled visualization of phagocytes that had engulfed cells undergoing apoptosis in situ . The studies showed that within a heterogeneous network of intestinal lamina propria phagocytes (40, 41), both subsets of macrophages and a single CD103 + subset out of three DC subsets are responsible for apoptotic IEC sampling (39). These phagocytes are appropriately positioned for the task; facing the basolateral surface of IEC and capable of extending their dendrites through epithelial tight junctions to sample luminal contents, commensal bacteria (41, 42), and apoptotic IEC (39).…”

Mechanisms and Significance of Phagocytic Elimination of Cells Undergoing Apoptotic Death

“…57,58) Cells that have become pathogenic to organisms are eliminated by apoptosis-dependent phagocytosis. Examples of these targets are cancer cells and virus-infected cells.…”