• Citer

beta-cell dysfunction in type 1 diabetes: the role of PTPN2 and short-chain fatty acid- enriched diets in autoimmune inflammatory pathways

par Vandenbempt, Valerie
Président du jury Le Moine, Alain
Promoteur Gurzov, Esteban Nicolas
Publication Non publié, 2025-06-26

Thèse de doctorat

• Accès en ligne
• Détails
• Contenu
• Statistiques

Résumé :

Type 1 diabetes (T1D) results from autoimmune destruction of pancreatic b cells.Hyperactivation of JAK/STAT signalling amplifies the inflammatory response in b cells,leading to cell death. Pharmacological JAK/STAT inhibitors have therapeutic potentialfor patients with T1D. However, it is currently unknown if physiological JAK/STATinhibitors, such as protein tyrosine phosphatases (PTPs), can be used as a therapeutictarget in T1D patients. PTPN2 is a candidate gene for T1D, in which loss-of-functionSNPs result in a higher risk of developing the disease at an earlier age. Here, weprovide a comprehensive study of PTPN2 and inflammatory signalling in autoimmunediabetes.In the first part of this PhD, we assessed the global protein and individual PTP profilesin the pancreas of non-obese diabetic (NOD) mice with reversed hyperglycaemia bytreatment with anti-CD3 monoclonal antibody and interleukin-1 receptor antagonist.This combination enhanced the expression of PTPN2 and endoplasmic reticulum (ER)chaperones in the pancreatic islets. To address the functional role of PTPN2 in b cells,we took advantage of novel generated models, including PTPN2-silenced EndoC-bH1cells and PTPN2-deficient human stem cell-derived islets (SC-islets). Wedemonstrated that PTPN2 inactivation in b cells exacerbate the interferon signallingand potential progression toward autoimmunity. Moreover, we determined the role ofthe 48kDa ER-located isoform of PTPN2 to modulate the calcium-dependent unfoldedprotein response and ER stress outcome in b cells. Adenovirus-mediated PTPN2overexpression partially protected the b cells against ER stress–induced cell death.In the second part of this study, we assessed PTPN2 expression in b cells of T1Dorgan donors and during SC-islet differentiation. PTPN2 expression was increased inb cells of early-stage T1D and decreased in long-standing T1D compared with healthycontrols. We found that PTPN2 expression was also significantly decreased during3SC-islet differentiation. PTPN2-knockout human embryonic stem cells showedenhanced interferon-induced inflammatory signalling in stem cells and differentiatedsomatic metabolic cells. Moreover, PTPN2-/- SC-islets exhibited reduced glycaemiccontrol after implantation under the kidney capsule of immune-deficient NOD/SCIDmice. Our study postulates a dual role of PTPN2, reducing inflammatory signalling andpreserving SC-islet function during metabolic stressFinally, we investigated the potential of short-chain fatty acids (SCFA) to improvedysfunctional signalling in pancreatic islets in T1D. We performed single-cell RNA-Sequencing on islet cells from NOD mice fed with an enriched acetate and butyrate(HAMSAB) or control diet. HAMSAB induced a tolerogenic gene expression profile inpancreas-infiltrated immune cells. Moreover, HAMSAB-fed mice showed preservedendocrine cell identity in the islets, as evaluated by decreased numbers of poly-hormonal cells and decreased cellular stress. SCFA increased insulin levels in humanSC-islets and improved implantation outcomes in NOD/SCID mice. Our findingssupport the use of metabolite-based diet as an attractive approach to improve glucosecontrol in T1D.