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Human islets express a marked pro-inflammatory molecular signature prior to transplantation


In the context of islet transplantation, experimental models show that induction of islet intrinsic NF-kappaB-dependent pro-inflammatory genes can contribute to islet graft rejection. Isolation of human islets triggers activation of the NF-kappaB and mitogen-activated kinase (MAPK) stress response pathways. However, the down stream NF-kappaB-target genes induced in human islets during the isolation process are poorly described. Therefore in this study, using microarray, bioinformatic, and RTqPCR approaches, we determined the pattern of genes expressed by a set of 14 human islet preparations. We found that isolated human islets express a panel of genes reminiscent of cells undergoing a marked NF- kappaB-dependent pro-inflammatory response. Expressed genes included; matrix metallopeptidase 1 (MMP1) and Fibronectin 1 (FN1), factors involved in tissue remodelling, adhesion and cell migration; inflammatory cytokines IL-1 beta and IL-8; genes regulating cell survival including A20 and ATF3; and notably high expression of a set of chemokines that would favour neutrophil and monocyte recruitment including CXCL2, CCL2, CXCL12, CXCL1, CXCL6, CCL28. Of note, the inflammatory profile of isolated human islets was maintained after transplantation into RAG-/- recipients. Thus human islets can provide a reservoir of NF- kappaBdependent inflammatory factors that have the potential to contribute to the anti-islet-graft immune response. To test this hypothesis we extracted rodent islets under optimal conditions, forced activation of NF- kappaB, and transplanted them into allogenic recipients. These NF- kappaB activated islets not only expressed the same chemokine profile observed in human islets, but also struggled to maintain normoglycemia post transplantation. Further, NF- kappaB activated islets were rejected with a faster tempo as compared to non-NF- kappaB-activated rodent islets. Thus isolated human islets can make cell autonomous contributions to the ensuing allograft response by elaborating inflammatory factors that contribute to their own demise. These data highlight the potential importance of islet intrinsic pro-inflammatory responses as targets for therapeutic intervention.

Type Journal
Authors Cowley, M. J.; Weinberg, A.; Zammit, N.; Walters, S. N.; Hawthorne, W. J.; Loudovaris, T.; Thomas, H.; Kay, T.; Gunton, J. E.; Alexander, S. I.; Kaplan, W.; Chapman, J.; O'Connell, P. J.; Grey, S. T.;
Published Date 2012-12-01
Published Volume 21
Published Pages 2063-2078
Status Published in-print
URL link to publisher's version
OpenAccess link to author's accepted manuscript version