Different tissue phagocytes sample apoptotic cells to direct distinct homeostasis programs.
Different tissue phagocytes sample apoptotic cells to direct distinct homeostasis programs.
复制标题
DOI：
10.1038/nature20138
复制
发表时间：
2016-11-24
期刊：
影响因子：
64.8
通讯作者：
Blander JM
中科院分区：
文献类型：
--
作者：
Cummings RJ;Barbet G;Bongers G;Hartmann BM;Gettler K;Muniz L;Furtado GC;Cho J;Lira SA;Blander JM
通过专职吞噬细胞（包括树突状细胞和巨噬细胞）识别和去除凋亡细胞，保持免疫自身耐受性并预防慢性炎症和自身免疫性病理。不同组织中吞噬细胞的多样性，加上凋亡细胞清除的必然性，使得原位研究这一过程变得困难。因此，由组织驻留的吞噬细胞响应稳态凋亡而执行的全部功能仍不清楚。在这里，我们表明，小鼠凋亡的肠上皮细胞（IEC），经历不断更新，以保持最佳的屏障和吸收功能，不仅被挤出，以保持稳态细胞数量，但也采样由一个单一的树突状细胞和两个巨噬细胞亚群内的一个良好的特征网络的吞噬细胞在小肠固有层。在凋亡IEC的原位取样之前和之后，每个子集内的转录组的表征揭示了每个吞噬细胞特有的基因表达特征，包括巨噬细胞特异性脂质代谢和氨基酸催化剂，以及调节CD4+ T细胞活化的树突细胞特异性程序。人们注意到了一种常见的“抑制炎症”特征，尽管所涉及的特定基因和途径在树突状细胞和巨噬细胞之间存在差异，反映了专门的功能。凋亡的IEC仅通过树突状细胞亚群运输到肠系膜淋巴结，并作为诱导致耐受性调节性CD4+ T细胞分化的关键决定因素。携带凋亡IEC的吞噬细胞差异表达的几个基因与炎症性肠病的易感基因重叠。总的来说，这些发现为凋亡细胞采样的后果提供了新的见解，推进了我们对粘膜内如何维持稳态的理解，并为开发新的治疗方法以减轻慢性炎症性疾病如炎症性肠病奠定了基础。
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.
登录
查看更多内容
影响因子：
44.1
作者：
Hu H;Sun SC
通讯作者：
Sun SC
影响因子：
32.4
作者：
Jung, S;Unutmaz, D;Lang, RA
通讯作者：
Lang, RA
影响因子：
64.8
作者：
Khor, Bernard;Gardet, Agnes;Xavier, Ramnik J.
通讯作者：
Xavier, Ramnik J.
影响因子：
29.7
作者：
Josefowicz SZ;Lu LF;Rudensky AY
通讯作者：
Rudensky AY
影响因子：
4.8
作者：
Madison, BB;Dunbar, L;Gumucio, DL
通讯作者：
Gumucio, DL