title: Hyper-inflammation and skin destruction mediated by rosiglitazone activation of macrophages in IL-6 deficiency.
abstract: Injury initiates recruitment of macrophages to support tissue repair; however, excessive macrophage activity may exacerbate tissue damage causing further destruction and subsequent delay in wound repair. Here we show that the peroxisome proliferation-activated receptor-γ agonist, rosiglitazone (Rosi), a medication recently reintroduced as a drug to treat diabetes and with known anti-inflammatory properties, paradoxically generates pro-inflammatory macrophages. This is observed in both IL-6-deficient mice and control wild-type mice experimentally induced to produce high titers of auto-antibodies against IL-6, mimicking IL-6 deficiency in human diseases. IL-6 deficiency when combined with Rosi-mediated upregulation of suppressor of cytokine signaling 3 leads to an altered ratio of nuclear signal transducer and activator of transcription 3/NF-κB that allows hyper-induction of inducible nitric oxide synthase (iNOS). Macrophages activated in this manner cause de novo tissue destruction, recapitulating human chronic wounds, and can be reversed in vivo by recombinant IL-6, blocking macrophage infiltration, or neutralizing iNOS. This study provides insight into an unanticipated paradoxical role of Rosi in mediating hyper-inflammatory macrophage activation significant for diseases associated with IL-6 deficiency.
authors.affiliation: Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Lopa M
authors.initials: LM
authors.lastname: Das
authors.affiliation: Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Rosenjack
authors.affiliation: Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Liemin
authors.initials: L
authors.lastname: Au
authors.affiliation: Centre of Inflammation and Metabolism, Rigshospitalet, National University Hospital, Copenhagen, Denmark; Department of Clinical Immunology, Rigshospitalet, National University Hospital, Copenhagen, Denmark.
authors.forename: Pia S
authors.initials: PS
authors.lastname: Galle
authors.affiliation: Centre of Inflammation and Metabolism, Rigshospitalet, National University Hospital, Copenhagen, Denmark.
authors.forename: Morten B
authors.initials: MB
authors.lastname: Hansen
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
authors.forename: Martha K
authors.initials: MK
authors.lastname: Cathcart
authors.affiliation: Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: McCormick
authors.affiliation: Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Cooper
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Roy L
authors.initials: RL
authors.lastname: Silverstein
authors.affiliation: Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA. Electronic address: kurt.lu@case.edu.
authors.forename: Kurt Q
authors.initials: KQ
authors.lastname: Lu
mesh_terms: D000818:Animals; D005260:Female; D007249:Inflammation / Q000209:etiology*; D015850:Interleukin-6 / Q000172:deficiency*; D008262:Macrophage Activation / Q000187:drug effects*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000502:physiology; D000077154:Rosiglitazone; D050796:STAT3 Transcription Factor / Q000502:physiology; D012867:Skin / Q000473:pathology*; D045162:Thiazolidinediones / Q000494:pharmacology*; D014945:Wound Healing
chemical_list: D015850:Interleukin-6; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D045162:Thiazolidinediones; C577686:interleukin-6, mouse; D000077154:Rosiglitazone; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse