Lymphocyte-Derived Exosomal MicroRNAs Promote Pancreatic β Cell Death and May Contribute to Type 1 Diabetes Development.

Cell Metab. 2019 Feb 5;29(2):348-361.e6. doi: 10.1016/j.cmet.2018.09.011. | PubMed

Claudiane Guay¹, Janine K Kruit², Sophie Rome³, Véronique Menoud¹, Niels L Mulder², Angelika Jurdzinski², Francesca Mancarella⁴, Guido Sebastiani⁴, Alena Donda⁵, Bryan J Gonzalez¹, Camilla Jandus⁶, Karim Bouzakri⁷, Michel Pinget⁷, Christian Boitard⁸, Pedro Romero⁵, Francesco Dotta⁴, Romano Regazzi⁹

1. Department of Fundamental Neurosciences, University of Lausanne, Rue du Bugnon 9, 1005 Lausanne, Switzerland.
2. Department of Pediatrics, Section Molecular Metabolism and Nutrition, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
3. CarMeN Laboratory (INSERM 1060, INRA 1362, INSA), University of Lyon, Faculté de Médecine de Lyon Sud, Lyon, France.
4. Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy; Umberto Di Mario ONLUS Foundation - Toscana Life Science Park, Siena, Italy.
5. Ludwig Center for Cancer Research, University of Lausanne, Lausanne, Switzerland.
6. Department of Oncology, CHUV, University of Lausanne, Lausanne, Switzerland.
7. UMR DIATHEC, EA 7294, Centre Européen d'Etude du Diabète, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France.
8. Institut National de Santé et de Recherche Médicale U1016, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
9. Department of Fundamental Neurosciences, University of Lausanne, Rue du Bugnon 9, 1005 Lausanne, Switzerland. Electronic address: romano.regazzi@unil.ch.

Abstract

Type 1 diabetes is an autoimmune disease initiated by the invasion of pancreatic islets by immune cells that selectively kill the β cells. We found that rodent and human T lymphocytes release exosomes containing the microRNAs (miRNAs) miR-142-3p, miR-142-5p, and miR-155, which can be transferred in active form to β cells favoring apoptosis. Inactivation of these miRNAs in recipient β cells prevents exosome-mediated apoptosis and protects non-obese diabetic (NOD) mice from diabetes development. Islets from protected NOD mice display higher insulin levels, lower insulitis scores, and reduced inflammation. Looking at the mechanisms underlying exosome action, we found that T lymphocyte exosomes trigger apoptosis and the expression of genes involved in chemokine signaling, including Ccl2, Ccl7, and Cxcl10, exclusively in β cells. The induction of these genes may promote the recruitment of immune cells and exacerbate β cell death during the autoimmune attack. Our data point to exosomal-miRNA transfer as a communication mode between immune and insulin-secreting cells.

Presented By Claudiane Guay