Reduction in shear stress, activation of the endothelium, and leukocyte priming are all required for leukocyte passage across the blood—retina barrier

Abstract

The passage of leukocytes across the blood-retina barrier at the early stages of an inflammatory reaction is influenced by a complex series of interactions about which little is known. In particular, the relationship between hydrodynamic factors, such as shear stress and leukocyte velocity, to the adherence and subsequent extravasation of leukocytes into the retina is unclear. We have used a physiological method, scanning laser ophthalmoscopy, to track labeled leukocytes circulating in the retina, followed by confocal microscopy of retinal flatmounts to detect infiltrating cells at the early stage of experimental autoimmune uveitis. This has shown that retinal vessels are subjected to high shear stress under normal circumstances. During the inflammatory reaction, shear stress in retinal veins is reduced 24 h before leukocyte infiltration. This reduction is negatively correlated with leukocyte rolling and sticking in veins and postcapillary venules, the sites of leukocyte extravasation. Activation of vascular endothelial cells is also a prerequisite for leukocyte rolling and infiltration. In addition, antigen priming of leukocytes is influential at the early stage of inflammation, and this is seen clearly in the reduction in rolling velocity and adherence of the primed leukocytes in activated retinal venules, 9 days postimmunization.

Recruitment of IFN-γ-Producing (Th1-Like) Cells into the Inflamed Retina In Vivo Is Preferentially Regulated by P-Selectin Glycoprotein Ligand 1:P/E-Selectin Interactions

“…Histological examination has shown that inflammatory cell infiltration and perivasculitis occur at day 9 pi, with infiltrating cells distributed in the ganglion layer and vitreous. Most of the photoreceptor layer remains normal at this time, but there is some focal photoreceptor cell damage (34). No rolling of Ag-primed leukocytes is seen before day 9 pi EAU (34).…”

“…Most of the photoreceptor layer remains normal at this time, but there is some focal photoreceptor cell damage (34). No rolling of Ag-primed leukocytes is seen before day 9 pi EAU (34).…”

“…When either population of labeled polarized cells was adoptively transferred into normal nonimmunized mice, no rolling cells were observed (data not shown). Similarly naive splenocytes have higher rolling velocities than do IRBP peptide in vivo-primed splenocytes (34).…”

Constitutive excessive erythrocytosis causes inflammation and increased vascular permeability in aged mouse brain

“…Indeed recent work suggests that shear stress may be the most critical factor affecting gene expression in endothelial cells and during inflammation. Data from in vitro (Stone et al, 2003;Walsh et al;Warabi et al, 2004) and in vivo (Xu et al, 2004;Yamawaki et al, 2003) studies indicate that low or low oscillating endothelial shear stress upregulates molecular and vascular responses that may be instrumental to progression of vascular-related diseases. Excessive erythrocytosis compromises vascular homeostasis as a result of significantly increased hematocrit and decreased plasma levels (Neunteufl et al, 2001).…”

Chronic excessive erythrocytosis induces endothelial activation and damage in mouse brain

“…Vascular endothelial cells are constantly subjected to shear stress imposed on them by blood flow, and shear stress may be a critical factor affecting gene expression in endothelial cells during inflammation. Data from in vitro (42) and in vivo (49,50) studies indicate that low or low-oscillating endothelial shear stress induces molecular and vascular responses that may be instrumental in progression of vascular-related diseases (47). Because shear stress is a function of blood viscosity, blood flow velocity, and vessel diameter, it is very difficult to assess this parameter in capillaries of tg6 mice.…”