Table of content
1 Summary ... 1
2 Introduction ... 3
2.1 The skin is the largest organ of the body! ... 3
2.2 Epidermis structure and differentiation... 3
2.3 Epidermal stem cell ... 6
2.3.1 Hair follicle morphogenesis and hair follicle stem cells ... 7
2.3.2 IFE stem cells ... 9
2.3.3 The contribution of epidermal stem cells in wound repair ... 10
2.4 Signaling events regulating the epidermis development ... 12
2.4.1 Role of Notch signaling in the skin ... 12
2.4.2 Role of RAS-ERK/Mapk signaling in the skin ... 14
2.4.3 Role of C/EBP in the skin ... 15
2.4.4 Role of Klf4 and Klf5 in the skin ... 15
2.4.5 Role of Grhl in the skin ... 17
2.4.5.1 Grhl1 ... 17
2.4.5.2 Grhl2 ... 17
2.4.5.3 Grhl 3 ... 17
2.4.6 Role of Irf6 in the skin... 18
2.4.7 Role of p63 in the skin ... 18
2.4.8 Role of AP-1 in the skin ... 21
2.4.8.1 Multiple roles of JUN proteins ... 23
2.4.8.2 Multiple roles of Fos proteins ... 23
2.4.9 Epidermal differentiation complex genes regulate the late terminal differentiation process……… ... 24
2.4.9.1 Cornified envelope precursors family ... 24
2.4.9.1.1 Involucrin ... 25
2.4.9.1.2 Loricrin ... 25
2.4.9.1.3 Small prolin-rich protein ... 26
2.4.9.2 Late cornified envelope family ... 26
2.4.9.3 S100 family ... 26
2.4.9.4 The S100 fused family ... 26
2.4.9.4.1 Pro-filaggrin and filaggrin ... 27
2.4.9.6 Dynamic Chromatin Architecture of the Epidermal Differentiation Complex ... 28
2.5 Dermis structure ... 29
2.5.1 The architecture of the dermis ... 29
2.5.2 The skin immunity ... 30
2.5.2.1 Keratinocyte, a dynamic player in the skin immune response ... 31
2.5.2.2 γδ T cells ... 32
2.5.2.3 Innate lymphoid cells ... 32
2.5.2.4 Dendritic cells ... 33
2.5.2.5 Macrophage and monocytes ... 34
2.5.2.6 Neutrophils ... 35
2.5.2.7 T cells ... 36
2.5.2.8 The initiation of immune response ... 36
2.5.2.8.1 Innate immune response ... 36
2.5.2.8.2 Recruitement of T cells to the skin ... 38
2.5.3 Skin angiogenesis... 40
2.5.3.1 VEGF family ... 41
2.5.3.2 Biology of VEGFA and its receptors ... 43
2.5.3.3 VEGFR2/Flk1 Signaling ... 44
2.5.3.4 VEGFR1/Flt1 Signaling ... 44
2.5.3.5 Nrp1, a co-receptor of VEGF... 46
2.5.4 Chronic skin inflammatory disorder ... 47
2.6 Psoriasis is a common skin disorder ... 48
2.7 Clinical features ... 48
2.8 Histology ... 49
2.9 Etiopathogenesis ... 49
2.9.1 Environmental factors ... 49
2.9.2 Genetic factors ... 50
2.9.2.1 Single nucleotide polymorphisms ... 51
2.9.2.1.1.1 Psoriasis susceptibility loci ... 51
2.9.2.1.2 Psoriasis associated genes beyond PSORS loci ... 54
2.9.2.1.3 Copy number variation ... 54
2.9.2.1.4 Epigenetic alterations ... 54
2.9.2.1.5 Differentially expressed genes in psoriasis ... 55
2.9.3 The link between genetics and immunity in the pathogenesis of psoriasis ... 55
2.9.3.1 Communication between innate and adaptive immunity in psoriasis ... 57
2.9.4 The contribution of keratinocytes in psoriasis ... 60
2.9.4.1 Keratinocyte-derived chemokines ... 61
2.9.4.2 Growth factors released by keratinocytes ... 61
2.9.5 The psoriatic microvasculature ... 61
2.10 Role of VEGFA in psoriasis ... 63
2.10.1 VEGF as a pharmacological target in psoriasis ... 64
2.10.2 VEGFR expression in keratinocytes ... 65
2.11 Psoriasis experimental model ... 66
2.11.1 Mouse model of psoriasis: How to define the ideal model?... 66
2.11.2 Spontaneous mouse models of psoriasis ... 66
2.11.3 The genetically engineered models ... 67
2.11.4 The xenotransplantation models ... 70
2.11.5 The induced model ... 71
3 Aims of the work ... 72
4 Results: Article ... 73
5 Article ... 74
6 Discussion ... 76
6.1 Epidermal autonomous Vegfa/Flt1/Nrp1 functions in psoriasis ... 76
6.2 Fosl1 is a key transcriptional factor in the pathogenesis of psoriasis ... 80
6.3 Chicken or egg: Which came first? ... 82
6.4 Keratinocyte, primary actor in the “domino effect” ... 82
6.5 Potential therapeutic effects of Nrp1 blocking therapy in psoriasis ... 83
7 Perspectives ... 84
7.1 Role of the microenvironment in mediating Vegfa-induced psoriasis? ... 84
7.2 Which transcription factor are crucial in the development of psoriasis ? ... 85
7.3 The crucial role of ECM in the pathogenesis of psoriasis ... 86
7.4 How does Vegfa/Nrp1/Flt1 regulate the immune infiltration and angiogenesis? ... 87
7.5 Relevance of VEGFA/Flt1/Nrp1/Fosl1 signaling in human psoriasis? ... 87
7.6 Pharmacological relevance of Nrp1 inhibitors in human psoriasis?... 88
7.7 Role of epidermal stem cell in psoriasis ... 90
8 Appendix ... 92
9 References ... 99
