Transient efferocytosis-induced activation of IKKβ reprograms macrophages to promote tissue resolution in mice

The clearance of apoptotic cells by macrophages, termed efferocytosis, activates multiple pro-resolving pathways, but whether there is a common upstream regulator remains unknown. Here, we report that in efferocytosing macrophages, MerTK activation by apoptotic cells rapidly and transiently activates an IKKβ-NFκB/-p38 pathway, which then promotes interleukin-10 (IL-10) production, continuing efferocytosis, and regulatory T cell expansion. The IKKβ and downstream resolution pathways are linked through the transcription factor Myc, the epigenetic modifier ten-eleven translocation-2 (TET2), and the immune checkpoint protein programmed cell death ligand 1 (PD-L1). Deletion of macrophage IKKβ in male mice blocks the above resolution pathways and compromises efferocytosis-mediated tissue repair in a model of thymic injury and in atherosclerosis regression. Thus, our findings illustrate the existence of a unifying upstream signal for efferocytosis-induced resolution, which could suggest therapeutic strategies to enhance multiple tissue resolution pathways and to optimize anti-inflammatory therapies by avoiding blocking IKKβ-NFκB/p38-mediated resolution. The clearance of apoptotic cells, or efferocytosis, reprograms macrophages towards a pro-resolving phenotype to facilitate tissue repair. Here, the authors identify IKKβ as an upstream regulator of immunoregulatory and reparative processes, showing that MerTK activation by apoptotic cells transiently activates an IKKβ-dependent NFKB/p38 axis, inducing IL-10 production, Rac1-mediated continuing efferocytosis, and activation of a Myc–TET2–PD-L1 pathway that promotes regulatory T cell expansion.