Roberts Allison W, Lee Bettina L, Deguine Jacques, John Shinu, Shlomchik Mark J, Barton Gregory M
Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Immunity. 2017 Nov 21;47(5):913-927.e6. doi: 10.1016/j.immuni.2017.10.006. Epub 2017 Nov 14.
Although apoptotic cells (ACs) contain nucleic acids that can be recognized by Toll-like receptors (TLRs), engulfment of ACs does not initiate inflammation in healthy organisms. Here we identified macrophage populations that continually engulf ACs in distinct tissues and found that these macrophages share characteristics compatible with immunologically silent clearance of ACs; such characteristics include high expression of AC recognition receptors, low expression of TLR9, and reduced TLR responsiveness to nucleic acids. Removal of the macrophages from tissues resulted in loss of many of these characteristics and the ability to generate inflammatory responses to AC-derived nucleic acids, suggesting that cues from the tissue microenvironment program macrophages for silent AC clearance. The transcription factors KLF2 and KLF4 control the expression of many genes within this AC clearance program. The coordinated expression of AC receptors with genes that limit responses to nucleic acids might ensure maintenance of homeostasis and thus represent a central feature of tissue macrophages.
尽管凋亡细胞（ACs）含有可被Toll样受体（TLRs）识别的核酸，但在健康生物体中，ACs的吞噬并不会引发炎症。在这里，我们鉴定出了在不同组织中持续吞噬ACs的巨噬细胞群体，并发现这些巨噬细胞具有与ACs免疫沉默清除相兼容的特征；这些特征包括AC识别受体的高表达、TLR9的低表达以及对核酸的TLR反应性降低。从组织中去除巨噬细胞会导致许多这些特征丧失，以及对AC衍生核酸产生炎症反应的能力丧失，这表明组织微环境的信号促使巨噬细胞进行AC的沉默清除。转录因子KLF2和KLF4控制着这个AC清除程序中许多基因的表达。AC受体与限制对核酸反应的基因的协调表达可能确保体内平衡的维持，因此代表了组织巨噬细胞的一个核心特征。
