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Serotonin 2A Receptor Attenuates Psoriatic Inflammation by Suppressing IL-23 Secretion in Monocyte-derived Langerhans cells (mouse)

ABSTRACT: Serotonin and its receptor are known to play a role in regulating immune cells. However, how they affect an autoimmune disease like psoriasis is not well-established and the mechanism remains to be elucidated. Here, we investigated the role played by serotonin 2A receptor (HTR2A) in regulating psoriasis. HTR2A antagonistic drug worsens psoriatic outcome and HTR2A modulation reduced psoriatic inflammation. Using Imiquimod-induced psoriasiform inflammation model, HTR2A-deficient mice experienced exacerbated inflammation. Hematopoietic cells, particularly monocyte-derived Langerhans cells, were responsible for this exacerbated inflammation. Mechanistically, the exacerbated inflammation is due to increased interleukin-23 (IL-23) secretion and HTR2A suppresses it by inhibiting the activation of non-canonical NFkB pathway. Platelet-derived serotonin is the putative agonist modulating HTR2A attenuating psoriatic inflammation. Lastly, our findings in mice were also reproduced clinically. Thus, our data demonstrate platelet serotonin putatively modulates HTR2A attenuating psoriatic inflammation by suppressing IL-23 secretion via inhibiting non-canonical NFkB pathway in monocyte-derived Langerhans cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE274941 | GEO | 2025/07/23

REPOSITORIES: GEO

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Serotonin 2A Receptor Attenuates Psoriatic Inflammation by Suppressing IL-23 Secretion in Monocyte-derived Langerhans cells

Project description:Serotonin and its receptor are known to play a role in regulating immune cells. However, how they affect an autoimmune disease like psoriasis is not well-established and the mechanism remains to be elucidated. Here, we investigated the role played by serotonin 2A receptor (HTR2A) in regulating psoriasis. HTR2A antagonistic drug worsens psoriatic outcome and HTR2A modulation reduced psoriatic inflammation. Using Imiquimod-induced psoriasiform inflammation model, HTR2A-deficient mice experienced exacerbated inflammation. Hematopoietic cells, particularly monocyte-derived Langerhans cells, were responsible for this exacerbated inflammation. Mechanistically, the exacerbated inflammation is due to increased interleukin-23 (IL-23) secretion and HTR2A suppresses it by inhibiting the activation of non-canonical NFkB pathway. Platelet-derived serotonin is the putative agonist modulating HTR2A attenuating psoriatic inflammation. Lastly, our findings in mice were also reproduced clinically. Thus, our data demonstrate platelet serotonin putatively modulates HTR2A attenuating psoriatic inflammation by suppressing IL-23 secretion via inhibiting non-canonical NFkB pathway in monocyte-derived Langerhans cells.

2025-07-23 | GSE274449 | GEO

Serotonin 2A Receptor Attenuates Psoriatic Inflammation by Suppressing IL-23 Secretion in Monocyte-derived Langerhans cells

Project description:Serotonin 2A Receptor Attenuates Psoriatic Inflammation by Suppressing IL-23 Secretion in Monocyte-derived Langerhans cells

| PRJNA1146441 | ENA

Serotonin 2A Receptor Attenuates Psoriatic Inflammation by Suppressing IL-23 Secretion in Monocyte-derived Langerhans cells (mouse)

Project description:Serotonin 2A Receptor Attenuates Psoriatic Inflammation by Suppressing IL-23 Secretion in Monocyte-derived Langerhans cells (mouse)

| PRJNA1148553 | ENA

Expression data from keratinocyte-specific Zfp36-deficient mouse skin treated with imiquimod

Project description:Tristetraprolin (TTP, encoded by Zfp36) regulates the mRNA stability of several important cytokines. Due to the critical role of this RNA-binding protein in the control of inflammation, TTP deficiency leads to the spontaneous development of a complex inflammatory syndrome. So far, this phenotype has been largely attributed to dysregulated production of TNF and IL-23 by myeloid cells such as macrophages or dendritic cells. Here, we generated mice with conditional deletion of TTP in keratinocytes. These mice developed exacerbated inflammation in the imiquimod-induced psoriasis model. Furthermore, these mice progressively developed a spontaneous pathology with systemic inflammation, psoriatic-like skin lesions and dactylitis. Finally, we provide evidence that keratinocyte-derived TNF productin drives the different pathological features. In summary, these findings expand current views on the initiation of psoriasis and related arthritis by revealing the keratinocyte-intrinsic role of TTP.

