Resistin-like molecule alpha (RELMα) dampens lung inflammation and promotes wound healing in helminth infection and a 3D lung repair model

Abstract

Abstract RELMα is a small secreted and immunoregulatory protein, also known as hypoxia-induced mitogenic factor (HIMF) and found in inflammatory zone (FIZZ). RELMα, produced by macrophages and epithelial cells in the lung and intestine, has recently been shown by our lab and others to induce wound healing during Nippostrongylus brasiliensis (Nb) infection. However, the mechanisms by which RELMα activates wound healing pathways and what cell-types are activated by RELMα are unclear. We generated constitutive RELMα−/−/TdTomato-red (TdT) reporter mice to delete the RELMα gene and track RELMα promoter activity. We found that following Nb infection, RELMα−/− macrophages exhibited reduced expression of genes associated with wound healing such as Arg1, Mmp19 and Pdgfra. To complement the RELMα−/− mouse in vivo studies, a new endotoxin-free RELMα-human Fc fusion protein was constructed and purified. A RELMα capture assay with the fusion protein demonstrated that RELMα binds to macrophage cell line RAW 264.7. Moreover, 3D lung scaffold and wound healing assays showed that RELMα-Fc promoted tissue repair by lung epithelial cells and mesenchymal stem cells. Lastly, RELMα function in vivo was characterized by RELMα-Fc fusion protein treatment of Nb-infected RELMα−/−/TdT mice, which downregulated immune cell recruitment in the lung compared to control Fc. Ongoing studies include identification of the RELMα receptor using the RELMα fusion proteins and testing whether the wound healing properties of RELMα are effective in the intestine following Heligosomoides polygyrus infection.