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Molecular Pathogenesis of Psoriasis and Biomarkers Reflecting Disease

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Molecular Pathogenesis of Psoriasis and Biomarkers Reflecting Disease Journal of Clinical Medicine Review Molecular Pathogenesis of Psoriasis and Biomarkers Reflecting Disease Activity Masaru Honma 1,2,* and Hiroyoshi Nozaki 1 1 Department of Dermatology, Asahikawa Medical University Hospital, 2-1-1-1 Midorigaoka-Higashi, Asahikawa 0788510, Japan; [email protected] 2 International Medical Support Center, Asahikawa Medical University Hospital, 2-1-1-1 Midorigaoka-Higashi, Asahikawa 0788510, Japan * Correspondence: [email protected]; Tel.: +81-166-68-2523 Abstract: Psoriasis is a chronic inflammatory skin disease induced by multifactorial causes and is characterized by bothersome, scaly reddish plaques, especially on frequently chafed body parts, such as extensor sites of the extremities. The latest advances in molecular-targeted therapies using biologics or small-molecule inhibitors help to sufficiently treat even the most severe psoriatic symptoms and the extra cutaneous comorbidities of psoriatic arthritis. The excellent clinical effects of these therapies provide a deeper understanding of the impaired quality of life caused by this disease and the detailed molecular mechanism in which the interleukin (IL)-23/IL-17 axis plays an essential role. To establish standardized therapeutic strategies, biomarkers that define deep remission are indispensable. Several molecules, such as cytokines, chemokines, antimicrobial peptides, and proteinase inhibitors, have been recognized as potent biomarker candidates. In particular, blood protein markers that are repeatedly measurable can be extremely useful in daily clinical practice. Herein, we summarize the molecular mechanism of psoriasis, and we describe the functions and induction mechanisms of these biomarker candidates. Citation: Honma, M.; Nozaki, H. Molecular Pathogenesis of Psoriasis Keywords: inflammatory skin disease; Th17 cells; adipokines; glycoproteins; fatty acid-binding protein and Biomarkers Reflecting Disease Activity. J. Clin. Med. 2021, 10, 3199. https://doi.org/10.3390/jcm10153199 1. Introduction Academic Editors: Mayumi Komine Psoriasis is a recurrent, persistent inflammatory skin disorder characterized by rough, and Stamatis Gregoriou reddish plaques on frequently chafed body parts, such as the extensor sites of the extremi- ties [1,2]. Individuals with this condition suffer from subjective symptoms, such as itching Received: 12 June 2021 and pain, but also from skin lesions, especially on exposed areas, such as the scalp, face, Accepted: 19 July 2021 Published: 21 July 2021 hands, and nails, which can have a prominent impact on the patients’ quality of life [3–6]. In fact, it has been suggested that the manifestation of psoriasis-related symptoms can Publisher’s Note: MDPI stays neutral trigger stigmatization, leading to social discrimination and alienation [7–9]. Psoriasis with regard to jurisdictional claims in often coexists with varied comorbidities represented by psoriatic arthritis (PsA), uveitis, published maps and institutional affil- psychiatric disorders, metabolic disorders, and cardiovascular diseases [2,10–13]. Psoriasis iations. is therefore considered to be part of systemic disorders characterized by skin lesions. The process that amplifies localized psoriatic molecular reactions into a systemic inflammatory response is called “psoriatic march” [14]. While severe psoriatic symptoms are often resistant to conventional treatment, recent advances in molecular-targeted therapies have enabled sufficient treatment and control in Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. most cases. The clinical effects of these therapies allow for markedly reduced skin lesions, This article is an open access article related symptoms, and comorbidities but also a deep understanding of the molecular distributed under the terms and mechanism of psoriatic diseases in which the interleukin (IL)-23/IL-17 axis based on conditions of the Creative Commons Th17-cell-mediating cytokine network plays an essential role [11,15]. Attribution (CC BY) license (https:// Biomarkers are indicators of normal physiological processes, pathogenic reactions, creativecommons.org/licenses/by/ and responses to pathogen/treatment exposure or intervention, including therapeutic 4.0/). interventions [16]. Biomarkers can have molecular biology, histology, radiological images, J. Clin. Med. 2021, 10, 3199. https://doi.org/10.3390/jcm10153199 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, x FOR PEER REVIEW 2 of 18 Biomarkers are indicators of normal physiological processes, pathogenic reactions, and responses to pathogen/treatment exposure or intervention, including therapeutic in- terventions [16]. Biomarkers can have molecular