Project 5 Myeloid Cells

Myeloid cell function in corneal hem- and lymphangiogenesis

Summary

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.

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.

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. Am J Pathol. 186:159-71.

Hos D, Dörrie J, Schaft N, Bock F, Notara M, Kruse FE, Krautwald S, Cursiefen C, Bachmann BO (2015) Blockade of CCR7 leads to decreased dendritic cell migration to draining lymph nodes and promotes graft survival in low-risk corneal transplantation. Exp Eye Res Dec 12. pii: S0014-4835(15)30089-0.[Epub ahead of print]

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.

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? Semin Cell Dev Biol. 38:117-30.

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.