4 Table of contents
Table of contents ... 4
List of abbreviations ... 6
I. Introduction ... 8
1. Immunity ... 8
1.1. Innate immunity ... 8
1.2. Innate immune cells ... 9
1.2.1. Granulocytes ... 10
1.2.2. Dendritic cells ... 10
1.2.3. Innate lymphoid cells ... 11
1.2.4. Monocytes/Macrophages ... 12
1.3. Adaptive immunity ... 12
2. The liver ... 14
2.1. Cellular components of the liver ... 15
2.1.1. Hepatocytes ... 15
2.1.2. Liver sinusoidal endothelial cells ... 16
2.1.3. Hepatic Stellate cells ... 17
2.1.4. Kupffer cells ... 19
2.1.5. Natural killer cells (NK cells) ... 23
2.1.6. NKT cells ... 25
2.1.7. Dendritic cells ... 26
2.1.8. Conventional T lymphocytes ... 28
2.1.9. γδ T Lymphocytes ... 29
3. Primary liver cancers ... 30
3.1. Cholangiocarcinoma ... 31
3.2. Hepatocellular Carcinoma ... 32
4. Liver regeneration ... 34
4.1. Clinical implications of liver regeneration ... 38
5. Cytokines ... 40
5.1. Tumor Necrosis Factor-α ... 40
5.1.1. Complex I ... 41
5.1.2. ComplexIIa/b ... 42
5.1.3. Necrosome ... 43
5
5.1.4. Inflammation and tumorigenesis ... 45
5.2. Interleukin-6 ... 46
5.3. Interleukin-1β ... 50
5.3.1. Inflammasome and pyroptosis ... 52
II. Research objectives ... 55
III. Results ... 56
1. Experimental set-up and models ... 56
1.1. Model of hepatectomy ... 56
1.2. Choice of tumoral model ... 57
2. Hepatocarcinoma induces a tumor necrosis factor-dependent Kupffer cell death pathway that favors its proliferation upon partial hepatectomy ... 59
3. Complementary observations ... 61
3.1. Liver regeneration in IL-6 KO mice ... 61
3.2. Rejection of the tumor is impaired in CD3 KO mice ... 62
3.3. Liver regeneration in Batf3 KO mice ... 62
3.4. Positive control staining of p-MLKL (Ser345) ... 63
IV. Discussion ... 64
1. Tumor development model ... 64
2. Impact of liver regeneration on tumoral growth/tumor rejection ... 66
3. Nature of Kupffer cells disappearance following PH ... 69
4. IL-6 importance for Kupffer cells survival and tumor rejection ... 72
5. Tumor growth modifies partial hepatectomy-induced death of KC ... 74
6. Differential recruitment of monocyte-derived cells is dictated by death pathway activation in KC ... 77
7. Possible clinical applications ... 79
8. Dendritic cells and liver regeneration ... 81
9. Kupffer cells potential interactions with other cells ... 83
V. Bibliography ... 85
VI. Summary ... 104
