Systems genetics identifies a macrophage cholesterol network associated with physiological wound healing.

Bagnati, Marta, Moreno-Moral, Aida, Ko, Jeong-Hun, Nicod, Jerome, Harmston, Nathan, Imprialou, Martha, Game, Laurence, Gil, Jesus, Petretto, Enrico and Behmoaras, Jacques 2019. Systems genetics identifies a macrophage cholesterol network associated with physiological wound healing. JCI Insight 4 (2) , 2379-3708. 10.1172/jci.insight.125736

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	American Society for Clinical Investigation
ISSN:	2379-3708
Date of Acceptance:	18 December 2018
Last Modified:	24 Aug 2023 12:00
URI:	https://orca.cardiff.ac.uk/id/eprint/161886

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