The identity of the apoptotic cell explains the functional diversity of the efferocytic macrophages

Macrophages are a functionally heterogeneous cell population, critical for the clearance of apoptotic cells. Apoptotic cells have so far been regarded as cells with homogeneous characteristics, often neglecting their original cell lineage identity. Contrary to this, we have observed that the identities of apoptotic cells matter, since they diversify the profile of efferocytic macrophages in vitro and in mouse models of tissue damage. Apoptotic neutrophils trigger a tissue remodeling macrophage signature, while T cells and hepatocytes respectively do not change or promote a tolerogenic macrophage response. Accordingly, the in vivo transfer of macrophages fed with apoptotic neutrophils, but not the transfer of macrophages fed with other apoptotic cells, promotes tissue remodeling. Finally, using a mouse model of parasite-induced tissue pathology, we found that the presence of specific apoptotic cells while simultaneously engaging select phagocytic receptors, i.e. AXL and MERTK by apoptotic neutrophils, diversifies macrophage function. These data reveal that the identity of an apoptotic cell should not be neglected since it drives macrophage transcriptomic and functional heterogeneity.