Study summary · research use only
HUMANIN produced by human efferocytic macrophages promotes the resolution of inflammation
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This study of human efferocytic macrophages (which clear apoptotic neutrophils) used RNA sequencing and identified genes including PLIN5, MTLN, and the mitochondrial gene MT-RNR2, which encodes a secreted factor called HUMANIN. In a mouse acute peritonitis model, preventive HUMANIN administration was associated with reduced leukocyte infiltration and pro-inflammatory cytokine secretion, along with an early CD11blow non-efferocytic macrophage phenotype and increased expression of Alox15 and Retnla. HUMANIN also reduced pro-inflammatory cytokine secretion in primary human neutrophils and was detected in gingival crevicular fluid from patients with periodontitis after inflammation onset. The authors describe these findings as pointing to a pro-resolving role for HUMANIN in 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.
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