A single-cell genomic based investigation of immune cells in the aorta and adipose tissue during metabolic disease progression
<p>Metabolic diseases such as obesity, type 2 diabetes and atherosclerosis are characterised by chronic inflammation that leads to the accumulation of immune cells in affected organs like the adipose tissue and arteries. Macrophages in the obese adipose tissue and the atherosclerotic plaque sh...
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| Other Authors: | |
| Format: | Thesis |
| Language: | English |
| Published: |
2023
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| _version_ | 1811139835735310336 |
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| author | Zurke, YX |
| author2 | Monaco, C |
| author_facet | Monaco, C Zurke, YX |
| author_sort | Zurke, YX |
| collection | OXFORD |
| description | <p>Metabolic diseases such as obesity, type 2 diabetes and atherosclerosis are characterised by chronic inflammation that leads to the accumulation of immune cells in affected organs like the adipose tissue and arteries. Macrophages in the obese adipose tissue and the atherosclerotic plaque show transcriptional, phenotypic and functional heterogeneity. The accumulation of CD11c+ macrophages has been associated with both atherosclerosis and obesity progression, suggesting the presence of conserved macrophage phenotypes in metabolic tissues. This thesis aimed to 1) characterise shared and distinct features of monocytes and macrophages in the aorta and adipose tissue in the context of metabolic disease 2) investigate the role of the transcription factor IRF5 on the modulation of myeloid phenotype in both diseases. Both aims were addressed using single-cell techniques.</p>
<p>Single-cell RNA sequencing of chimeric mice during a time course of metabolic disease progression and data integration with non-irradiated community datasets demonstrated that resident macrophages in the adipose tissue could be replenished by monocyte-derived macrophages, while the perturbation of the vascular macrophage niche via irradiation resulted in transcriptional activation of macrophages and loss of some of the bona fide transcriptional features of vascular resident macrophages. Integrated analysis of the aortic and adipose tissue mononuclear phagocyte compartments revealed that resident macrophages in the aorta and adipose tissue display tissue-specific transcriptional programs. Although vascular resident Folr2+Lyve1+ macrophages were identifiable also within the adipose tissue, the majority of resident adipose tissue macrophages expressed genes associated with lipid metabolism, cell adhesion and proliferation, highlighting that cell maintenance and function of tissue resident macrophages differ between the aorta and adipose tissue.</p>
<p>In my analysis, two CD11c<sup>+</sup> macrophage subsets were identified according to their expression of CD226 and CD63/TREM2 using both scRNAseq and CyTOF. CD11c<sup>+</sup> macrophage subsets were conserved across multiple metabolic disease models and shared transcriptional signatures between metabolic tissues. In disease, CD11c<sup>+</sup>Trem2<sup>hi</sup> foamy macrophages expanded in the aorta and the adipose tissue, while CD11c<sup>+</sup>CD226<sup>+</sup> macrophages did not. The transcription factor IRF5, a potential regulator of CD11c<sup>+</sup> macrophages in metabolic disease, has been shown to induce atherosclerotic lesion formation and insulin resistance in experimental models of atherosclerosis and obesity. IRF5 promoted expansion of Trem2<sup>hi</sup> macrophages in the aorta in chimeras, but not in the adipose tissue, further highlighting that tissue niche affects macrophage activation and transcriptional regulation patterns.</p>
<p>In conclusion, macrophages in the adipose tissue and atherosclerotic aorta show both conserved and tissue specific transcriptional phenotypes and dynamics in response to genotoxic damage and during metabolic disease progression. Understanding similarities and differences between the two tissues will be important to inform identification of new therapeutic targets for cardiometabolic diseases.</p> |
| first_indexed | 2024-09-25T04:12:24Z |
| format | Thesis |
