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.
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.
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)
Kim CS#, Ding X#, Allmeroth K, Biggs LC, Kolenc OI, L’Hoest N, Chacón-Martínez CA, Edlich-Muth C, Giavalisco P, Quinn KP, Denzel, Eming SA* and Wickström SA*. (2020). Glutamine metabolism controls stem cell fate reversibility and long-term maintenance in the hair follicle. Cell Metab. 32:629-642.e8 (# shared first authorship; * corresponding authors)
Ding X, Willenborg, S, Bloch W, Wickström S, Wagle P, Brodesser S, Roers A, Jais A, Brüning JC, Hall MN, Rüegg M, Eming SA. (2020). Epidermal mTORC2 controls lipid synthesis and filaggrin processing in epidermal barrier formation. J Allergy Clin Immunol. 145:283-300
Schönborn K, Willenborg S, Schulz J, Imhof T, Eming SA, Quondamatteo F, Brinckmann J, Niehoff A, Paulsson M, Koch M, Eckes B, and Krieg T. (2020). Role of collagen XII in skin homeostasis and repair. Matrix Biol. Sep 2:S0945-053X(20)30087-1
Eming SA, Wynn TA, Martin P. Inflammation and metabolism in tissue repair and regeneration. Science 356(6342):1026-1030, 2017.
Knipper JA, Willenborg S, Brinckmann J, Bloch W, Maaß T, Wagener R, Willenborg S, Krieg T, Sutherland T, Migge T, Richardson R, Hammerschmidt M, Allen JE, Eming SA, IL-4Rα signaling in myeloid cells controls collagen fibril assembly in skin repair. Immunity 43:803-16, 2015.
Eming SA, Martin P, Tomic-Canic M, Wound Repair and Regeneration: Mechanisms, signaling, and translation. Sci Transl Med 6(265):265sr6, 2014.
Willenborg S, Lucas T, Geert van Loo, Knipper J, Krieg T, Ingo Haase, Bent Brachvogel, Matthias Hammerschmidt, Nagy A, Ferrara N, Pasparakis M, Eming SA, CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair. Blood 120:613-625, 2012.
Lucas T, Waisman A, Ranjan R, Roes J, Krieg T, Müller W, Roers A, Eming SA, Differential roles of macrophages in diverse phases of skin repair. J Immunol 184(7):3964-77, 2010.