title: Interleukin-4 Receptor α Signaling in Myeloid Cells Controls Collagen Fibril Assembly in Skin Repair.
abstract: Activation of the immune response during injury is a critical early event that determines whether the outcome of tissue restoration is regeneration or replacement of the damaged tissue with a scar. The mechanisms by which immune signals control these fundamentally different regenerative pathways are largely unknown. We have demonstrated that, during skin repair in mice, interleukin-4 receptor α (IL-4Rα)-dependent macrophage activation controlled collagen fibril assembly and that this process was important for effective repair while having adverse pro-fibrotic effects. We identified Relm-α as one important player in the pathway from IL-4Rα signaling in macrophages to the induction of lysyl hydroxylase 2 (LH2), an enzyme that directs persistent pro-fibrotic collagen cross-links, in fibroblasts. Notably, Relm-β induced LH2 in human fibroblasts, and expression of both factors was increased in lipodermatosclerosis, a condition of excessive human skin fibrosis. Collectively, our findings provide mechanistic insights into the link between type 2 immunity and initiation of pro-fibrotic pathways.
authors.affiliation: Department of Dermatology, University of Cologne, 50937 Cologne, Germany.
authors.forename: Johanna A
authors.initials: JA
authors.lastname: Knipper
authors.affiliation: Department of Dermatology, University of Cologne, 50937 Cologne, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Willenborg
authors.affiliation: Department of Dermatology and Institute of Virology and Cell Biology, University of Lübeck, 23562 Lübeck, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brinckmann
authors.affiliation: Department of Molecular and Cellular Sport Medicine, German Sport University Cologne, 50933 Cologne, Germany.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Bloch
authors.affiliation: Department of Biochemistry, University of Cologne, 50937 Cologne, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Maaß
authors.affiliation: Department of Biochemistry, University of Cologne, 50937 Cologne, Germany.
authors.forename: Raimund
authors.initials: R
authors.lastname: Wagener
authors.affiliation: Department of Dermatology, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50674 Cologne, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Krieg
authors.affiliation: Institute of Immunology and Infection Research, Centre for Immunity, Infection & Evolution, School of Biological Sciences, University of Edinburgh, EH9 3FL Edinburgh, UK.
authors.forename: Tara
authors.initials: T
authors.lastname: Sutherland
authors.affiliation: Department of Clinical Microbiology and Immunology, The Sackler School of Medicine, The Tel-Aviv University, Ramat Aviv 69978, Israel.
authors.forename: Ariel
authors.initials: A
authors.lastname: Munitz
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229-3039, USA.
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
authors.affiliation: Institute of Biomechanics & Orthopedics, German Sport University Cologne, 50933 Cologne, Germany; Cologne Center for Musculoskeletal Biomechanics, University of Cologne, 50931 Cologne, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Niehoff
authors.affiliation: Institute of Developmental Biology, University of Cologne, 50674 Cologne, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Richardson
authors.affiliation: Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50674 Cologne, Germany; Institute of Developmental Biology, University of Cologne, 50674 Cologne, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hammerschmidt
authors.affiliation: Institute of Immunology and Infection Research, Centre for Immunity, Infection & Evolution, School of Biological Sciences, University of Edinburgh, EH9 3FL Edinburgh, UK.
authors.forename: Judith E
authors.initials: JE
authors.lastname: Allen
authors.affiliation: Department of Dermatology, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50674 Cologne, Germany. Electronic address: sabine.eming@uni-koeln.de.
authors.forename: Sabine A
authors.initials: SA
authors.lastname: Eming
mesh_terms: D000818:Animals; D002921:Cicatrix / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D018920:Coculture Techniques; D003094:Collagen / Q000378:metabolism*; D003872:Dermatitis / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000502:physiology*; D007378:Interleukins / Q000502:physiology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D020894:Microfibrils / Q000378:metabolism / Q000648:ultrastructure; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000096:biosynthesis / Q000235:genetics; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000502:physiology*; D012594:Scleroderma, Localized / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*; D012867:Skin / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D014945:Wound Healing / Q000502:physiology*; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D003094:Collagen; D036341:Intercellular Signaling Peptides and Proteins; D007378:Interleukins; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; D011956:Receptors, Cell Surface; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; C486574:RETNLB protein, human; C413576:Retnla protein, mouse; C479138:PLOD2 protein, human; C582419:lysyl hydroxylase 2, mouse