- Titel
- Myeloid Cell-Specific Interleukin-4 and 6 Receptor α Knockouts in Mice
- Untertitel
- Effects on Adipose Tissue, Adipose Tissue Macrophages and Metabolic Phenotype
- Zitierfähige Url:
- https://nbn-resolving.org/urn:nbn:de:bsz:15-qucosa2-946443
- Datum der Einreichung
- 02.05.2024
- Datum der Verteidigung
- 14.11.2024
- Abstract (EN)
- The worldwide prevalence of obesity and type 2 diabetes is rapidly increasing and both diseases substantially reduce life quality, life expectancy and cause enormous social costs. Obesity is a major risk factor for the development of type 2 diabetes, but the molecular and cellular mechanisms that link both diseases are not sufficiently understood. Obesity leads to a sterile adipose tissue inflammation with increased macrophage invasion and an enhanced release of pro-inflammatory mediators from adipose tissue. Over the past 20 years, the understanding of adipose tissue biology and the interplay between adipocytes and adipose tissue leucocytes has substantially evolved. Strong evidence has accumulated that adipose tissue macrophages are the main source of the pro-inflammatory cytokine release and that impeding macrophage invasion into AT or reducing the number of pro-inflammatory adipose tissue macrophages (M1-like macrophages) can protect from obesity-induced insulin resistance. Interleukin (IL)-4, 6 and 13 are intensively linked to metabolism, distinct macrophage phenotypes and macrophage proliferation. Thus, we decided to investigate C57BL/6J mice with a myeloid cell-specific disruption of IL-6 or IL-4 and 13 signaling on normal and high fat diet to study the effects on adipose tissue, adipose tissue macrophages and metabolic phenotype. Since the application of IL-4 and 13 protects from type 2 diabetes during obesity and both cytokines are well characterized triggers of macrophage proliferation and anti-inflammatory alternative macrophage polarization, we hypothesized that IL-4 Receptor α (IL-4Rα) knockout would cause a substantial pro-inflammatory shift of adipose tissue macrophages and a deteriorated metabolic phenotype. In lean Il4raΔmyel mice, we found a decreased insulin sensitivity, no divergent adipose tissue macrophage polarization, but an increased percentage of CD8+ T cells in visceral adipose tissue, which we interpret as a deteriorated metabolic phenotype. Unexpectedly, obese Il4raΔmyel mice are partially protected from adipose tissue inflammation. They exhibit better glucose tolerance, no changes in the lymphocyte compartment and fewer M1 macrophages in visceral adipose tissue. Additionally, we were unable to measure differences in adipose tissue macrophage proliferation, indicating that IL-4 and intlerleukin-13 are expandable drivers of the obesity-induced adipose tissue macrophage proliferation. By further investigating IL-4Rα signaling, we found that IL-13 directly augments pro-inflammatory Itgax (Cd11c) gene expression in bone marrow-derived macrophages and increased the amount of CD11c+ macrophages in adipose tissue explants. Hence, IL-4Rα signaling is apparently less important for maintaining the anti-inflammatory adipose tissue M2 macrophage population. Moreover, our data indicate that IL-13 signaling can play a pro-inflammatory role in adipose tissue inflammation by directly upregulating CD11c on adipose tissue macrophages. IL-6 induces macrophage M2 polarization and local proliferation in adipose tissue. It was also shown that obese Il6raΔmyel mice had increased adipose tissue inflammation and decreased insulin sensitivity. Some evidence exists that these effects depend on IL-4Rα. By investigating Il6raΔmyel mice in our laboratory we aimed at getting deeper insights into IL- 6 induced adipose tissue macrophage proliferation in vivo and planned to study the signaling behind IL-6 induced macrophage M2 polarization. With our dietary regimen, lean and obese Il6raΔmyel mice showed no altered metabolic phenotype (equal glucose and insulin tolerance) or increased histological markers of AT inflammation. However, we found fewer M2 macrophages and fewer Ki67 expressing macrophages in visceral adipose tissue of obese Il6raΔmyel mice, indicating an inferior role of local ATM proliferation and M2-like macrophages in maintaining a healthy glucose metabolism. With adipose tissue explants and bone marrow-derived macrophages, we could demonstrate that IL-6 induces anti-inflammatory macrophage phenotypes independently of Il4ra. In summary, IL-6 has reproducible anti-inflammatory effects in adipose tissue macrophages that are mostly independent of IL-4Rα but did not significantly affect metabolism.
- Freie Schlagwörter (EN)
- Macrophages, Obesity, Diabetes, Inflammation, Immunity
- Klassifikation (DDC)
- 610
- BetreuerIn Hochschule / Universität
- Prof. Martin Gericke
- Den akademischen Grad verleihende / prüfende Institution
- Universität Leipzig, Leipzig
- Version / Begutachtungsstatus
- angenommene Version / Postprint / Autorenversion
- URN Qucosa
- urn:nbn:de:bsz:15-qucosa2-946443
- Veröffentlichungsdatum Qucosa
- 29.11.2024
- Dokumenttyp
- Dissertation
- Sprache des Dokumentes
- Englisch
- Lizenz / Rechtehinweis
CC BY-NC 4.0- Inhaltsverzeichnis
1 Introduction 1.1 Obesity 1.2 Diabetes mellitus 1.3 Adipose tissue 1.3.1 Adipose tissue during obesity 1.3.2 Causes of adipocyte death 1.4 Immune system 1.5 Inflammation 1.6 Macrophages 1.6.1 Resident macrophages, monocytes, and dendritic cells 1.6.2 Local proliferation of macrophages 1.6.3 Phagocytosis 1.6.4 Targeting macrophages 1.6.5 Diversity of macrophage phenotypes 1.6.6 Adipose tissue macrophages and the link between obesity and type 2 diabetes 1.6.7 Itgax or CD11c as M1 marker 1.6.8 Metabolic activation of macrophages 1.7 T cells 1.7.1 Lymphocytes and type 2 diabetes 1.8 Interleukin-4 and interleukin-13 1.9 Interleukin-6 2 Posing of question 3 References of the introduction 4 Publications 4.1 Myeloid Cell-Specific IL-4 Receptor Knockout Partially Protects from Adipose Tissue Inflammation 4.2 IL-6 signaling as a driver of self-renewal and alternative activation of adipose tissue macrophages 5 Summary 6 Erklärung über den wissenschaftlichen Beitrag des Promovenden zu der Publikation 7 Erklärung über die eigenständige Abfassung der Arbeit 8 Lebenslauf 9 Danksagung