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Tian Yu, Gerard J Graham, Lucia Kuffova, John V Forrester; Role of atypical chemokine receptor-2 in murine corneal herpes simplex virus type 1 infection. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1846.
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The atypical chemokine receptor-2 (ACKR2) is known to scavenge pro-inflammatory CC chemokines and is expressed mainly on lymphatic endothelial cells, but also on some leukocyte subsets. As well as a role in clearance of excess inflammatory chemokines and a contribution to the resolution phase of inflammation, ACKR2 has been proposed to facilitate the selective expression of homeostatic chemokines which are essential for the migration of antigen-presenting cells (APC) from peripheral tissues to the secondary lymphoid organs (SLO). Therefore, the current study was conducted to investigate this hypothesis and the role of ACKR2 during corneal herpes simplex virus type 1 (HSV-1) infection.
C57BL/6 wild type (wt) and ACKR2-/- mice were infected with topically applied HSV-1 after abrasion of the corneal epithelium. Herpetic stromal keratitis (HSK) was evaluated clinically and the degree of corneal opacification was scored. Corneal whole mounts were stained with CD31 and LYVE-1 for quantification of neovascularization by confocal microscopy. Cell infiltration into the cornea, trigeminal ganglion (TG) and eye-draining lymph node (DLN) were analyzed by flow cytometry.
Wt mice typically developed mild and transient HSK indicated by increased corneal opacification at d2 to d7 post infection (p.i.). In contrast, ACKR2-/- mice developed severe HSK of longer duration (onset d2 p.i., duration 21d) with increased HSK severity at d7, 14 p.i. compared to wt (p<0.01) and some mice developed hypopyon. Increased HSK severity in ACKR2-/- mice was followed by more extensive neovascularization at d14, 21 and 42 p.i. (p<0.05) compared to wt mice both clinically and immunohistologically (corneal whole mounts), increased leukocyte infiltration was also seen at d7 and 14 p.i. in the cornea. Concomitantly, fewer T cells and myeloid cells were found in the DLN of ACKR2-/- mice at d5 p.i. (p<0.05). In contrast, increased number of CD11b+ cells were found in the TG of ACKR2-/- mice at d7 p.i.
Absence of ACKR2 allows development of HSK which is more severe than in wt mice and characterized by increased neovascularization and opacification together with increased leukocytes infiltration in the cornea. We suggest that this may be due to failed resolution of the HSV-induced inflammatory response occurring at the tissue level, due to leukocyte crowding and impaired trafficking in dysfunctional lymphatics.
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