Renal ischemia-reperfusion injury and adenosine 2A receptor-mediated tissue protection: the role of CD4+ T cells and IFN-γ

YJ Day, L Huang, H Ye, L Li, J Linden… - The Journal of …, 2006 - journals.aai.org
YJ Day, L Huang, H Ye, L Li, J Linden, MD Okusa
The Journal of Immunology, 2006journals.aai.org
Abstract A 2A adenosine receptor (A 2A R)-expressing bone marrow (BM)-derived cells
contribute to the renal protective effect of A 2A agonists in renal ischemia-reperfusion injury
(IRI). We performed IRI in mice lacking T and B cells to determine whether A 2A R expressed
in CD4+ cells mediate protection from IRI. Rag-1 knockout (KO) mice were protected in
comparison to wild-type (WT) mice when subjected to IRI. ATL146e, a selective A 2A
agonist, did not confer additional protection. IFN-γ is an important early signal in IRI and is …
Abstract
A 2A adenosine receptor (A 2A R)-expressing bone marrow (BM)-derived cells contribute to the renal protective effect of A 2A agonists in renal ischemia-reperfusion injury (IRI). We performed IRI in mice lacking T and B cells to determine whether A 2A R expressed in CD4+ cells mediate protection from IRI. Rag-1 knockout (KO) mice were protected in comparison to wild-type (WT) mice when subjected to IRI. ATL146e, a selective A 2A agonist, did not confer additional protection. IFN-γ is an important early signal in IRI and is thought to contribute to reperfusion injury. Because IFN-γ is produced by kidney cells and T cells we performed IRI in BM chimeras in which the BM of WT mice was reconstituted with BM from IFN-γ KO mice (IFN-γ KO→ WT chimera). We observed marked reduction in IRI in comparison to WT→ WT chimeras providing additional indirect support for the role of T cells. To confirm the role of CD4+ A 2A R in mediating protection from IRI, Rag-1 KO mice were subjected to ischemia-reperfusion. The protection observed in Rag-1 KO mice was reversed in Rag-1 KO mice that were adoptively transferred WT CD4+ cells (WT CD4+→ Rag-1 KO) or A 2A KO CD4+ cells (A 2A KO CD4+→ Rag-1 KO). ATL146e reduced injury in WT CD4+→ Rag-1 KO mice but not in A 2A KO CD4+→ Rag-1 KO mice. Rag-1 KO mice reconstituted with CD4+ cells derived from IFN-γ KO mice (IFN-γ CD4+→ Rag-1 KO) were protected from IRI; ATL146e conferred no additional protection. These studies demonstrate that CD4+ IFN-γ contributes to IRI and that A 2A agonists mediate protection from IRI through action on CD4+ cells.
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