LAUSR

SUMMARY 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. HIGHLIGHTSSpecific populations of macrophages clear apoptotic cells (ACs) in certain tissuesThese macrophages share features that limit recognition of nucleic acids within ACsCues from the tissue microenvironment program macrophages for silent AC clearanceKLF2 and KLF4 control expression of genes necessary for silent AC clearance Inappropriate inflammatory responses to apoptotic cells (ACs) can trigger autoimmune disease. Roberts et al. now show that the tissue microenvironment programs resident macrophages so that clearance of ACs is linked to limited responses to AC‐derived nucleic acids. This program is reversible upon removal of the macrophages from tissue and is dependent on the transcription factors KLF2 and KLF4.