¹Zentrum für Personalisierte Medizin (ZPMi) Ulm, Ulm
²Universitätsklinik für Dermatologie & Allergologie Ulm, Ulm

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Introduction: Generalized pustular psoriasis (GPP) is characterized by a dominant autoinflammatory component next to activation of the typical psoriatic IL-23/IL-17 cascade. GPP is an orphan disease with recurrent potentially life-threatening flares. According to psoriasis it is linked to several comorbidities like metabolic and cardiovascular diseases or depressive disorders.

The objective of our study was to further decode immunological pathways in GPP as the maximal variant of pustular psoriasis in comparison to localized palmoplantar pustular psoriasis (PPP).

Methods: Focusing on transcriptomic differences in GPP versus PPP, bulk RNA sequencing of affected and healthy skin of 3 GPP and 3 PPP patients was performed, and results between entities compared.

Results: As a striking incidental finding a marked up-regulation of kynurenine (KYNU) and TDO2 (tryptophan 2,3-dioxygenase 2) was detected in GPP affected skin.

Interestingly, in localized PPP KYNU and IDO1 (indoleamine 2,3-dioxygenase 1) were overexpressed in unaffected skin.

Conclusion: The essential amino acid tryptophan is either metabolized in the KYNU pathway (catabolized by IDO and TDO) or serotonin pathway.

The KYNU pathway is known to play a major role in T cell modulation. KYNU is e.g. involved in immune tolerance in gravidity and T cell apoptosis. Its metabolite quinolinic acid (QA) has direct pro-depressive neurotoxic effects and competes with glutamate which is crucial in the development of anxiety.

Serotonin and its metabolite melatonin are important mood and sleep regulators. If KYNU is overexpressed due to the need of immunomodulation in acute disease or chronic inflammatory diseases (CID) a relative tryptophan lack towards serotonin pathway will result.

Up-regulations of KYNU, IDO and TDO have already been found in periodontitis, hidradenitis suppurativa, inflammatory bowel diseases and COVID-19 infections. In the latter it led to a significant increase of suicidal behavior.

Recently, markers of tryptophan catabolism were suggested as potential severity markers for diverse CID.

Our findings close another gap between neuroimmunological animal models and clinical presentation of patients with CID. Sleeping disorders, depression and anxiety in CID seem to be caused to a significant degree by biochemical disturbances and require a consequent anti-inflammatory therapy.

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