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Tian Yu, Kenny Pallas, HuiRong Jiang, Gerry Graham, Lucia Kuffova, John V Forrester; Role of ACKR2 in ocular inflammation. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1878.
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ACKR2 (atypical chemokine receptor 2), formally known as D6 or CCBP2, actively scavenges CC inflammatory chemokines during inflammation and has been proposed to facilitate efficient lymph flow and trafficking of antigen presenting cells (APCs) from the periphery to the draining lymph nodes. Our study investigates the effect of ACKR2 in ocular inflammation using ACKR2-/- mice and two models - experimental autoimmune uveoretinitis (EAU) and corneal allotransplantation.
EAU was induced by subcutaneous injection of IRBP 1-20 peptide emulsified in CFA with or without pertussis toxin (PTX) given intraperitoneally. EAU was monitored clinically by endoscopic fundus imaging at 14, 21 and 28 days (d) post immunisation (p.i.). On d28 mice were sacrificed and eyes collected for histology scoring. Corneal transplantation: Donor cornea from Balb/c (H-2d) (diameter of 2.0mm) was transplanted into 1.5mm corneal graft bed [ACKR2-/- and WT mice (H-2b)] and secured with one continuous suture. Corneal graft opacification was graded 3 times weekly; mice with opacity grade 2 and higher were scored as rejectors.
Clinically ACKR2-/- mice showed significantly (p<0.05) increased severity of EAU compared to WT mice at 21d p.i. when no PTX and low dose PTX (500ng/mouse), characterised by large confluent choroidal lesions, vasculitis and increased vitreous haze. EAU development in ACKR2-/- mice peaked at d21 whereas in WT mice the disease peaked at d28. By histological evaluation at d28 of the experiment, EAU in mice given low dose PTX was also found to be more severe in ACKR2-/- compared to WT mice (P<0.0001). In experiment given high dose PTX (1µg/mouse) and additional mycobacteria in CFA, there was no significant difference in severity of EAU. Corneal allograft survival in ACKR2-/- and WT mice showed no statistical difference between the groups, the mean peak of rejection days (95% CI) are day 14.1 (12.8, 15.4) and day 15.6 (14.9, 16.4) respectively.
PTX inhibits activity of GPCRs (e.g. chemokine receptors) and has additional broader effects on activation of the innate immune system. The data here suggest that any effect of ACKR2 as a regulator of chemokine function is lost when high doses of PTX are used to induce EAU. However, in the absence of PTX a role for ACKR2 in regulating inflammation in EAU has been revealed. In corneal allograft rejection, it is likely that the strength of the allo-immune response overwhelms the regulatory role of ACKR2.
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