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Anecdotal evidence has suggested an association between psychiatric drug use and improved psoriatic outcomes, however, consensus is absent due to conflicting reports and the mechanism remains poorly defined. Here, we investigated the role played by serotonin 2A receptor (HTR2A), which is commonly targeted by psychiatric drugs, in regulating psoriasis. HTR2A antagonistic drugs worsened psoriatic outcome and HTR2A modulation reduced psoriatic inflammation. Using Imiquimod-induced psoriasiform model, HTR2A-deficient mice experienced exacerbated inflammation. Hematopoietic cells, particularly monocyte-derived Langerhans cells (moLC), were responsible for this phenotype. 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 validated clinically. Our data demonstrate platelet serotonin putatively modulates HTR2A, attenuating psoriatic inflammation by suppressing IL-23 secretion via inhibiting non-canonical NFkB pathway in moLCs.

Taiwan International Graduate Program in Molecular Medicine,
National Yang-Ming University and Academia Sinica
Doctoral Dissertation