Interleukin-4 Receptor α Signaling in Myeloid Cells Controls Collagen Fibril Assembly in Skin Repair

Johanna A Knipper; Sebastian Willenborg; Jürgen Brinckmann; Wilhelm Bloch; Tobias Maaß; Raimund Wagener; Thomas Krieg; Tara Sutherland; Ariel Munitz; Marc E Rothenberg; Anja Niehoff; Rebecca Richardson; Matthias Hammerschmidt; Judith E Allen; Sabine A Eming

doi:10.1016/j.immuni.2015.09.005

Interleukin-4 Receptor α Signaling in Myeloid Cells Controls Collagen Fibril Assembly in Skin Repair

Immunity. 2015 Oct 20;43(4):803-16. doi: 10.1016/j.immuni.2015.09.005.

Authors

Affiliations

¹ Department of Dermatology, University of Cologne, 50937 Cologne, Germany.
² Department of Dermatology and Institute of Virology and Cell Biology, University of Lübeck, 23562 Lübeck, Germany.
³ Department of Molecular and Cellular Sport Medicine, German Sport University Cologne, 50933 Cologne, Germany.
⁴ Department of Biochemistry, University of Cologne, 50937 Cologne, Germany.
⁵ 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.
⁶ Institute of Immunology and Infection Research, Centre for Immunity, Infection & Evolution, School of Biological Sciences, University of Edinburgh, EH9 3FL Edinburgh, UK.
⁷ Department of Clinical Microbiology and Immunology, The Sackler School of Medicine, The Tel-Aviv University, Ramat Aviv 69978, Israel.
⁸ Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229-3039, USA.
⁹ Institute of Biomechanics & Orthopedics, German Sport University Cologne, 50933 Cologne, Germany; Cologne Center for Musculoskeletal Biomechanics, University of Cologne, 50931 Cologne, Germany.
¹⁰ Institute of Developmental Biology, University of Cologne, 50674 Cologne, Germany.
¹¹ 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.
¹² 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: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cicatrix / etiology*
Cicatrix / metabolism
Cicatrix / pathology
Coculture Techniques
Collagen / metabolism*
Dermatitis / metabolism
Dermatitis / pathology
Fibroblasts / metabolism
Humans
Intercellular Signaling Peptides and Proteins / deficiency
Intercellular Signaling Peptides and Proteins / physiology*
Interleukins / physiology
Macrophages / metabolism*
Mice
Mice, Inbred BALB C
Mice, Knockout
Microfibrils / metabolism
Microfibrils / ultrastructure
Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / biosynthesis
Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / genetics
Receptors, Cell Surface / deficiency
Receptors, Cell Surface / physiology*
Scleroderma, Localized / metabolism
Scleroderma, Localized / pathology
Signal Transduction / physiology*
Skin / injuries
Skin / metabolism
Skin / pathology
Wound Healing / physiology*

Substances

Il4ra protein, mouse
Intercellular Signaling Peptides and Proteins
Interleukins
RETNLB protein, human
Receptors, Cell Surface
Retnla protein, mouse
Collagen
PLOD2 protein, human
Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase
lysyl hydroxylase 2, mouse

Supplementary concepts

Lipodermatosclerosis

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding