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Hoffmann, Anne L. C.; Hauck, Stefanie M. ORCID: 0000-0002-1630-6827; Deeg, Cornelia A. ORCID: 0000-0003-0375-3190; Degroote, Roxane L. ORCID: 0000-0003-2680-7227 (2022): Pre-Activated Granulocytes from an Autoimmune Uveitis Model Show Divergent Pathway Activation Profiles upon IL8 Stimulation In Vitro. International Journal of Molecular Sciences, 23 (17): 9555. ISSN 1422-0067

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In the pathophysiology of autoimmune-mediated uveitis, granulocytes have emerged as possi-ble disease mediators and were shown to be pre-activated in equine recurrent uveitis (ERU), a spontaneous disease model. We therefore used granulocytes from ERU horses to identify early molecular mechanisms involved in this dysregulated innate immune response. Primary granu-locytes from healthy and ERU horses were stimulated with IL8, and cellular response was ana-lyzed with differential proteomics, which revealed significant differences in protein abundance of 170 proteins in ERU. Subsequent ingenuity pathway analysis identified three activated canon-ical pathways “PKA signaling”, “PTEN signaling” and “leukocyte extravasation”. Clustered to the leukocyte extravasation pathway, we found the membrane-type GPI-anchored protease MMP25, which was increased in IL8 stimulated ERU granulocytes. These findings point to MMP25 as a possible regulator of granulocyte extravasation in uveitis and a role of this mole-cule in the impaired integrity of the blood-retina-barrier. In conclusion, our analyses show a clearly divergent reaction profile of pre-activated granulocytes upon IL8 stimulation and pro-vide basic information for further in-depth studies on early granulocyte activation in non-infectious ocular diseases. This may be of interest for the development of new approaches in uveitis diagnostics and therapy. Raw data are available via ProteomeXchange with identifier PXD013648.

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