Immunity 47, 913–927 (2017).

Apoptotic-cell-derived nucleic acids do not initiate inflammation in healthy tissues, although professional phagocytes express nucleic-acid-sensing receptors, such as TLR7 and TLR9, in the phagosomal compartment. In Immunity, Barton and colleagues report the use of a system that allows tracking of phagocytic cells in vivo to identify Tim-4+ peritoneal macrophages, Tim-4+ pleural cavity macrophages and Tim-4– lung alveolar macrophages as populations that clear apoptotic cells at steady state. These macrophages lack TLR9 expression and have high expression of apoptotic cell receptors and inhibitors of TLR signaling in vivo, and they do not induce an inflammatory response to apoptotic cells ex vivo. However, after 3 days of in vitro culture, they acquire TLR9 expression and the ability to induce a proinflammatory response to apoptotic cells. This in vitro ‘deprogramming’ is associated with the downregulation of the transcription factor Klf2, which seems to control a tissue-enforced program for silent clearance of apoptotic cells. IV