title: Myeloid Cell-Restricted Insulin/IGF-1 Receptor Deficiency Protects against Skin Inflammation.
abstract: Myeloid cells are key regulators of tissue homeostasis and disease. Alterations in cell-autonomous insulin/IGF-1 signaling in myeloid cells have recently been implicated in the development of systemic inflammation and insulin-resistant diabetes mellitus type 2 (DM). Impaired wound healing and inflammatory skin diseases are frequent DM-associated skin pathologies, yet the underlying mechanisms are elusive. In this study, we investigated whether myeloid cell-restricted IR/IGF-1R signaling provides a pathophysiologic link between systemic insulin resistance and the development of cutaneous inflammation. Therefore, we generated mice lacking both the insulin and IGF-1 receptor in myeloid cells (IR/IGF-1R(MKO)). Whereas the kinetics of wound closure following acute skin injury was similar in control and IR/IGF-1R(MKO) mice, in two different conditions of dermatitis either induced by repetitive topical applications of the detergent SDS or by high-dose UV B radiation, IR/IGF-1R(MKO) mice were protected from inflammation, whereas controls developed severe skin dermatitis. Notably, whereas during the early phase in both inflammatory conditions the induction of epidermal proinflammatory cytokine expression was similar in control and IR/IGF-1R(MKO) mice, during the late stage, epidermal cytokine expression was sustained in controls but virtually abrogated in IR/IGF-1R(MKO) mice. This distinct kinetic of epidermal cytokine expression was paralleled by proinflammatory macrophage activation in controls and a noninflammatory phenotype in mutants. Collectively, our findings provide evidence for a proinflammatory IR/IGF-1R-dependent pathway in myeloid cells that plays a critical role in the dynamics of an epidermal-dermal cross-talk in cutaneous inflammatory responses, and may add to the mechanistic understanding of diseases associated with disturbances in myeloid cell IR/IGF-1R signaling, including DM.
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Knuever
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Willenborg
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Ding
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Germany.
authors.forename: Mehmet D
authors.initials: MD
authors.lastname: Akyüz
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Germany.|Max Planck Institute for Biology of Ageing, Cologne, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Partridge
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany.
authors.forename: Carien M
authors.initials: CM
authors.lastname: Niessen
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany.|Max Planck Institute for Metabolism Research, Cologne, Germany.|Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Cologne, Germany.
authors.forename: Jens C
authors.initials: JC
authors.lastname: Brüning
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany.
authors.forename: Sabine A
authors.initials: SA
authors.lastname: Eming
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003872:Dermatitis / Q000235:genetics / Q000276:immunology*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D007333:Insulin Resistance / Q000235:genetics / Q000276:immunology; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017526:Receptor, IGF Type 1 / Q000235:genetics*; D011972:Receptor, Insulin / Q000235:genetics*; D015398:Signal Transduction / Q000276:immunology; D012867:Skin / Q000276:immunology*; D012967:Sodium Dodecyl Sulfate / Q000009:adverse effects; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D016207:Cytokines; D012967:Sodium Dodecyl Sulfate; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin