The Brain-Skin Connection and the Pathogenesis of Psoriasis: A Review with a Focus on the Serotonergic System

Abstract

Psoriasis is a common non-communicable chronic immune-mediated skin disease, affecting approximately 125 million people in the world. Its pathogenesis results from a combination of genetic and environmental factors. The pathogenesis of psoriasis seems to be driven by the interaction between innate immune cells, adaptive immune cells and keratinocytes, in a process mediated by cytokines (including interleukins (IL)-6, IL-17 and IL-22, interferon and tumor necrosis factor) and other signaling molecules. This leads to an inflammatory process with increased proliferation of epidermal cells, neo-angiogenesis and infiltration of dendritic cells in the skin. Dysfunctional de novo glucocorticoid synthesis in psoriatic keratinocytes and the skin microbiome have also been suggested as mediators in the pathogenesis of this disease. To understand psoriasis, it is essential to comprehend the processes underlying the skin immunity and neuroendocrinology. This review paper focuses on the skin as a neuroendocrine organ and summarizes what is known about the skin immune system, the brain-skin connection and the role played by the serotonergic system in skin. Subsequently, the alterations of neuroimmune processes and of the serotonergic system in psoriatic skin are discussed, as well as, briefly, the genetic basis of psoriasis.

Keywords: skin, psoriasis, auto-immunity, inflammation, keratinocytes, cytokines, serotonin..

Figure 1

Location of key cells of the innate and adaptive immune systems in the skin. The figure shows the main participants in the innate immune system (IIS) and adaptive immune system (AIS) in the epidermis and dermis. The cells of the IIS have pattern recognition receptors (PPRs) on their surface. Once these are activated, the cells shown in orange (LCs, Langerhans cells, and dDCs, dermal dendritic cells) acquire potent antigen-presenting capacities (APCs) and produce proinflammatory cytokines. The activated orange cells also drive the differentiation of T cells into Treg, Th1, Th2 and Th17 which are part of the AIS [16,25]. Additionally, the APCs also control the influx of neutrophils through the production of TNF and with the help of mast cells (MCs) [25]. Keratinocytes and melanocytes produce autoantigens that are involved in the activation of IIS cells and subsequent differentiation of T cells. Keratinocytes are particularly important in skin immunity, interacting with cells of the IIS and AIS.

Figure 2

Differentiation of naïve T cells induced by cytokines produced by dendritic cells of the innate immune system.

Figure 3

Serotonin, serotonin transporter (SERT) and serotonin receptors (5-HTRs) in human skin immunocytes and non-immunocytes. The cell activation state and environment influence the effects of 5-hydroxytryptamine (5-HT) by changing the receptor and transporter expression. The figure shows all the membrane proteins that may be present at any given time. Double arrows represent the production of 5-HT by the cells and the effect of 5-HT on the same cells; single arrows initiating in cells represent the production of 5-HT by these cells, while arrows initiating in 5-HT represent the direct or indirect effects of 5-HT on these cells. LCs, Langerhans cells; dDCs, dermal dendritic cells; MCs, mast cells.

Figure 4

The inflammation loop at the core of psoriasis pathogenesis. The pathogenesis of psoriasis involves an interplay between innate immune cells (pDCs, mDCs, neutrophils, etc.), skin cells (keratinocytes, melanocytes, etc.) and adaptive immune cells (CD4+ and CD8+ T cells, Th1, Th17, Th22, Treg, etc.). The crosstalk between these cells is mediated by molecules such as antimicrobial peptides LL37 and ADAMTSL5, produced by keratinocytes and/or melanocytes, which act like autoantigens. Additionally, several cytokines, shown in red, and chemokines are fundamental in the process. DCs, dendritic cells; pDCs, plasmacytoid dendritic cells; mDCs, myeloid dendritic cells; IL, interleukin; TNF, tumor necrosis factor; IFN, interferon; TGF, transforming growth factor.