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Thomas Clahsen, Birgit Regenfuss, Christian Büttner, Tim Gabriel, Felix Bock, Andre Reis, Claus Cursiefen; Tyrosinase downregulates Fibromodulin-induced lymphangiogenesis . Invest. Ophthalmol. Vis. Sci. 2018;59(9):3330.
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Lymphangiogenesis is involved in several diseases like corneal graft rejection, tumor metastasis, and dry eye disease. However the endogenous regulation is poorly understood. In previous work using BALB/c x C57BL/6 intercross for QTL analysis we identified the Tyrosinase gene as being responsible for the differences in the limbal lymphatic vessel architecture. Here we analyze the influence of Tyrosinase on inflammation-induced lymphangiogenesis and whether Fibromodulin (FMOD), a strong angiogenic factor downstream of Tyrosinase, also contains lymphangiogenic potential.<div class="grammarly-disable-indicator"> </div>
Three 11-0 nylon sutures were placed into the cornea stroma of C57BL/6N and B6N-Tyrc-Brd mice and were left in place for 14 days. Inflamed corneas were excised and whole-mounts were stained with LYVE-1. Vessel area was analyzed by using cellF software. Proliferation of human dermal lymphatic endothelial cells (HDLEC) was measured by using IncuCyte Zoom. Fibromodulin expression was quantified in primary human dermal lymphatic endothelial cells in vitro using qRT-PCR.<div class="grammarly-disable-indicator"> </div>
The comparison of both strains showed a significant increase in lymph vessel area in B6N-Tyrc-Brd mice compared to C57BL/6N mice. In addition we could show that Tyrosinase is expressed at low levels in HDLECs compared to the malignant melanoma cell line A-375. Furthermore in vitro experiments revealed that Tyrosinase inhibits proliferation of HDLECs in a dose-dependent manner whereas stimulation with FMOD, the downstream modulator of Tyrosinase, led to a dose-dependent and significant increase in proliferation. In addition quantitative RT-PCR revealed that stimulation with Tyrosinase lead to significantly reduced mRNA expression of FMOD.<div class="grammarly-disable-indicator"> </div>
We identified Tyrosinase not only as a novel endogenous regulator of developmental lymphangiogenesis, but also as a regulator of inflammatory lymphangiogenesis. Furthermore, like in melanocytes, Tyrosinase reduced the expression of the downstream modulator FMOD. Overall, our findings identify FMOD as a novel therapeutic target for the eye diseases associated with pathologic lymphangiogenesis.<div class="grammarly-disable-indicator"> </div>
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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