Identification of a distinct cluster of GDF15highmacrophages exhibiting anti-inflammatory activities

Abstract

AbstractMacrophage-mediated inflammatory response may have crucial roles in the pathogenesis of a variety of human diseases. Growth differentiation factor 15 (GDF15) is a cytokine of the transforming growth factor-β superfamily, with potential anti-inflammatory activities. Previous studies observed in human lungs some macrophages which expressed a high level of GDF15. In the present study, we employed multiple techniques, including immunofluorescence, flow cytometry, and single-cell RNA sequencing, in order to further clarify the identity of such GDF15highmacrophages. We demonstrated that macrophages derived from human peripheral blood mononuclear cells and rat bone marrow mononuclear cells byin vitrodifferentiation with granulocyte-macrophage colony stimulating factor contained a minor population (∼1%) of GDF15highcells. GDF15highmacrophages did not exhibit a typical M1 or M2 phenotype, but had a unique molecular signature as revealed by single-cell RNA sequencing. Functionally, GDF15highmacrophages were associated with reduced responsiveness to pro-inflammatory activation; furthermore, GDF15highmacrophages could inhibit the pro-inflammatory functions of other macrophages via a paracrine mechanism. We further confirmed that GDF15per sewas a key mediator of the anti-inflammatory effects of GDF15highmacrophage. Also, we provided direct evidence showing that GDF15highmacrophages were also present in other macrophage-residing human tissues in addition to the lungs. Our results suggest that the GDF15highmacrophage may represent a distinct cluster of macrophage cells with intrinsic anti-inflammatory functions. The (patho)physiological importance of these cellsin vivowarrants further investigation.