TY - JOUR
T1 - Interleukin-4 Receptor α Signaling in Myeloid Cells Controls Collagen Fibril Assembly in Skin Repair.
AU - Knipper, Johanna A
AU - Willenborg, Sebastian
AU - Brinckmann, Jürgen
AU - Bloch, Wilhelm
AU - Maaß, Tobias
AU - Wagener, Raimund
AU - Krieg, Thomas
AU - Sutherland, Tara
AU - Munitz, Ariel
AU - Rothenberg, Marc E
AU - Niehoff, Anja
AU - Richardson, Rebecca
AU - Hammerschmidt, Matthias
AU - Allen, Judith E
AU - Eming, Sabine A
N1 - Acknowledgments
The authors thank Michael Piekarek, Sebastian Wüst, Christoph Göttlinger, and Gunter Rappl (Central Cell Sorting Facility, Center for Molecular Medicine Cologne, University of Cologne) for excellent technical assistance. The authors are grateful to Dr. Brombacher for providing Il4rafl/fl mice and Dr. Irmgard Förster for providing Lyz2-cre mice, Regeneron Pharmaceuticals for providing the Retnla−/− mice, Dr. Peter Bruckner and Dr. Uwe Hansen for advice in ECM analysis, and Dr. David Artis and Dr. Meera Nair for providing the plasmid of murine Relm-α. The main funding source for this manuscript was the Deutsche Forschungsgemeinschaft (SFB829 to S.A.E., T.K., R.W., and M.H.). J.E.A. and T.S. were supported by the Medical Research Council (MR/J001929/1) and M.E.R. by NIH R37 AI045898.
PY - 2015/10/20
Y1 - 2015/10/20
N2 - 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.
AB - 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.
U2 - 10.1016/j.immuni.2015.09.005
DO - 10.1016/j.immuni.2015.09.005
M3 - Article
VL - 43
SP - 803
EP - 816
JO - Immunity
JF - Immunity
SN - 1074-7613
IS - 4
ER -