Markers of psoriatic skin phenotype: androgen/estrogen and cortisone/cortisol imbalance, and DNA damage

Patients prone to psoriasis suffer after a breakdown of the epidermal barrier and develop poorly healing lesions with abnormal proliferation of keratinocytes. Strong inflammatory reactions with genotoxicity (short telomeres) suggest impaired immune defences with DNA damage repair response (DDR) in patients with psoriasis. Recent evidence indicates the existence of crosstalk mechanisms linking the DDR machinery and hormonal signalling pathways that cooperate to influence both progressions of many diseases and responses to treatment. The aim of this study was to clarify whether steroid biosynthesis and genomic stability markers are altered in parallel during the formation of psoriatic skin. Understanding between the interaction of the steroid pathway and DNA damage response is crucial to addressing underlying fundamental issues and managing resulting epidermal barrier disruption in psoriasis. Twenty patients with psoriasis and fifteen healthy volunteers were included in this study. Transcription levels of estrogen ( ESR1, ESR2 ), androgen ( AR ), glucocorticoid/mineralocorticoid receptors ( NR3C1, NR3C2 ), HSD11B1/HSD11B2 genes, and DNA damage sensors ( SMC1A, TREX1, TREX2, SSBP3, RAD1, RAD18, EXO1, POLH, HUS1 ) were determined by Real-Time-PCR in blood and skin samples (Lesional, non-lesional) from psoriasis and control groups. Results We found that ESR1, ESR2, HSD11B1, NR3C1, NR3C2, POLH , and SMC1A transcripts were significantly decreased and AR, TREX1, RAD1 , and SSBP3 transcripts were increased dramatically in the lesional skin compared to skin samples of controls. As a result, we found that the regulation of the steroidogenic pathway was disrupted in the lesional tissue of psoriasis patients and that a sufficient glucocorticoid and mineralocorticoid response did not form and the estrogen/androgen balance was altered in favour of androgens. We suggest that an increased androgen response in the presence of DDR increases the risk of developing psoriasis. Although this situation may be the cause or the consequence of a disruption of the epidermal barrier, our data suggest developing new therapeutic strategies. ### Competing Interest Statement The authors have declared that no competing interests exist. ### Funding Statement Supported by the Erciyes University Research Projects Unit. Grant owner: Murat Borlu, Project no: TCD-2019-9240 ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the Human Ethics Committee of the Erciyes University on 20/02/2019, with the decision number 2019/121 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All relevant data are within the manuscript and its Supporting Information files.