The atypical chemokine receptor-2 does not alter corneal graft survival but regulates early stage of corneal graft-induced lymphangiogenesis

Abstract

PurposeTo re-evaluate the role of the atypical chemokine receptor-2 (ACKR2) in corneal graft rejection and investigate the effect of ACKR2 on inflammation-associated lymphangiogenesis using murine orthotopic corneal transplantation.MethodsCorneal grafts were performed and evaluated in the settings of syngeneic, allogeneic and single antigen (HY-antigen) disparity pairings. Corneal vessels were quantified in whole mounts from WT, ACKR2−/− and F4/80−/−ACKR2−/− mice that received syngeneic or allogeneic grafts using anti-CD31 and anti-Lyve-1 antibodies.ResultsSyngeneic corneal grafts in WT and ACKR2−/− mice were 100% accepted. Fully histo-incompatible allogeneic grafts were rapidly rejected (100%) with similar tempo in both WT and ACKR2−/− hosts. Around 50% of single-antigen (HY) disparity grafts rejected at a slow but similar tempo (60 days) in WT and ACKR2−/− mice. Prior to grafting, F4/80−/−ACKR2−/− mice had lower baseline levels of limbal blood and lymphatic vessels compared to ACKR2−/− mice. Syngeneic grafts, but not allogeneic grafts, in ACKR2−/− and F4/80−/−ACKR2−/− mice induced higher levels of lymphatic sprouting and infiltration of Lyve-1+ cells during the early (3d) post-graft (pg) stage but lymphatic density was similar to WT grafted mice by 7d pg.ConclusionsOur results indicate that the chemokine scavenger receptor, ACKR2, has no role to play in the survival of allogeneic grafts. A minor role in regulation of lymphangiogenesis in the early stage of wound healing in syngeneic grafts is suggested, but this effect is probably masked by the more pronounced lymphangiogenic inflammatory response in allogeneic grafts. No additional effect was observed with the deletion of the resident macrophage gene, F4/80.

The atypical chemokine receptor-2 fine-tunes the immune response in herpes stromal keratitis

“…The role of ACKR2 in the inflammatory response has been investigated in several animal models, including chemical- and bacterial- induced inflammation, autoimmune disease and alloimmune disease, but with limited exploration in viral infection ( 16 , 26 , 29 – 32 ). Contradictory findings have been reported in both experimental autoimmune encephalomyelitis and experimental colitis where opposing disease phenotypes were reported in mice with deletion of ACKR2 ( 29 , 30 , 33 , 34 ).…”

“…In terms of HSV-1 induced corneal lymphangiogenesis, previous studies have shown that macrophages are not required for corneal lymphangiogenesis at least in the early stage after HSV-1 infection as depletion of corneal macrophages does not affect HSV-1 induced corneal lymphangiogenesis, but identified VEGF-A produced by infected corneal epithelial cells as the main driven factor ( 49 ). Furthermore, we have reported previously that in the ACKR2 -/- mice, there was accelerated corneal lymphangiogenesis after corneal syngeneic grafting which is likely promoted by increased numbers of infiltrating single Lyve-1 + cells in the cornea ( 26 ). Interestingly, this discrete Lyve-1 + population was not observed in corneas after HSV-1 infection ( Figure 4C ).…”

“…Recently, the mechanism of ACKR2 involvement in the development of mammary gland has been further linked to the regulation of CCL7 and subsequently orchestration of CD206 + macrophages ( 25 ). Furthermore, we have also shown that while ACKR2 played no role in murine corneal allograft rejection, syngeneic corneal grafts (effectively a corneal wound healing model) in ACKR2 deficient mice presented with greater numbers of single Lyve-1 + cells around lymphatic vessels and accelerated corneal lymphangiogenesis ( 26 ). We therefore investigated the role of ACKR2 in corneal angiogenesis in the HSK murine model in which both blood and lymphatic new vessel formation are prominent pathologies.…”

The Role of Atypical Chemokine Receptor D6 (ACKR2) in Physiological and Pathological Conditions; Friend, Foe, or Both?

“…Despite the reduced allospecific T-cell response shown in ACKR2 –/– mice, no difference in allograft survival was observed between WT and ACKR2 –/– mice, suggesting that any such impact was limited to syngeneic grafts ( 134 ). The alternative suggested role of ACKR2 in allograft rejection was attributed to its role in the development of lymphatic vessels and lymphangiogenesis ( 135 ). Syngeneic grafts, but not allogeneic grafts, increased lymphatic sprouting and infiltration of Lyve-1 + cells (LEC cells) in ACKR2 –/– mice at the early post-graft stage, although lymphatic density was comparable to that of WT grafted mice.…”

“…It was proposed that deletion of ACKR2 increases the proximity of pro-lymphangiogenic macrophages to LECs. Therefore, it was proposed that ACKR2, through modulating lymphangiogenesis, might be involved in the suppression of corneal allograft rejection ( 135 ).…”