2017-06-14 | GSE90450 | GEO

Serotonin signals through a gut-liver axis to regulate hepatic steatosis

Project description:Purpose: While various functions of peripheral serotonin are known, the direct role of serotonin in regulating hepatic lipid metabolism in vivo is not well understood. We studied whether serotonin directly acts on liver to regulate lipid metabolism. Methods: Methods: 12 weeks aged liver-specific Htr2a KO (Albumin-Cre+/-; Htr2aflox/flox, herein named Htr2a LKO) mice and wildtype (WT) littermates were fed a high-fat diet (HFD, 60% fat calories) for 8 weeks. Results: Hepatic lipid droplet accumulation, NAFLD activity score, and hepatic triglyceride levels were dramatically reduced in HFD-fed Htr2a LKO mice compared to WT littermates. Conclusions: Gut-derived serotonin is a direct regulator of hepatic lipid metabolism via a gut TPH1-liver HTR2A endocrine axis. And shows promise as a novel drug target to ameliorate NAFLD with minimal systemic metabolic effects.

2018-11-27 | GSE120662 | GEO

Transcriptional regulatory networks of psoriasis

Project description:Psoriasis is a common inflammatory skin disease with complex etiology and chronic progression. To provide novel insights into the molecular mechanisms of regulation of the disease we performed RNA sequencing (RNA-Seq) analysis of fourteen pairs of skin samples collected from psoriatic patients with consequent pathway analysis and identification of the main transcriptional regulators of psoriasis-associated pathways. In order to identify the most important regulators of the disease, we combined the results obtained with MetaCore Interactome enrichment tool and cisExpress algorithm and compared them to regulatory psoriasis response elements found in literature. Comparative approach allowed us to identify 42 core transcriptional regulators of the disease associated with inflammation (NFkB, IRF9, JUN, FOS, SRF), activity of T-cells in the psoriatic lesions (STAT6, FOXP3, NFATC2, GATA3, TCF7, RUNX1, etc.), hyper-proliferation and migration of keratinocytes (JUN, FOS, NFIB, TFAP2A, TFAP2C), and with lipid metabolism (TFAP2, RARA, VDR). We also identified 66 transcription factors not previously associated with psoriasis. Using MetaCore pathway maps we illustrated and described the molecular basis of psoriatic skin lesions.

2017-09-14 | GSE78023 | GEO

Proliferating Langerhans cells dampen inflammation in established mouse psoriatic lesions

Project description:Psoriasis is a chronic inflammatory skin disease of unknown etiology. Although macrophages and dendritic cells (DCs) have been proposed to drive the psoriatic cascade, their largely overlapping phenotype hampered studying their respective role. Topical application of Imiquimod, a Toll-like receptor 7 agonist, induces psoriasis in patients and psoriasiform inflammation in mice. We showed that daily application of Imiquimod for 14 days recapitulated both the initiation and the maintenance phase of psoriasis. Based on our ability to discriminate Langerhans cells (LCs), conventional DCs, monocytes, monocyte-derived DCs and macrophages in the skin, we characterized their dynamics during both phases of psoriasis. During the initiation phase, neutrophils infiltrated the epidermis whereas monocytes and monocyte-derived DCs were predominant in the dermis. During the maintenance phase, LCs and macrophage numbers increased in the epidermis and dermis, respectively. LC expansion resulted from local proliferation, a conclusion supported by transcriptional analysis. Continuous depletion of LCs during the course of Imiquimod treatment aggravated chronic psoriatic symptoms as documented by an increased influx of neutrophils and a stronger inflammation. Therefore, by developing a mouse model that mimics the human disease more accurately, we established that LCs play a negative regulatory role during the maintenance phase of psoriasis.

