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Table of contents
ACKNOWLEDGEMENTS
ABBREVIATIONS
INTRODUCTION
1. Macrophages, swiss army knifes of the innate immune system
1.1. The innate immune system
1.2. The origins of Macrophages
1.3. Inflammation
1.4. Ageing and the innate immune system
2. The liver
2.1. General considerations
2.1.1. Development
2.1.2. General anatomy
2.1.3. Functions
2.2. Liver cell types
2.2.1. The hepatocytes
2.2.2. The hepatic stellate cells
2.2.5. Innate immune cells
2.2.5.2. Liver Capsular Macrophages (LCMs)
2.2.5.3. Neutrophils
2.2.5.4. Dendritic Cells (DCs)
2.2.5.5. Natural Killer (NK) cells and other innate lymphoid cells(?)
2.2.5.6. Monocytes
2.2.5.7. Infiltrating Macrophages
2.3. Liver diseases
2.3.1. Acute injury and liver failure
2.3.2. Fibrosis and cirrhosis
2.4. Liver Ageing
3. Kupffer Cells
3.1. First and foremost, Phagocytes
3.2. Transcriptional control of KC identity
3.3. The Kupffer Cell Niche
3.4. CSF1 signalling
3.5. Non-immune functions
3.5.1. Clearance of dead and senescent cells
3.5.2. Iron recycling
3.5.3. Lipid removal
3.6. Functions in tissue repair
3.7. Tools to study KC maintenance
3.7.1. Fate mapping
3.7.2. Flt3Cre Rosa26YFP
3.7.3. Csf1rMeriCreMer Rosa26Tomato
3.7.4. CCR2CreERT2 Rosa26Tomato
3.7.5. Selective depletion
3.7.5.1. Plexxikon
3.7.5.2. Genetic models
AIMS AND OBJECTIVES
RESULTS
1. Kupffer Cell Maintenance in Ageing
2. Preliminary data: Kupffer cell maintenance after PLX depletion
3. Preliminary data: Maintenance of Kupffer Cells in Acetaminophen Induced Liver Injury
3.1. Acute Acetaminophen Induced Liver Injury
3.2. Repeated Acetaminophen Induced Liver Injury
4. Methods (Maintenance after PLX5622 and Injury)
CONCLUSION
DISCUSSION
1. Effects of inflammation on Kupffer Cell viability
1.1. Apoptosis
1.2. Pyroptosis
1.3. Necroptosis
2. Determinants of IMs persistence and differentiation into KCs
2.1. Absence of competition
2.2. An adequate niche
2.3. Inhibition of infiltrating macrophage clearance
2.3.1. The role of CSF1/CSF1R
2.3.2. The role of CX3CL1/CX3CR1
3. Age-associated ultrastructural changes in liver
3.1. LSEC fenestrations
3.2. Liver fibrosis
3.3. Ageing is a dynamic and multi-factorial process
4. KC loss in ageing: impact in age related diseases
4.1. Lipid accumulation
4.2. Senescent cells and fibrosis
4.3. Relevance in age related human diseases
5. Challenges in studying KC specific functions in injury
5.1. Inflammation and depletion
5.2. Heterogeneity beyond ontogeny
6. Perspectives
6.1. In situ observation of KCs
6.2. Macrophage transplant
6.3. Phagocytosis and cellular longevity
6.4. Repeated Injury
REFERENCES
RESUME DÉTAILLÉ EN FRANCAIS
ABSTRACT
RESUME
