HUMANIN produced by human efferocytic macrophages promotes the resolution of inflammation

Abstract Elimination of apoptotic neutrophils by macrophages, a process called efferocytosis, is a critical step in the resolution of inflammation. Efferocytosis induces the reprogramming of macrophages towards a pro-resolving phenotype and triggers the secretion of pro-resolving factors. While mouse efferocytic macrophages are well-described, less is known about human efferocytic macrophages. Here, using RNA sequencing analysis of three different types of in vitro-derived human efferocytic macrophages, we observed a common modulation of mitochondrial metabolism-related genes in human M0, M1, and M2a-like macrophages, thus correlating with some previous results obtained in other non-human models. These results led us to identify for the first time some particular genes regulated in humans like PLIN5 and MTLN. We also shed light on a mitochondrial gene (MT-RNR2) coding a secreted factor called HUMANIN. Mainly known for its antioxidant and neuroprotective effects, we found that HUMANIN was also associated with pro-resolving properties in human and mouse models. Indeed, HUMANIN was produced early during the resolution of inflammation in an acute peritonitis mouse model. Preventive HUMANIN administration in this model reduced leukocyte infiltration and pro-inflammatory cytokine secretion. These anti-inflammatory properties were accompanied by the early acquisition of a CD11blow non-efferocytic phenotype by mouse macrophages and by an enhanced expression of pro-resolving genes including Alox15 and Retnla. The ability of HUMANIN to dampen pro-inflammatory cytokine secretion was also confirmed in primary human neutrophils. Finally, HUMANIN was also detected in gingival crevicular fluids of patients suffering from periodontitis after the onset of inflammation, suggesting a role of HUMANIN in the control of inflammation. Overall, our data shed light on new aspects of efferocytosis in humans and identify the pro-resolving potential of HUMANIN. This illustrates its prospective therapeutic interest in inflammatory disorders.