FOR2599Project 2

Regulators of type 2 immunity in tissue repair and regeneration

Sabine Eming, Department of Dermatology, University of Cologne

Type 2 immunity drives fibrogenesis: we identified IL-4Ra-signaling in late stage wound macrophages as critical regulator of collagen fibril assembly and ECM function. We also could show that in scleroderma or lipodermatosclerosis, both conditions of excessive skin fibrosis, expression of key effector molecules along the pro-fibrotic IL-4Ra-macrophage-Relm-Lysyl hydroxylase-2 axis are increased. The goal of this project is to identify regulators and effectors of the type 2 immune response in skin regenerative processes.

Summary

Tissue injury induces a complex, dynamic cellular program proceeding in sequential phases of inflammation, followed by tissue growth and differentiation. Depending on the tissue’s regenerative capacity and quality of the inflammatory response, the outcome is generally imperfect with some degree of fibrosis. Myeloid cells are an essential component of the body’s innate ability to restore tissue function after injury by facilitating wound debridement and by producing chemokines and growth factors. If this well-orchestrated response becomes dysregulated, it can become a chronic wound or progressively fibrotic with both outcomes impairing tissue function that can ultimately lead to organ failure and death.

In recent studies we were able to link phase specific monocyte/macrophage activation phenotypes to specific repair responses in different models of acute and chronic skin injury. Our published and preliminary findings suggest that polarization dynamics of wound macrophages are critical to instruct tissue resident cells to initiate the cutaneous healing response, but also to coordinate differentiation and termination signals. Whereas early stage wound macrophages reflect a type-1 immune response, late stage wound macrophages are characterized by a type-2 immune response. Specifically, during maturation of the healing response we identified IL-4Ra-signaling in late stage wound macrophages as critical regulator of collagen fibril assembly and ECM function. Currently it is unresolved how signalling pathways and transcriptional networks in monocytes/macrophages coordinate their functional plasticity during the sequential repair stages.

The goal of this project is to identify regulators and effectors of the type 2 immune response in skin regenerative processes. We propose that these analyses provide a comprehensive and systematic approach to deliver new mechanistic insights into how type 2 cytokines mediate tissue protective functions in skin maintenance, damage and repair.

Selected Publications

Type 2 Immunity Regulates Dermal White Adipose Tissue Function. Satzinger S, Willenborg S, Ding X, Klose CSN, Radtke D, Voehringer D, Eming SA.  J Invest Dermatol. 2023 Jun 8:S0022-202X(23)02141-3. doi: 10.1016/j.jid.2023.05.017.

Isolation of macrophages from mouse skin wounds for single-cell RNA sequencing. Willenborg S, Roscito JG, Gerbaulet A, Roers A, Dahl A, Eming SA, Reinhardt S. STAR Protoc. 2022 Apr 19;3(2):101337. doi: 10.1016/j.xpro.2022.101337. eCollection 2022 Jun 17.

A common framework of monocyte-derived macrophage activation.  Sanin DE, Ge Y, Marinkovic E, Kabat AM, Castoldi A, Caputa G, Grzes KM, Curtis JD, Thompson EA, Willenborg S, Dichtl S, Reinhardt S, Dahl A, Pearce EL, Eming SA, Gerbaulet A, Roers A, Murray PJ, Pearce EJ. Sci Immunol. 2022 Apr 15;7(70):eabl7482. doi: 10.1126/sciimmunol.abl7482.

Gene-selective transcription promotes the inhibition of tissue reparative macrophages by TNF. Dichtl S, Sanin DE, Koss CK, Willenborg S, Petzold A, Tanzer MC, Dahl A, Kabat AM, Lindenthal L, Zeitler L, Satzinger S, Strasser A, Mann M, Roers A, Eming SA, El Kasmi KC, Pearce EJ, Murray PJ.  Life Sci Alliance. 2022 Jan 13;5(4):e202101315. doi: 10.26508/lsa.202101315.

