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.

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

Medical Sciences

Research output: Contribution to journal › Article › peer-review

232 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 language	English
Pages (from-to)	803-816
Number of pages	14
Journal	Immunity
Volume	43
Issue number	4
Early online date	17 Oct 2015
DOIs	https://doi.org/10.1016/j.immuni.2015.09.005
Publication status	Published - 20 Oct 2015

Bibliographical note

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.

Access to Document

10.1016/j.immuni.2015.09.005Licence: Other

Cite this

Knipper, J. A., Willenborg, S., Brinckmann, J., Bloch, W., Maaß, T., Wagener, R., Krieg, T., Sutherland, T., Munitz, A., Rothenberg, M. E., Niehoff, A., Richardson, R., Hammerschmidt, M., Allen, J. E., & Eming, S. A. (2015). Interleukin-4 Receptor α Signaling in Myeloid Cells Controls Collagen Fibril Assembly in Skin Repair. Immunity, 43(4), 803-816. https://doi.org/10.1016/j.immuni.2015.09.005

Knipper, JA, Willenborg, S, Brinckmann, J, Bloch, W, Maaß, T, Wagener, R, Krieg, T, Sutherland, T, Munitz, A, Rothenberg, ME, Niehoff, A, Richardson, R, Hammerschmidt, M, Allen, JE & Eming, SA 2015, 'Interleukin-4 Receptor α Signaling in Myeloid Cells Controls Collagen Fibril Assembly in Skin Repair.', Immunity, vol. 43, no. 4, pp. 803-816. https://doi.org/10.1016/j.immuni.2015.09.005

@article{51c1c67057a64de3a594eb28a24c5709,

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.",

author = "Knipper, {Johanna A} and Sebastian Willenborg and J{\"u}rgen Brinckmann and Wilhelm Bloch and Tobias Maa{\ss} and Raimund Wagener and Thomas Krieg and Tara Sutherland and Ariel Munitz and Rothenberg, {Marc E} and Anja Niehoff and Rebecca Richardson and Matthias Hammerschmidt and Allen, {Judith E} and Eming, {Sabine A}",

note = "Acknowledgments The authors thank Michael Piekarek, Sebastian W{\"u}st, Christoph G{\"o}ttlinger, 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 F{\"o}rster 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.",

year = "2015",

month = oct,

day = "20",

doi = "10.1016/j.immuni.2015.09.005",

language = "English",

volume = "43",

pages = "803--816",

journal = "Immunity",

issn = "1074-7613",

publisher = "Cell Press",

number = "4",

}

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

SN - 1074-7613

VL - 43

SP - 803

EP - 816

JO - Immunity

JF - Immunity

IS - 4

ER -

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

Abstract

Bibliographical note

Access to Document

Fingerprint

Cite this