Role of neutrophils in complications of diabetes

Pan, Chang (2023): Role of neutrophils in complications of diabetes: lessons from atherosclerosis. Dissertation, LMU München: Medizinische Fakultät

Abstract

Diabetes, both type 1 diabetes and type 2 diabetes, has been recognized as a risk factor for cardiovascular diseases (CVD) and atherosclerosis is the main underlying cause of CVD. Destabilization and rupture of atherosclerotic lesions account for most acute cardiovascular events; however, little direct evidence shows that diabetes can promote lesion rupture. In this project, a diabetes-induced atherosclerosis destabilization model was generated and it confirmed that diabetes greatly impairs lesion stability. Further, two neutrophil-centered mechanisms were discovered to play a role in the destabilization of the diabetes-induced atherosclerotic lesion. Firstly, diabetes triggered the formation of neutrophil extracellular traps (NETs) in atherosclerosis. Secondly, diabetes downregulated the peroxisome proliferator-activated receptors (PPAR) signaling pathway. These two processes caused an imbalance in cell death and dead cell clearance, leading to the formation and expansion of the necrotic core. Inspiringly, the present study revealed that the dysregulation of NET formation and PPAR signaling pathway presented in a variety of other complications of diabetes as well, which implied that neutrophil-related mechanisms could serve as a broad-spectrum therapy to target these complications. On the other hand, both hyperglycemia and hypercholesterolemia have been reported to strongly impact granulopoiesis, resulting in neutrophilia. However, the mechanism is not very well-studied yet. Moreover, cellular metabolism supports cell function and fate decision-making. Here, we observed that diabetes significantly enriched circulating neutrophils into a cluster with increased glucose metabolism (glycolysis and pentose phosphate pathway). This cluster of neutrophils was more prone to undergo NETosis. Further analysis revealed that this cluster of neutrophils had a higher maturation and senescence score. Additionally, in the bone marrow, diabetes speeded up metabolic shifts during neutrophil differentiation and maturation, which potentially fueled granulopoiesis. Time-restricted feeding (TRF) emerges into the field of circadian rhythmicity because of its ability to synchronize the rhythm by interfering with the amplitude of the oscillation. In the last part of this project, it was hypothesized that TRF could be implemented as a lifestyle therapeutic approach to treat atherosclerosis since atherosclerosis has been defined to be related to metabolic disorders and circadian rhythm disruption. Surprisingly, instead of less atherosclerosis formation, hypercholesterolemic mice with TRF showed more atherosclerotic burden. Mechanistically, TRF optimized neutrophil rhythmical oscillation of both counts and vascular adhesion. The optimized oscillation increased the number of circulating neutrophils and macro-circulation adherent neutrophils in the resting phase of the mice, while a lower count of adherent neutrophils in the micro-circulation during the active phase. Ultimately, this project revealed the dark side of neutrophils in the complications of diabetes. Therefore, a therapy that targets the neutrophils and corrects their behavior might be a prospective therapy to treat complications of diabetes.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: Diabetes, Atherosclerosis, Complications of diabetes, neutrophil, metabolism, time restricted feeding, circadian
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 25. Januar 2023
• 1. Bericht­erstatter:in: Söhnlein, Oliver