Human islets express a marked proinflammatory molecular signature prior to transplantation

Mark J. Cowley, Anita Weinberg, Nathan W. Zammit, Stacey N. Walters, Wayne J. Hawthorne, Thomas Loudovaris, Helen Thomas, Tom Kay, Jenny E. Gunton, Stephen I. Alexander, Warren Kaplan, Jeremy Chapman, Philip J. O'Connell, Shane T. Grey

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

In the context of islet transplantation, experimental models show that induction of islet intrinsic NF-kBdependent proinflammatory genes can contribute to islet graft rejection. Isolation of human islets triggers activation of the NF-kB and mitogen-activated kinase (MAPK) stress response pathways. However, the downstream NF-kβ 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-kB-dependent proinflammatory response. Expressed genes included matrix metallopeptidase 1 (MMP1) and fibronectin 1 (FN1), factors involved in tissue remodeling, adhesion, and cell migration; inflammatory cytokines IL-1β and IL-8; genes regulating cell survival including A20 and ATF3; and notably high expression of a set of chemokines that would favor neutrophil and monocyte recruitment including CXCL2, CCL2, CXCL12, CXCL1, CXCL6, and 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-kB-dependent inflammatory factors that have the potential to contribute to the antiislet- graft immune response. To test this hypothesis, we extracted rodent islets under optimal conditions, forced activation of NF-kB, and transplanted them into allogenic recipients. These NF-kB activated islets not only expressed the same chemokine profile observed in human islets but also struggled to maintain normoglycemia posttransplantation. Further, NF-kB-activated islets were rejected with a faster tempo as compared to non-NFkB- 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 proinflammatory responses as targets for therapeutic intervention.

Original languageEnglish (US)
Pages (from-to)2063-2078
Number of pages16
JournalCell transplantation
Volume21
Issue number9
DOIs
StatePublished - 2012
Externally publishedYes

Keywords

  • Gene expression
  • Gene set enrichment analysis
  • Human islet
  • Inflammation
  • Islet
  • Islet transplantation
  • NF-kB

ASJC Scopus subject areas

  • Biomedical Engineering
  • Cell Biology
  • Transplantation

Fingerprint

Dive into the research topics of 'Human islets express a marked proinflammatory molecular signature prior to transplantation'. Together they form a unique fingerprint.

Cite this