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*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

153 Citations (Scopus)

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.

Original languageEnglish
Article number3173
Pages (from-to)803-816
Number of pages14
JournalImmunity
Volume43
Issue number4
DOIs
Publication statusPublished - 20 Oct 2015

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