title: Epigenetic changes in bone marrow progenitor cells influence the inflammatory phenotype and alter wound healing in type 2 diabetes.
abstract: Classically activated (M1) macrophages are known to play a role in the development of chronic inflammation associated with impaired wound healing in type 2 diabetes (T2D); however, the mechanism responsible for the dominant proinflammatory (M1) macrophage phenotype in T2D wounds is unknown. Since epigenetic enzymes can direct macrophage phenotypes, we assessed the role of histone methylation in bone marrow (BM) stem/progenitor cells in the programming of macrophages toward a proinflammatory phenotype. We have found that a repressive histone methylation mark, H3K27me3, is decreased at the promoter of the IL-12 gene in BM progenitors and this epigenetic signature is passed down to wound macrophages in a murine model of glucose intolerance (diet-induced obese). These epigenetically "preprogrammed" macrophages result in poised macrophages in peripheral tissue and negatively impact wound repair. We found that in diabetic conditions the H3K27 demethylase Jmjd3 drives IL-12 production in macrophages and that IL-12 production can be modulated by inhibiting Jmjd3. Using human T2D tissue and murine models, we have identified a previously unrecognized mechanism by which macrophages are programmed toward a proinflammatory phenotype, establishing a pattern of unrestrained inflammation associated with nonhealing wounds. Hence, histone demethylase inhibitor-based therapy may represent a novel treatment option for diabetic wounds.
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, MI kgallag@med.umich.edu.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Gallagher
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, MI.
authors.forename: Amrita
authors.initials: A
authors.lastname: Joshi
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI.
authors.forename: William F
authors.initials: WF
authors.lastname: Carson
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI.
authors.forename: Matthew
authors.initials: M
authors.lastname: Schaller
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI.
authors.forename: Ronald
authors.initials: R
authors.lastname: Allen
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI.
authors.forename: Sumanta
authors.initials: S
authors.lastname: Mukerjee
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI.
authors.forename: Nico
authors.initials: N
authors.lastname: Kittan
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI.
authors.forename: Eva L
authors.initials: EL
authors.lastname: Feldman
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, MI.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Henke
authors.affiliation: Department of Medicine, Cedars-Sinai, Los Angeles, CA.
authors.forename: Cory
authors.initials: C
authors.lastname: Hogaboam
authors.affiliation: Department of Medicine, University of Michigan, Ann Arbor, MI.
authors.forename: Charles F
authors.initials: CF
authors.lastname: Burant
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kunkel
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D044127:Epigenesis, Genetic; D006801:Humans; D007249:Inflammation; D018664:Interleukin-12 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D010641:Phenotype; D011401:Promoter Regions, Genetic; D013234:Stem Cells / Q000378:metabolism*; D014945:Wound Healing / Q000502:physiology*
chemical_list: D018664:Interleukin-12