Abstract
Among other cells, macrophages regulate the inflammatory and reparative phases during wound healing but genetic determinants and detailed molecular pathways that modulate these processes are not fully elucidated. Here, we took advantage of normal variation in wound healing in 1,378 genetically outbred mice, and carried out macrophage RNA-sequencing profiling of mice with extreme wound healing phenotypes (i.e., slow and fast healers, n = 146 in total). The resulting macrophage coexpression networks were genetically mapped and led to the identification of a unique module under strong trans-acting genetic control by the Runx2 locus. This macrophage-mediated healing network was specifically enriched for cholesterol and fatty acid biosynthetic processes. Pharmacological blockage of fatty acid synthesis with cerulenin resulted in delayed wound healing in vivo, and increased macrophage infiltration in the wounded skin, suggesting the persistence of an unresolved inflammation. We show how naturally occurring sequence variation controls transcriptional networks in macrophages, which in turn regulate specific metabolic pathways that could be targeted in wound healing.
Highlights
Wound healing is the repair of damaged and injured skin
Genetically heterogeneous colonies that commercial mouse breeders maintain. These colonies present the necessary genetic structure and variation to allow high resolution mapping of complex traits, which can be exploited for gene identification by genome-wide association studies (GWAS)
The available resources for these 146 mice were (a) quantitative differences in wound healing indicated as ear area, (b) bone marrow–derived macrophages (BMDMs) mRNA expression by RNA-seq, and (c) genome-wide SNP genotyping imputed from low-coverage sequencing (Figure 1)
Summary
Wound healing is the repair of damaged and injured skin. It is a complex and highly dynamic process consisting of overlapping phases that include inflammation, tissue formation and remodeling, which can lead to the production of a nonfunctioning mass of fibrotic tissue known as the scar [1]. Macrophages are pivotal effector cells during wound healing. They dynamically change their activity throughout the healing process as their immune/phagocytic properties gradually convert into a more reparative and immunomodulatory phenotype [4, 5]. Macrophages are present during all stages of the repair process and their depletion with anti-macrophage serum results in impaired wound healing [6]. Different macrophage polarization stages correspond to different phases of tissue repair: proinflammatory macrophages infiltrating during the initial inflammatory phase are later antagonized by immunomodulatory macrophages that promote tissue repair and fibrosis [5, 8]
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