title: Enforced Expression of Hoxa3 Inhibits Classical and Promotes Alternative Activation of Macrophages In Vitro and In Vivo.
abstract: The regulated differentiation of macrophages (mφs) and their subsequent activation into proinflammatory or prohealing subtypes is critical for efficient wound healing. Chronic wounds such as diabetic (db) ulcers are associated with dysregulation of macrophage function. Whereas non-db mφs polarize to an M2-like, prohealing phenotype during the late stages of healing, db-derived mφs continue to display an M1-like, proinflammatory, or a mixed M1-like/M2-like phenotype. We have previously shown that sustained expression of Hoxa3 reduces the excessive number of leukocytes within the db wound; however, the effect of Hoxa3 on mφ polarization was unknown. In this study, we show that Hoxa3 protein transduction of mφs in vitro enhances macrophage maturation, inhibits M1 polarization, and promotes M2 polarization, in part via regulation of Pu.1/Spi1 and Stat6. Sustained expression of Hoxa3 in vivo in db wounds reduces the number of Nos2(+) (M1-like) mφs, increases the number of Arg1(+) and VEGF(+) (M2-like) mφs, and accelerates healing in a DNA-binding independent manner. Our findings suggest a role for Hox protein activity in promoting M1-to-M2-like phenotypic switching via interactions with myeloid transcription factors and provide insight into mechanisms regulating this process in db wound healing.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
authors.forename: Hadeel
authors.initials: H
authors.lastname: Al Sadoun
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
authors.forename: Matthew
authors.identifier: 0000-0001-9666-6787
authors.initials: M
authors.lastname: Burgess
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
authors.forename: Kathryn E
authors.identifier: 0000-0001-8917-3765
authors.initials: KE
authors.lastname: Hentges
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom kimberly.mace@manchester.ac.uk.
authors.forename: Kimberly A
authors.identifier: 0000-0002-3184-878X
authors.initials: KA
authors.lastname: Mace
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000276:immunology*; D048909:Diabetes Complications / Q000276:immunology / Q000378:metabolism; D003920:Diabetes Mellitus; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D016133:Polymerase Chain Reaction; D059467:Transcriptome; D014945:Wound Healing / Q000276:immunology*
chemical_list: D018398:Homeodomain Proteins; C080331:Hoxa3 protein, mouse