Mitochondrial metabolism coordinates stage-specific repair processes in macrophages during wound healing.Willenborg S, Sanin DE, Jais A, Ding X, Ulas T, Nüchel J, Popović M, MacVicar T, Langer T, Schultze JL, Gerbaulet A, Roers A, Pearce EJ, Brüning JC, Trifunovic A, Eming SA.  Cell Metab. 2021 Dec 7;33(12):2398-2414.e9. doi: 10.1016/j.cmet.2021.10.004. 

Regulation of the Wound Healing Response during Aging. Ding X, Kakanj P, Leptin M, Eming SA. J Invest Dermatol. 2021 Apr;141(4S):1063-1070.

Metabolic orchestration of the wound healing response. Eming SA, Murray PJ, Pearce EJ. Cell Metab. 2021 Sep 7;33(9):1726-1743.

A common framework of monocyte-derived macrophage activation. Sanin DE, Ge Y, Marinkovic E, Kabat AM, Castoldi A, Caputa G, Grzes KM, Curtis JD, Thompson EA, Willenborg S, Dichtl S, Reinhardt S, Dahl A, Pearce EL, Eming SA, Gerbaulet A, Roers A, Murray PJ, Pearce EJ.Sci Immunol. 2022 Apr 15;7(70):eabl7482.

Eming SA, principle investigator, A randomized, double blind, placebo-controlled phase IIa clinical trial to evaluate the efficacy and safety of subcutaneous Dupilumab in localized scleroderma (DupiMorph) (https://clinicaltrials.gov)

Glutamine Metabolism Controls Stem Cell Fate Reversibility and Long-Term Maintenance in the Hair Follicle. Kim CS, Ding X, Allmeroth K, Biggs LC, Kolenc OI, L'Hoest N, Chacón-Martínez CA, Edlich-Muth C, Giavalisco P, Quinn KP, Denzel MS, Eming SA, Wickström SA.Cell Metab. 2020 Oct 6;32(4):629-642.e8.

Epidermal mammalian target of rapamycin complex 2 controls lipid synthesis and filaggrin processing in epidermal barrier formation. Ding X, Willenborg S, Bloch W, Wickström SA, Wagle P, Brodesser S, Roers A, Jais A, Brüning JC, Hall MN, Rüegg MA, Eming SA. J Allergy Clin Immunol. 2020 Jan;145(1):283-300.e8.

Role of collagen XII in skin homeostasis and repair. Schönborn K, Willenborg S, Schulz JN, Imhof T, Eming SA, Quondamatteo F, Brinckmann J, Niehoff A, Paulsson M, Koch M, Eckes B, Krieg T.Matrix Biol. 2020 Dec;94:57-76.

Inflammation and metabolism in tissue repair and regeneration. Eming SA, Wynn TA, Martin P.Science. 2017 Jun 9;356(6342):1026-1030. doi: 10.1126/science.aam7928. Epub 2017 Jun 8.

Interleukin-4 Receptor α Signaling in Myeloid Cells Controls Collagen Fibril Assembly in Skin Repair. 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.Immunity. 2015 Oct 20;43(4):803-16.

Wound repair and regeneration: mechanisms, signaling, and translation. Eming SA, Martin P, Tomic-Canic M.Sci Transl Med. 2014 Dec 3;6(265):265sr6. doi: 10.1126/scitranslmed.3009337.

CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair. Willenborg S, Lucas T, van Loo G, Knipper JA, Krieg T, Haase I, Brachvogel B, Hammerschmidt M, Nagy A, Ferrara N, Pasparakis M, Eming SA.Blood. 2012 Jul 19;120(3):613-25.

Differential roles of macrophages in diverse phases of skin repair. Lucas T, Waisman A, Ranjan R, Roes J, Krieg T, Müller W, Roers A, Eming SA.J Immunol. 2010 Apr 1;184(7):3964-77. doi: 10.4049/jimmunol.0903356. Epub 2010 Feb 22.