Inflammation and Wound Healing in the Mouse Cornea



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Corneal abrasion elicits an inflammatory cascade prompting inflammatory cells to exit the vasculature and accumulate at the limbus. Extravasated platelets, being non-motile, remain at the limbus while neutrophils migrate toward the wound. Lam and colleagues showed platelets are crucial for wound healing, suggesting CD18 as a possible mechanism for platelet extravasation. Other studies suggest platelets promote macrophage phagocytosis changing macrophage phenotype (M1, pro-inflammatory); potentially influencing the course of inflammation. The limbus has a large population of perivascular macrophages suggesting possible phagocytosis of platelets after injury. The relative distribution of macrophage phenotype within the cornea and contribution to the inflammatory cascade remains unclear. The Aims of this research were: 1) Determine the role of CD18 on platelet extravasation in this mouse model of inflammation, focusing on two relevant cell types that express CD18: PMNs and mast cells 2) Determine if macrophage numbers, phenotypes and distributions change to reflect the pro-inflammatory state of the injured cornea during the first 24 hours following a central epithelial abrasion. Following corneal abrasion, we discovered extravascular RBCs alongside extravasated PMNs and platelets. Platelet and RBC extravasation requires adequate levels of CD18, evidenced by reduced extravasated platelets and RBCs in mice with low CD18 expression. Ultrastructural observations of engorged limbal venules showed platelets and RBCs passing through endothelial pores. Venule engorgement is reduced when mast cell degranulation is absent or reduced. Mast cell-deficient mice and mice with antibody-induced depletion of circulating PMNs showed reduced venule engorgement, and extravasation of PMNs, platelets, and RBCs. Extravasated RBCs and platelets are phagocytosed by perivascular macrophages. The overall distribution of macrophages after injury decreases at the limbus and increases paralimbus to wound center. Reduction of limbal macrophages correlated with decreased M2 macrophages in the anterior stroma. This dissertation introduces RBCs and macrophages as active participants in the inflammatory response. We conclude in the injured cornea: (1) platelet and RBC extravasation depends on CD18, PMNs, and mast cell degranulation (2) macrophage redistribution occurs due to decreased M2 macrophages at the limbus (anterior stroma), followed by increases in M1 and M2 phenotypes across the cornea.



inflammation, corneal wound healing, erythrocyte, extravasation, macrophages, macrophage phenotype,


Portions of this document appear in: De La Cruz, A., Hargrave, A., Magadi, S., Courson, J. A., Landry, P. T., Zhang, W., Lam, F. W., Bray, M. A., Smith, C. W., Burns, A. R., & Rumbaut, R. E. (2021a). Platelet and erythrocyte extravasation across inflamed corneal venules depend on CD18, neutrophils and mast cell degranulation. International Journal of Molecular Sciences, 22(14).