title: Deletion of a tumor necrosis superfamily gene in mice leads to impaired healing that mimics chronic wounds in humans.
abstract: Proper healing of cutaneous wounds progresses through a series of overlapping phases. Nonhealing wounds are defective in one or more of these processes and represent a major clinical problem. A critical issue in developing treatments for chronic wounds is the paucity of animal models to study the mechanisms underlying the defects in healing. Here we show that deletion of tumor necrosis factor superfamily member 14 (TNFSF14/LIGHT) leads to impaired wounds in mice that have the characteristics of nonchronic and chronic ulcers. These wounds show: (1) excessive production of cytokines, in particular three chemokines (KC/CXCL8, MCP-1/CCL2, IP-10/CXCL10), that may be key to the abnormal initiation and resolution of inflammation; (2) defective basement membranes, explaining blood vessel leakage and disruption of dermal/epidermal interactions; and (3) granulation tissue that contains high levels of Coll III, whereas Coll I is virtually absent and does not form fibrils. We also see major differences between nonchronic and chronic wounds, with the latter populated by bacterial films and producing eotaxin, a chemokine that attracts leukocytes that combat multicellular organisms (which biofilms can be considered to be). This new mouse model captures many defects observed in impaired and chronic human wounds and provides a vehicle to address their underlying cell and molecular mechanisms.
authors.affiliation: Department of Cell Biology and Neuroscience, University of California-Riverside, 900 University Ave., Riverside, CA 92521, USA.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Petreaca
authors.forename: Danh
authors.initials: D
authors.lastname: Do
authors.forename: Sandeep
authors.initials: S
authors.lastname: Dhall
authors.forename: Darcie
authors.initials: D
authors.lastname: McLelland
authors.forename: Avo
authors.initials: A
authors.lastname: Serafino
authors.forename: Julia
authors.initials: J
authors.lastname: Lyubovitsky
authors.forename: Neal
authors.initials: N
authors.lastname: Schiller
authors.forename: Manuela M
authors.initials: MM
authors.lastname: Martins-Green
mesh_terms: D000818:Animals; D018441:Biofilms / Q000254:growth & development; D018932:Chemokine CCL2 / Q000378:metabolism*; D054357:Chemokine CXCL10 / Q000378:metabolism*; D002908:Chronic Disease; D004195:Disease Models, Animal; D017353:Gene Deletion; D016209:Interleukin-8 / Q000378:metabolism*; D051379:Mice; D012883:Skin Ulcer / Q000235:genetics / Q000382:microbiology / Q000473:pathology; D013207:Staphylococcal Skin Infections / Q000235:genetics / Q000382:microbiology / Q000473:pathology; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000235:genetics* / Q000378:metabolism; D014945:Wound Healing / Q000235:genetics; D014946:Wound Infection / Q000235:genetics* / Q000382:microbiology / Q000473:pathology
chemical_list: D018932:Chemokine CCL2; D054357:Chemokine CXCL10; D016209:Interleukin-8; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14