Project 5 Myeloid Cells

Myeloid cell function in corneal hem- and lymphangiogenesis


Injury-associated ingrowth of blood and lymphatic vessels into the physiologically avascular cornea significantly impairs visual acuity and mediates diseases like corneal transplant rejection, dry eye disease, and allergy. Macrophages are important mediators of inflammatory corneal hem- and lymphangiogenesis. Yet, the exact mechanisms of blood monocyte recruitment, corneal macrophage activation and the functional consequences of this process for corneal hem-/lymphangiogenesis are not fully understood. In the current funding period we identified distinct functions of macrophages during diverse phases of injury-induced corneal hem- and lymphangiogenesis. In addition, we uncovered a critical role for IL-10 signaling in macrophages regulating the resolution of corneal inflammation via lymphatic vessels after corneal injury. In the next funding period, we are aiming to further characterize the specific regulation and function of myeloid cell subsets in hem- and lymphangiogenesis after corneal tissue damage. Specifically, we will identify the functional role of CX3CR1 in corneal hem- and lymphangiogenesis after acute or chronic injury. Furthermore, we will characterize the contribution of macrophages in the regulation of cornea edema and edema-associated lymphangiogenesis. Together, this work will unravel the precise role of blood monocytes/macrophages recruited to sites of corneal damage and should provide novel immunomodulatory therapies promoting corneal repair or preventing disease.

Influx and activation of myeloid cells represent early defense mechanisms after tissue injury. The primary function of this process is to mount an immune response that effectively kills invading pathogens, and at the same time, induces successful repair and homeostasis of the damaged tissue. Our previous work in cornea and skin wound healing provides substantial evidence for a dual role of myeloid cell-mediated hem- and/or lymphangiogenesis in both beneficial but also harmful effects leading either to an effective repair response or causing disease. In skin we recently provided novel mechanistic insights into the recruitment of blood monocyte subsets into damaged tissue and their differentiation in diverse monocyte/macrophage phenotypes with specific functions during the sequential stages of skin repair. In corneal injury the mechanisms of blood monocyte recruitment, their activation in different macrophage phenotypes and functional consequences of this process for hem-/lymphangiogenesis are not understood so far. The overall goal of this project is to investigate the specific role of myeloid cells in hem- and lymphangiogenesis in acute and chronic corneal tissue damage. Specifically, we will identify the functional impact of myeloid cells on the induction and regression of vascular structures in corneal injury. Furthermore, we will examine the functional relevance of myeloid cell-restricted chemokine (C-C-motif) receptor 2 (CCR2) in the recruitment of blood monocytes into the injured cornea and their differentiation into macrophage subsets with specific functions during hem-/lymphangiogenesis. Together, this work will provide deeper insight into the functional relationship between monocytes/macrophages and vascular growth, and should contribute to future immunomodulatory therapeutic interventions promoting repair and/or preventing disease.

Selected Key Publications of Project 5

Bukowiecki A, Hos D, Cursiefen C, Eming SA (2017) Wound-Healing Studies in Cornea and Skin: Parallels, Differences and Opportunities. International journal of molecular sciences 18

Eming SA, Wynn TA, Martin P (2017) Inflammation and metabolism in tissue repair and regeneration. Science (New York, NY) 356: 1026-1030

Hos D, Bukowiecki A, Horstmann J, Bock F, Bucher F, Heindl LM, Siebelmann S, Steven P, Dana R, Eming SA, Cursiefen C (2017) Transient Ingrowth of Lymphatic Vessels into the Physiologically Avascular Cornea Regulates Corneal Edema and Transparency. Scientific reports 7: 7227

Hos NJ, Ganesan R, Gutierrez S, Hos D, Klimek J, Abdullah Z, Kronke M, Robinson N (2017) Type I interferon enhances necroptosis of Salmonella Typhimurium-infected macrophages by impairing antioxidative stress responses. The Journal of cell biology 216: 4107-4121

Lucas T, Schafer F, Muller P, Eming SA, Heckel A, Dimmeler S (2017) Light-inducible antimiR-92a as a therapeutic strategy to promote skin repair in healing-impaired diabetic mice. Nature communications 8: 15162

Hos D, Bucher F, Regenfuss B, Dreisow ML, Bock F, Heindl LM, Eming SA, Cursiefen C (2016) IL-10 Indirectly Regulates Corneal Lymphangiogenesis and Resolution of Inflammation via Macrophages. The American journal of pathology 186: 159-71

Hos D, Dorrie J, Schaft N, Bock F, Notara M, Kruse FE, Krautwald S, Cursiefen C, Bachmann BO (2016) Blockade of CCR7 leads to decreased dendritic cell migration to draining lymph nodes and promotes graft survival in low-risk corneal transplantation. Experimental eye research 146: 1-6

Hos D, Schlereth SL, Bock F, Heindl LM, Cursiefen C (2015) Antilymphangiogenic therapy to promote transplant survival and to reduce cancer metastasis: what can we learn from the eye? Seminars in cell & developmental biology 38: 117-30

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 alpha Signaling in Myeloid Cells Controls Collagen Fibril Assembly in Skin Repair. Immunity 43: 803-16

Knuever J, Willenborg S, Ding X, Akyuz MD, Partridge L, Niessen CM, Bruning JC, Eming SA (2015) Myeloid Cell-Restricted Insulin/IGF-1 Receptor Deficiency Protects against Skin Inflammation. Journal of immunology (Baltimore, Md : 1950) 195: 5296-5308

More Publications of Project 5

Cursiefen C, Bock F, Clahsen T, Regenfuss B, Reis A, Steven P, Heindl LM, Bosch JJ, Hos D, Eming S, Grajewski R, Heiligenhaus A, Fauser S, Austin J, Langmann T. [New Therapeutic Approaches in Inflammatory Diseases of the Eye – Targeting Lymphangiogenesis and Cellular Immunity: Research Unit FOR 2240 Presents Itself]. Klin Monbl Augenheilkd. 2017 May;234(5):679-685.

