Journal
JOURNAL OF IMMUNOLOGY
Volume 176, Issue 5, Pages 3108-3114Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.176.5.3108
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Funding
- NHLBI NIH HHS [HL37942] Funding Source: Medline
- NIDDK NIH HHS [DK62324, DK65957, DK56223] Funding Source: Medline
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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-gamma is an important early signal in IRI and is thought to contribute to reperfusion injury. Because IFN-gamma 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-gamma KO mice (IFN-gamma 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-gamma KO mice (IFN-gamma CD4(+)-Rag-1 KO) were protected from IRI; ATL146e conferred no additional protection. These studies demonstrate that CD4(+) IFN-gamma contributes to IRI and that A(2A) agonists mediate protection from IRI through action on CD4(+) cells.
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