The Brain–Skin Connection and the Pathogenesis of Psoriasis: A Review with a Focus on the Serotonergic System
Abstract
:1. Introduction
2. The Brain–Skin Connection
2.1. The Skin as a Neuroendocrine Organ
2.2. The Skin Immune System
2.3. The Serotonin System and Its Importance in Skin Neuroendocrine and Immune Systems
2.3.1. Serotonin Metabolism, Transport and Function
2.3.2. Serotonin and the Immune System
2.3.3. Serotonin in Skin
2.4. Effects of Psychological Stress on the Skin
3. Psoriasis
3.1. Introduction
3.2. The Pathogenesis of Psoriasis
3.2.1. Genetic Basis of Psoriasis
3.2.2. Neuroimmune Basis of Psoriasis
3.2.3. The Role of Serotonin in Psoriasis
4. Conclusions and Future Directions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Cells | 5-HT Metabolism and Transport | 5-HT Receptors | |
---|---|---|---|
Innate immune system | Dendritic cells | SERT [40] | 5-HT1BR, 5-HT1ER, 5-HT2AR, 5-HT2BR, 5-HT3R, 5-HT4R, 5-HT7R [41] |
Mast cells | TPH1 [42] | 5-HT1AR (main receptor in human and mice); human MCs also express mRNA for receptors 5-HT1B, 5-HT1E, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT4 and 5-HT7 [43] | |
Macrophages | SERT [44] | 5-HT1AR, 5-HT2AR, 5-HT2BR, 5-HT2CR, 5-HT3R, 5-HT7R [45,46] | |
Adaptive immune system | T cells | TPH1 [47], MAO, SERT [48] | 5-HT1AR [49], 5-HT1BR [47], 5-HT2BR [50]; 5-HT3AR (in activated CD4+ Th) [51,52] |
B cells | SERT [53] | 5-HT1AR [54], 5-HT3AR [55] | |
Skin cells | Keratinocytes | TPH1 [21] | 5-HT1AR, 5HT1BR, 5-HT2AR, 5-HT2BR, 5-HT2CR, 5-HT7R [56], 5-HT3R [57] |
Melanocytes | TPH1 [21] | 5-HT1AR, 5-HT1BR, 5-HT2AR, 5-HT2BR, 5-HT2CR, 5-HT7R [56] |
Type | Name | Action | |
---|---|---|---|
Cells | Innate immunocytes | Antigen-presenting cells (APCs) | Include Langerhans cells (LCs) in the epidermis, dendritic cells (DCs) and macrophages in the dermis. They present the antigen to T cells which recognize it via a T-cell receptor and become activated. |
Mast cells (MCs) | Granulocyte cells that contain histamine and are involved in allergy reactions, but can also activate and recruit immune-competent cells; can be induced to become APCs. | ||
Neutrophils | Most common type of leukocytes in the blood, early markers of inflammation; can be induced to become APCs. | ||
Natural killer (NK) cells | Cytotoxic lymphocytes which do not require activation to kill cells that do not have markers (antigens). | ||
Adaptive immunocytes | Conventional T cells | T lymphocytes: CD4+ Th cells, cytotoxic CD8+ T cells, which can become long-term resident memory T cells (TRMs). Depending on the cytokine milieu, naïve CD4+ T cells differentiate into Th1, Th2, Th17, Treg, etc. | |
NK T cells | Innate-like T lymphocytes that share surface markers and functional characteristics with conventional T cells and NK cells. | ||
B cells | B lymphocytes that express B cell receptors on their cell membrane that can bind to an antigen initiating the antibody production (humoral immunity). | ||
Non-immunocytes | Keratinocytes (KCs) | Epidermal cells responsible for the protective barrier function of the skin. Upon invasion of the upper layer of the epidermis, they produce proinflammatory signals (IL-1 family cytokines, AMPs, chemokines) which mediate their crosstalk with innate and adaptive immune cells. | |
Melanocytes | Epidermal cells that generate the autoantigen ADAMTS-like protein 5 (ADAMTSL5). | ||
Signaling molecules | Cytokines | Interleukins (IL) | Th1-type proinflammatory ILs: IL-2; Th2-type anti-inflammatory interleukins: IL-4, IL-5, IL-6, IL-9, IL-10, IL-13; Th17-type pro-inflammatory IL-17; IL-1-type pro-inflammatory IL-36; Th22-type pro-inflammatory IL-22; IL-12 family pro-inflammatory IL-23. |
Interferon (IFN)-α | Pro-inflammatory cytokine mainly produced by plasmacytoid dendritic cells (pDCs) during the early phases of psoriasis. | ||
Interferon (IFN)-γ | Th1-type proinflammatory cytokines; mainly produced by NK and NK T cells, CD4+ Th1 and Th17 cells, and CD8+ cytotoxic T cells. | ||
Tumor necrosis factor (TNF)-α | Proinflammatory cytokine produced by macrophages, monocytes, endothelial cells, neutrophils and activated lymphocytes. | ||
Tumor necrosis factor (TNF)-β | Proinflammatory cytokine mainly produced by KCs. | ||
Chemokines | CXCL9, CXCL10, CXCL11, CCL20, chemerin, etc. | Small cytokines which act as mediators of innate immune cells chemotaxis, may be produced by KCs and leukocytes. | |
Autoantigens | LL37 | Produced by KCs, it complexes with self-nucleic acids derived from damaged KCs and neutrophils, and acts as an autoantigen, activating pDCs via TLRs, and also being recognized by CD4+ and CD8+ T cells. | |
ADAMTSL5 | Produced by melanocytes and KCs, it is able to activate DCs and is recognized as an autoantigen by CD8+ T cells. |
Changes in Psoriatic Skin | ||
---|---|---|
Serotonin | 5-HT | Expression increased in epithelial and adnexal structures of psoriatic skin [127]. |
Expression increased in basal and suprabasal skin layers in psoriatic skin [128]. | ||
5-HT receptors | 5-HT1AR | Lower expression in psoriatic dermis [129]. |
5-HT2AR | Increased expression in psoriatic dermis [129]. | |
5-HT3R | Increased expression in the basal epidermis of noninvolved psoriatic skin [129]. | |
Increased expression in sensory nerve endings [68]. | ||
5-HT transporter | SERT | Increased expression in DCs and other inflammatory cells in the epidermis [6,40]. |
Increased expression in MCs and lymphocytes in the dermis [6,40]. |
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Martins, A.M.; Ascenso, A.; Ribeiro, H.M.; Marto, J. The Brain–Skin Connection and the Pathogenesis of Psoriasis: A Review with a Focus on the Serotonergic System. Cells 2020, 9, 796. https://doi.org/10.3390/cells9040796
Martins AM, Ascenso A, Ribeiro HM, Marto J. The Brain–Skin Connection and the Pathogenesis of Psoriasis: A Review with a Focus on the Serotonergic System. Cells. 2020; 9(4):796. https://doi.org/10.3390/cells9040796
Chicago/Turabian StyleMartins, Ana M., Andreia Ascenso, Helena M. Ribeiro, and Joana Marto. 2020. "The Brain–Skin Connection and the Pathogenesis of Psoriasis: A Review with a Focus on the Serotonergic System" Cells 9, no. 4: 796. https://doi.org/10.3390/cells9040796