Hos D, Tuac O, Schaub F, Stanzel TP, Schrittenlocher S, Hellmich M, Bachmann  BO, Cursiefen C. Incidence and Clinical Course of Immune Reactions after Descemet Membrane Endothelial Keratoplasty: Retrospective Analysis of 1000 Consecutive Eyes. Ophthalmology. 2017 Apr;124(4):512-518.

Lee HS, Hos D, Blanco T, Bock F, Reyes NJ, Mathew R, Cursiefen C, Dana R, Saban DR (2015) Involvement of corneal lymphangiogenesis in a mouse model of allergic eye disease. Invest Ophthalmol Vis Sci. 56(5):3140-8.

Ding X, Lucas T, Marcuzzi GP, Pfister H, Eming SA (2015) Distinct functions of epidermal and myeloid-derived VEGF-A in skin tumorigenesis mediated by HPV8. Cancer Res. 75(2):330-43.

Willenborg S, Eckes B, Brinckmann J, Krieg T, Waisman A, Hartman K, Roers A, Eming SA (2014) Genetic ablation of mast cells redefines the role of mast cells in skin wound healing and bleomycin-induced fibrosis. J Invest Dermatol 134:2005-2015.

Traub S, Morgner J, Martino MM, Höning S, Swartz MA, Wickström SA, Hubbell JA, Eming SA (2013) The promotion of endothelial cell attachment and spreading using FNIII10 fused to VEGF-A165. Biomaterials 34:5958-68.

Hoffmann DC, Willenborg S, Koch M, Zwolanek D, Müller S, Becker AK, Metzger S, Ehrbar M, Kurschat P, Hellmich M, Hubbell JA, Eming SA (2013) Proteolytic processing regulates placental growth factor activities. J Biol Chem 288:17976-89.

Hos D, Koch KR, Bucher F, Bock F, Cursiefen C, Heindl LM (2013) Serum eyedrops antagonize the anti(lymph)angiogenic effects of bevacizumab in vitro and in vivo. Invest Ophthalmol Vis Sci 54:6133-42.

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 (2012) CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair. Blood 120: 613-25.

Hos D, Regenfuss B, Bock F, Onderka J, Cursiefen C (2011) Blockade of insulin receptor substrate-1 inhibits corneal lymphangiogenesis. Invest Ophthalmol Vis Sci 52:5778-85.

Hos D, Saban DR, Bock F, Regenfuss B, Onderka J, Masli S, Cursiefen C (2011) Suppression of inflammatory corneal lymphangiogenesis by application of topical corticosteroids. Arch Ophthalmol 129:445-52.

Lucas T, Waisman A, Ranjan R, Roes J, Krieg T, Müller W, Roers A, Eming SA (2010) Differential roles of macrophages in diverse phases of skin repair. Journal of Immunology 184: 3964-77.

Hos D, Bock F, Dietrich T, Onderka J, Kruse FE, Thierauch KH, Cursiefen C (2008) Inflammatory corneal (lymph)angiogenesis is blocked by VEGFR-tyrosine kinase inhibitor ZK 261991, resulting in improved graft survival after corneal transplantation. Invest Ophthalmol Vis Sci 49:1836-42.

Hos D, Bachmann B, Bock F, Onderka J, Cursiefen C (2008) Age-related changes in murine limbal lymphatic vessels and corneal lymphangiogenesis. Exp Eye Res 87:427-32.

Hos D, Matthaei M, Bock F, Maruyama K, Notara M, Clahsen T, Hou Y, Le VNH, Salabarria AC, Horstmann J, Bachmann BO, Cursiefen C (2019) Immune reactions after modern lamellar (DALK, DSAEK, DMEK) versus conventional penetrating corneal transplantation. Prog Retin Eye Res (in press)

Hos D, Le VNH, Hellmich M, Siebelmann S, Roters S, Bachmann BO, Cursiefen C (2019) Risk of Corneal Graft Rejection After High-risk Keratoplasty Following Fine-needle Vessel Coagulation of Corneal Neovascularization Combined With Bevacizumab: A Pilot Study. Transplant Direct. 5(5):e452

Kiesewetter A, Cursiefen C, Eming SA, Hos D (2019) Phase-specific functions of macrophages determine injury-mediated corneal hem- and lymphangiogenesis. Sci Rep (1):308.

Hos D, Tuac O, Schaub F, Stanzel TP, Schrittenlocher S, Hellmich M, Bachmann BO, Cursiefen C (2017) Incidence and Clinical Course of Immune Reactions after Descemet Membrane Endothelial Keratoplasty: Retrospective Analysis of 1000 Consecutive Eyes. Ophthalmology 124(4):512-518