Pancreatic β-Cell production of CXCR3 ligands precedes diabetes onset.
Type 1 diabetes mellitus (T1DM) results from immune cell-mediated reductions in function and mass of the insulin-producing β-cells within the pancreatic islets. While the initial trigger(s) that initiates the autoimmune process is unknown, there is a leukocytic infiltration that precedes islet β-cell death and dysfunction. Herein, we demonstrate that genes encoding the chemokines CXCL9, 10, and 11 are primary response genes in pancreatic β-cells and are also elevated as part of the inflammatory response in mouse, rat, and human islets. We further established that STAT1 participates in the transcriptional control of these genes in response to the pro-inflammatory cytokines IL-1β and IFN-γ. STAT1 is phosphorylated within five minutes after β-cell exposure to IFN-γ, with subsequent occupancy at proximal and distal response elements within the Cxcl9 and Cxcl11 gene promoters. This increase in STAT1 binding is coupled to the rapid appearance of chemokine transcript. Moreover, circulating levels of chemokines that activate CXCR3 are elevated in non-obese diabetic (NOD) mice, consistent with clinical findings in human diabetes. We also report herein that mice with genetic deletion of CXCR3 (receptor for ligands CXCL9, 10, and 11) exhibit a delay in diabetes development after being injected with multiple low doses of streptozotocin. Therefore, we conclude that production of CXCL9, 10, and 11 from islet β-cells controls leukocyte migration and activity into pancreatic tissue, which ultimately influences islet β-cell mass and function. © 2016 BioFactors, 42(6):703-715, 2016.
Laboratory of Islet Biology and Inflammation, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
Susan J
SJ
Burke
Department of Surgery, Graduate School of Medicine, University of Tennessee Health Science Center, Knoxville, TN, USA.
Michael D
MD
Karlstad
Department of Surgery, Graduate School of Medicine, University of Tennessee Health Science Center, Knoxville, TN, USA.
Adrianna E
AE
Eder
Department of Surgery, Graduate School of Medicine, University of Tennessee Health Science Center, Knoxville, TN, USA.
Kellie M
KM
Regal
Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA.
Danhong
D
Lu
Cell Biology and Bioimaging Core Facility, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
David H
DH
Burk
Laboratory of Islet Biology and Inflammation, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
J Jason
http://orcid.org/0000-0003-2817-4152
JJ
Collier
D000818:Animals; D001786:Blood Glucose; D002460:Cell Line; D054371:Chemokine CXCL11 / Q000097:blood / Q000235:genetics; D054370:Chemokine CXCL9 / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism; D008024:Ligands; D008297:Male; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D011401:Promoter Regions, Genetic; D051381:Rats; D054367:Receptors, CXCR3 / Q000502:physiology; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015533:Transcriptional Activation
D001786:Blood Glucose; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; C515203:Cxcl11 protein, mouse; C485969:Cxcl9 protein, mouse; C515188:Cxcr3 protein, mouse; D008024:Ligands; D054367:Receptors, CXCR3; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D053612:Janus Kinases
autoimmunity; chemokine; diabetes; inflammation; islets; transcription