2015-10-12 | GSE65309 | GEO

Spreading of inflammation: the skin-joint axis

Project description:The spread of inflammation from the skin to the joints is a key issue in the pathogenesis of psoriatic arthritis (PsA). Psoriasis (PsO), one of the most common skin diseases, usually precedes joint manifestations, suggesting skin-joint disease spread, which occurs in about 30% of psoriasis patients. Until now, it has been unclear why the inflammatory process remains restricted to the skin in some patients with PsO, whereas it spreads to tendons and joints in others. Using a preclinical model of PsA, we aimed to elucidate the skin-joint axis, i.e. the spread of psoriatic inflammation from the skin to the joints. KAEDE transgenic mice expressing a photo-convertible fluorescent reporter were used to assess cell trafficking from inflamed skin to other organs in the mouse model of IL-23 overexpression (IL-23OE) induced PsA. Psoriatic skin lesions were irradiated with UV light to induce the photoswitch from KAEDE-GREEN to KAEDE-RED. Migrating cells were characterised by scRNAseq.

2024-01-16 | GSE228629 | GEO

Group IVE Cytosolic Phospholipase A2 Limits Psoriatic Inflammation by Mobilizing the Anti-inflammatory Lipid N-Acylethanolamine

Project description:Psoriasis is an inflammatory disorder characterized by keratinocyte hyper-proliferation and Th17-type immune responses. However, the roles of bioactive lipids and the regulation of their biosynthesis in this chronic skin disease are not fully understood. Herein, we show that group IVE cytosolic phospholipase A2 (cPLA2epsilon/PLA2G4E) plays a counterregulatory role against psoriatic inflammation by producing the non-canonical anti-inflammatory lipid N-acylethanolamine (NAE). Lipidomics analysis of mouse skin revealed that NAE species and their precursors (N-acyl-phosphatidylethanolamine and glycerophospho-N-acylethanolamine) were robustly increased in parallel with the ongoing process of imiquimod (IMQ)-induced psoriasis, accompanied by a marked upregulation of cPLA2epsilon in epidermal keratinocytes. Genetic deletion of cPLA2epsilon/Pla2g4e exacerbated IMQ-induced ear swelling and psoriatic marker expression, with a dramatic reduction of NAE-related lipids in IMQ-treated, and even normal, skin. Stimulation of cultured human keratinocytes with psoriatic cytokines concomitantly increased PLA2G4E expression and NAE production, and supplementation with NAEs significantly attenuated the cytokine-induced upregulation of the psoriatic marker S100A9. Increased expression of cPLA2epsilon was also evident in the epidermis of psoriatic patients. These findings reveal for the first time the in vivo role of cPLA2epsilon, which is highly induced in the keratinocytes of the psoriatic skin, promotes the biosynthesis of NAE-related lipids, and contributes to limiting psoriatic inflammation.

2022-03-31 | GSE196431 | GEO

T cell-intrinsic prostaglandin E2-EP2/EP4 signaling is critical in pathogenic Th17 cell-driven inflammation

Project description:IL-23 induces ptgs2 encoding cyclooxygenase 2 in Th17 cells and produces PGE2, which acts back on PGE2 receptors EP2 and EP4 in these cells and enhances IL-23-induced expression of an IL-23 receptor subunit gene, Il23r, by activating STAT3, CREB1 and NF-κB through cAMP-protein kinase A signaling. This PGE2 signaling also induces expression of various inflammation-related genes, which possibly function in Th17 cell-mediated pathology. Combined deletion of EP2 and EP4 selectively in T cells suppressed accumulation of IL-17A+ and IL-17A+IFN-γ+ pathogenic Th17 cells and abolished skin inflammation in IL-23-induced psoriasis mouse model. Analysis of human psoriatic skin biopsies shows positive correlation between PGE2 signaling and the IL-23/Th17 pathway.

2021-02-23 | GSE167248 | GEO

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