| id | oxford-uuid:8fc5609d-054d-48ec-a5c5-a1d9a68e747d |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:12:24Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | oxford-uuid:8fc5609d-054d-48ec-a5c5-a1d9a68e747d2024-07-01T12:05:31ZA single-cell genomic based investigation of immune cells in the aorta and adipose tissue during metabolic disease progressionThesishttp://purl.org/coar/resource_type/c_db06uuid:8fc5609d-054d-48ec-a5c5-a1d9a68e747dImmunologyMacrophagesAtherosclerosisObesityEnglishHyrax Deposit2023Zurke, YXMonaco, CSansom, SDib, L<p>Metabolic diseases such as obesity, type 2 diabetes and atherosclerosis are characterised by chronic inflammation that leads to the accumulation of immune cells in affected organs like the adipose tissue and arteries. Macrophages in the obese adipose tissue and the atherosclerotic plaque show transcriptional, phenotypic and functional heterogeneity. The accumulation of CD11c+ macrophages has been associated with both atherosclerosis and obesity progression, suggesting the presence of conserved macrophage phenotypes in metabolic tissues. This thesis aimed to 1) characterise shared and distinct features of monocytes and macrophages in the aorta and adipose tissue in the context of metabolic disease 2) investigate the role of the transcription factor IRF5 on the modulation of myeloid phenotype in both diseases. Both aims were addressed using single-cell techniques.</p> <p>Single-cell RNA sequencing of chimeric mice during a time course of metabolic disease progression and data integration with non-irradiated community datasets demonstrated that resident macrophages in the adipose tissue could be replenished by monocyte-derived macrophages, while the perturbation of the vascular macrophage niche via irradiation resulted in transcriptional activation of macrophages and loss of some of the bona fide transcriptional features of vascular resident macrophages. Integrated analysis of the aortic and adipose tissue mononuclear phagocyte compartments revealed that resident macrophages in the aorta and adipose tissue display tissue-specific transcriptional programs. Although vascular resident Folr2+Lyve1+ macrophages were identifiable also within the adipose tissue, the majority of resident adipose tissue macrophages expressed genes associated with lipid metabolism, cell adhesion and proliferation, highlighting that cell maintenance and function of tissue resident macrophages differ between the aorta and adipose tissue.</p> <p>In my analysis, two CD11c<sup>+</sup> macrophage subsets were identified according to their expression of CD226 and CD63/TREM2 using both scRNAseq and CyTOF. CD11c<sup>+</sup> macrophage subsets were conserved across multiple metabolic disease models and shared transcriptional signatures between metabolic tissues. In disease, CD11c<sup>+</sup>Trem2<sup>hi</sup> foamy macrophages expanded in the aorta and the adipose tissue, while CD11c<sup>+</sup>CD226<sup>+</sup> macrophages did not. The transcription factor IRF5, a potential regulator of CD11c<sup>+</sup> macrophages in metabolic disease, has been shown to induce atherosclerotic lesion formation and insulin resistance in experimental models of atherosclerosis and obesity. IRF5 promoted expansion of Trem2<sup>hi</sup> macrophages in the aorta in chimeras, but not in the adipose tissue, further highlighting that tissue niche affects macrophage activation and transcriptional regulation patterns.</p> <p>In conclusion, macrophages in the adipose tissue and atherosclerotic aorta show both conserved and tissue specific transcriptional phenotypes and dynamics in response to genotoxic damage and during metabolic disease progression. Understanding similarities and differences between the two tissues will be important to inform identification of new therapeutic targets for cardiometabolic diseases.</p> |
| spellingShingle | Immunology Macrophages Atherosclerosis Obesity Zurke, YX A single-cell genomic based investigation of immune cells in the aorta and adipose tissue during metabolic disease progression |
| title | A single-cell genomic based investigation of immune cells in the aorta and adipose tissue during metabolic disease progression |
| title_full | A single-cell genomic based investigation of immune cells in the aorta and adipose tissue during metabolic disease progression |
| title_fullStr | A single-cell genomic based investigation of immune cells in the aorta and adipose tissue during metabolic disease progression |
| title_full_unstemmed | A single-cell genomic based investigation of immune cells in the aorta and adipose tissue during metabolic disease progression |
| title_short | A single-cell genomic based investigation of immune cells in the aorta and adipose tissue during metabolic disease progression |
| title_sort | single cell genomic based investigation of immune cells in the aorta and adipose tissue during metabolic disease progression |
| topic | Immunology Macrophages Atherosclerosis Obesity |
| work_keys_str_mv | AT zurkeyx asinglecellgenomicbasedinvestigationofimmunecellsintheaortaandadiposetissueduringmetabolicdiseaseprogression AT zurkeyx singlecellgenomicbasedinvestigationofimmunecellsintheaortaandadiposetissueduringmetabolicdiseaseprogression |