Regulation of Expression of Keratins and their Pathogenic Roles in Keratinopathies

Keratins are the epithelia-specific members of intermediate filament superfamily and consist of 54 members. They serve primarily as cytoskeletons, which sustain cell structures. They also influence on cell proliferation and motility by rapidly changing their morphology and distribution through post-translational modification. The expression of keratins genes is regulated by various cytokines and growth factors, mainly through distinct transcription factors. Mutations in keratin genes cause various cutaneous diseases as well as predisposition to inflammatory disorders of internal organ, such as the intestine and the liver. Keratins directly interact signaling molecules, which affects inflammatory processes, and cancer progression. The mechanism of keratin involvement in many diseases will be elucidated in future, which would help identifying novel target for treatment

Pathogenic Role of Cytokines and Effect of Their Inhibition in Psoriasis

The pathogenesis of psoriasis is complex, and cytokines play an important role in mediating cell-cell interactions that result in abnormal structures and functions of many cell types in psoriasis, such as abnormal proliferation and differentiation of keratinocytes, abnormal proliferation of blood vessels, stimulation of immune cells, and driving abnormal immune reactions. In this chapter, we summarize the roles and functions of inflammatory cytokines that play a crucial role in psoriasis such as tumor necrosis factor (TNF)-α, interleukin (IL)-12/IL-23, and IL-17, as well as their inhibitors that are used to treat psoriasis

Genetic Abnormalities, Melanosomal Transfer, and Degradation Inside Keratinocytes Affect Skin Pigmentation

Skin pigmentation is a specific and complex mechanism that occurs as a result of the quantity and quality of melanin produced, as well as the size, number, composition, mode of transfer, distribution, and degradation of the melanosomes inside keratinocytes and the handling of the melanin product by the keratinocyte consumer. Melanocyte numbers typically remain relatively constant. Melanin synthesis, melanosome maturation, and melanoblast translocation are considered to be responsible for hereditary pigmentary disorders. Keratinocytes play a significant role in regulating the adhesion, proliferation, survival, and morphology of melanocytes. In the epidermis, each melanocyte is surrounded by 30–40 keratinocytes through dendrites and transfers mature melanosomes into the cytoplasm of keratinocytes, which are then digested. Melanocytes are believed to transfer melanosomes to neighboring keratinocytes via exocytosis-endocytosis, microvesicle shedding, phagocytosis, or the fusion of the plasma membrane, protecting skin cells against ultraviolet (UV) damage by creating a physical barrier (cap structure) over the nucleus. An understanding of the factors of melanocytes and keratinocytes that induce pigmentation and the transfer mechanism of melanosomes to keratinocytes and how genetic abnormalities in keratinocytes affect pigmentary skin disorders will help us to elucidate hereditary pigmentary disorders more transparently and provide a conceptual framework for the importance of keratinocytes in the case of pigmentary disorders

The involvement of Gab1 and PI 3-kinase in β1 integrin signaling in keratinocytes

金沢大学大学院医学系研究科血管分子科学The control of the stem cell compartment in epidermis is closely linked to the regulation of keratinocyte proliferation and differentiation. β1 integrins are expressed 2-fold higher by stem cells than transit-amplifying cells. Signaling from these β1 integrins is critical for the regulation of the epidermal stem cell compartment. To clarify the functional relevance of this differential expression of β1 integrins, we established HaCaT cells with high β1integrin expression by repeated flow cytometric sorting of this population from the parental cell line. In these obtained cells expressing β1 integrins by 5-fold, MAPK activation was markedly increased. Regarding the upstream of MAPK, Gab1 phosphorylation was also higher with high β1 integrin expression, while Shc phosphorylation was not altered. In addition, enhanced phosphatidylinositol 3-kinase activation was also observed. These observations suggest that Gab1 and phosphatidylinositol 3-kinase play pivotal roles in the β1 integrin-mediated regulation of the epidermal stem cell compartment. © 2007 Elsevier Inc. All rights reserved

Recent Advances in Psoriasis Research; the Clue to Mysterious Relation to Gut Microbiome

Psoriasis is a chronic inflammatory cutaneous disease, characterized by activated plasmacytoid dendritic cells, myeloid dendritic cells, Th17 cells, and hyperproliferating keratinocytes. Recent studies revealed skin-resident cells have pivotal roles in developing psoriatic skin lesions. The balance in effector T cells and regulatory T cells is disturbed, leading Foxp3-positive regulatory T cells to produce proinflammatory IL-17. Not only acquired but also innate immunity is important in psoriasis pathogenesis, especially in triggering the disease. Group 3 innate lymphoid cell are considered one of IL-17-producing cells in psoriasis. Short chain fatty acids produced by gut microbiota stabilize expression of Foxp3 in regulatory T cells, thereby stabilizing their function. The composition of gut microbiota influences the systemic inflammatory status, and associations been shown with diabetes mellitus, cardiovascular diseases, psychomotor diseases, and other systemic inflammatory disorders. Psoriasis has been shown to frequently comorbid with diabetes mellitus, cardiovascular diseases, psychomotor disease and obesity, and recent report suggested the similar abnormality in gut microbiota as the above comorbid diseases. However, the precise mechanism and relation between psoriasis pathogenesis and gut microbiota needs further investigation. This review introduces the recent advances in psoriasis research and tries to provide clues to solve the mysterious relation of psoriasis and gut microbiota

Diagnosis and Intervention in Early Psoriatic Arthritis

Psoriatic arthritis (PsA) is a chronic inflammatory disorder that affects approximately 20–30% of patients with psoriasis. PsA causes deformities and joint damage, impairing quality of life and causing long-term functional disability. Several recent studies demonstrated that early diagnosis and intervention for PsA prevents permanent invalidity. However, the clinical features of PsA vary and are shared with other differential diseases, such as reactive arthritis, osteoarthritis, and ankylosing spondylitis. The common and overlapping features among these diseases complicate the accurate early diagnosis and intervention of PsA. Therefore, this review focuses on the current knowledge of the diagnosis of early PsA and discusses the meaning of early intervention for early PsA