biology, histology, radiological images, or other physiologic characteristics [16]. A reliable indicator that reflects sufficient remis- sion of disease activity is indispensable for establishing standardized therapeutic strate- J. Clin. Med. 2021, 10, 3199 gies. To date, several biomarker candidates have been proposed to reflect2 of improvement 19 in psoriasis during treatment. Consequently, this review describes the molecular patho- genesis of psoriasis and changes in biomarkers that occur along its disease activity, focus- ing onor blood-protein other physiologic markers characteristics that [16 can]. A be reliable repeatedly indicator thatmeasured reflects sufficient in daily remission clinical practice. of disease activity is indispensable for establishing standardized therapeutic strategies. To date, several biomarker candidates have been proposed to reflect improvement in psoriasis 2. Molecularduring treatment. Pathogenesis Consequently, of Psoriasis this review describes the molecular pathogenesis of Aspsoriasis shown and by changes the remarkable in biomarkers efficacy that occur of mo alonglecular-targeted its disease activity, therapies, focusing the on IL-23/IL-17 axis, whichblood-protein depends markers mainly that canon beTh17-cell repeatedly function, measured inis dailyconsidered clinical practice. the most essential mech- anism2. of Molecular psoriasis Pathogenesis (Figure 1) of Psoriasis[1,2,10,15,17]. Molecules regulated in the downstream of Th17 cytokinesAs shown are by identified the remarkable as biomarker efficacy of molecular-targetedcandidates (Table therapies, 1). In the the IL-23/IL-initial stage, a com- plex of17 antimicrobial axis, which depends peptides mainly (AMP), on Th17-cell such function, as LL-37, is considered and self-nuc the mostleotides essential derived from mechanism of psoriasis (Figure1)[ 1,2,10,15,17]. Molecules regulated in the downstream damagedof Th17 keratinocytes cytokines are identifiedvia toll-like as biomarker receptors candidates (TLRs), (Table potentiate1). In the the initial function stage, a of plasmacy- toid dendriticcomplex of cells antimicrobial (pDCs) to peptides produce (AMP), substantive such as LL-37, interferon and self-nucleotides (IFN)-α, which derived activates my- eloid (conventional)from damaged keratinocytes DCs [18–20]. via These toll-like activated receptors (TLRs),DCs release potentiate tumor the functionnecrosis of factor (TNF) and IL-23plasmacytoid that synergistically dendritic cells (pDCs)propel to the produce immune substantive response interferon process. (IFN)- TNFα, which stimulates DCs activates myeloid (conventional) DCs [18–20]. These activated DCs release tumor necrosis in an autocrinefactor (TNF) manner and IL-23 but that inhibits synergistically the function propel the of immune pDCs [1,2,10,15,17]. response process. A TNF paradoxical re- actionstimulates during treatment DCs in an autocrine using TNF manner inhibitors but inhibits can the depend function ofon pDCs pDC [1 activation,2,10,15,17]. Aby cancelling TNF-mediatedparadoxical inhibition reaction during [21]. treatment using TNF inhibitors can depend on pDC activation by cancelling TNF-mediated inhibition [21]. Figure 1. SummarizedFigure 1. Summarized molecular molecular mechanism mechanism of psoriasis of psoriasis.. IFN- IFN-ααreleased released from from activated activated pDCs stimulates pDCs stimulates myeloid DCs myeloid to DCs to produce TNFproduce and IL-23. TNF and TNF IL-23. activates TNF activates DCs DCs in an in anautocrine autocrine manner and and enhances enhances the inflammatory the inflammatory responses responses of various of various immunocytes.immunocytes. Naïve CD4-positive Naïve CD4-positive T cells T cellsdifferentiate differentiate into into Th17 cells cells in thein the presence presence of the transformingof the transforming growth factor growth factor (TGF)-β, IL-21, and IL-6. The pathogenicity of Th17 cells is potentiated by IL-23. IL-17 and IL-22 are produced by Th17 and (TGF)-β, IL-21, and IL-6. The pathogenicity of Th17 cells is potentiated by IL-23. IL-17 and IL-22 are produced by Th17 other cells with more innate characteristics (e.g., innate lymphoid cell (ILC)-3 and gamma delta T cells). IL-17 and Il-22 and other cellsinduce with epidermal more innate hyperproliferation. characteristics IL-17 and (e.g., TNF innate synergistically lymphoid accelerate cell (ILC)-3 the production and gamma of inflammatory delta T cytokines cells). IL-17 and Il- 22 induce epidermaland chemokines hyperproliferation. from the epidermal keratinocytes,IL-17 and TNF resulting synergis in a vicioustically circle accelerate of inflammatory the production reactions. of inflammatory cyto- kines and chemokines from the epidermal keratinocytes, resulting in a vicious circle of inflammatory reactions. J. Clin. Med. 2021, 10, 3199 3 of 19 Table 1. Summary of
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