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  • Compelling evidence now indicates that DR is

    2022-12-02

    Compelling evidence now indicates that DR is a multifactorial disease that involves chronic inflammation at every stage, from initiation to progression and eventually to ischemia and NV [6,7]. Data from animal studies suggest that leukocyte-endothelial cell adhesion and entrapment (leukostasis) are rate-limiting steps for initiation of retinal inflammatory response prior to any clinical sign of DR [8,9]. Further studies using human tissues demonstrated an increase in leukocyte density in human eyes with DR and strong relationship between leukocyte-endothelial cell adhesion and retinal capillary damage in diabetes [10]. Once leukocytes have attached to the endothelial cells, pro-inflammatory cytokines and chemokines are released. These mediators are known to alter endothelial cell junctional proteins, allowing leukocytic infiltration into the retina, with concomitant compromise of the BRB [11]. Attachment and extravasation of these leukocytes are mediated by adhesive interactions between molecules present on leukocytes and their counter receptors expressed on activated endothelial cells such as the E- and P-selectins and intercellular cell adhesion molecule (ICAM)-1 [12,13]. ICAM-1 is directly up-regulated by diabetes [10] in the retinal vasculature where its blockade has highlighted it as a potential target for DR therapies, both clinically [14] and experimentally [15]. Yet, the exact underlying mechanisms of how hyperglycemia mediates ICAM-1 upregulation and hence leukocyte-endothelial cell adhesion need to be further elucidated. Several mechanisms have been suggested to account for the causal association of ICAM-1 induction and leukocyte adhesion with DR, including oxidative stress [16], NF-κB [17], PKC [18], and bioactive lipids [19]. Our previous studies highlighted the role of bioactive lipid metabolites derived from 12/15-lipoxygenase (LO) in pathogenesis of the inflammatory response in early DR. We have shown an increase in the retinal 12/15-LO expression and activity, evident by elevated levels of 12/15-LO-derived hydroxyeicosatetraenoic PU-WS13 (HETE) locally; in the vitreous of patients with DR [20], diabetic mouse retinas [21], and human retinal endothelial cells (HRECs) incubated with high glucose [22]. Additionally, we have reported a reduction in diabetes-induced retinal ICAM-1 expression by the pharmacological inhibition of 12/15-LO [21]. Furthermore, our very recent studies have demonstrated the ability of intravitreally injected 12-HETE to compromise endothelial barrier function in the retina associated with the induction of a pro-inflammatory phenotype (increased in retinal ICAM-1 expression and leukocyte adhesion) [22,23]. As a further support for the role of 12/15-LO in early DR, we have shown by using fluorescein angiography (FA) and retinal albumin leakage assay a significant reduction in retinal barrier dysfunction in diabetic mice lacking global expression of 12/15-LO compared to diabetic wild type (WT) mice [22]. Two distinct mammalian 12/15-Lipoxygenases have been characterized on the basis of their products from arachidonic acid (AA); 15-lipoxygenase (15-LO) in humans [24] and rabbits [25], and its orthologue the “leukocyte-type” known as 12-lipoxygenase (12-LO) in pig, rat, and mouse [26]. Leukocyte 12-LO and 15-LO are highly related in their enzymological characteristics as well as primary structures, and both are collectively called 12/15-LO [27]. A variety of cells, including vascular and myeloid lineage cells such as endothelial cells, smooth muscle cells, platelets, and monocytes/macrophages, express 12/15-LO [28]. By looking at the 12/15-LO activity in different cell types, it has been shown that 12/15-LO may have opposing effects. For instance, overexpression of 12/15-LO in endothelial cells enhances atherogenic responses [29], while overexpression of 12/15-LO in monocytes/macrophages protects against atherogenesis [30]. These observations raised the possibility that different cellular expression of 12/15-LO may have different effects on pathogenesis of DR and this has not been previously addressed. Therefore, the current study aimed to characterize the relative contribution of retinal endothelial versus monocytic/macrophagic 12/15-LO to inflammatory responses in DR. To achieve this goal, we first evaluated the changes in circulating 12/15-LO activity by measuring its derived metabolites in the plasma of diabetic WT mice compared to non-diabetic controls. This was followed by comparing the in vitro endothelium-leukocytes interaction between leukocytes isolated from 12/15-LO−/− versus those isolated from WT mice. Finally, we examined the effects of knocking down or inhibiting endothelial 12/15-LO on diabetes-induced HREC activation and ICAM-1 expression.