*Article* **Differential Expression of Estrogen-Responsive Genes in Women with Psoriasis**

**Vladimir Sobolev 1, \* , Anna Soboleva 1,2 , Elena Denisova 1,3 , Malika Denieva 4 , Eugenia Dvoryankova 1 , Elkhan Suleymanov 5 , Olga V. Zhukova 3 , Nikolay Potekaev 3 , Irina Korsunskaya <sup>1</sup> and Alexandre Mezentsev 1**


**Abstract:** In women, the flow of psoriasis is influenced by each phase of a woman's life cycle.

**\*** Correspondence: vlsobolew@gmail.com

According to previous findings, significant changes in the levels of sex hormones affect the severity of the disease. **Aim**: The aim of this study was to identify the estrogen-responsive genes that could be responsible for the exacerbation of psoriasis in menopausal women. **Methods**: Skin samples of lesional skin donated by psoriasis patients (n = 5) were compared with skin samples of healthy volunteers (n = 5) using liquid chromatography–tandem mass spectrometry (LC–MS/MS). The set of differentially expressed proteins was subjected to protein ontology analysis to identify differentially expressed estrogen-responsive proteins. The expression of discovered proteins was validated by qPCR and ELISA on four groups of female participants. The first group included ten psoriasis patients without menopause; the second included eleven postmenopausal patients; the third included five healthy volunteers without menopause; and the fourth included six postmenopausal volunteers. Moreover, the participants' blood samples were used to assess the levels of estradiol, progesterone, and testosterone. **Results**: We found that the levels of estradiol and progesterone were significantly lower and the levels of testosterone were significantly higher in the blood of patients compared to the control. The protein ontology analysis of LC–MS/MS data identified six proteins, namely HMOX1, KRT19, LDHA, HSPD1, MAPK1, and CA2, differentially expressed in the lesional skin of female patients compared to male patients. ELISA and qPCR experiments confirmed differential expression of the named proteins and their mRNA. The genes encoding the named proteins were differentially expressed in patients compared to volunteers. However, *KRT19* and *LDHA* were not differentially expressed when we compared patients with and without menopause. All genes, except *MAPK1*, were differentially expressed in patients with menopause compared to the volunteers with menopause. *HMOX1*, *KRT19*, *HSPD1*, and *LDHA* were differentially expressed in patients without menopause compared to the volunteers without menopause. However, no significant changes were found when we compared healthy volunteers with and without menopause. **Conclusion**: Our experiments discovered a differential expression of six estrogen-controlled genes in the skin of female patients. Identification of these genes and assessment of the changes in their expression provide insight into the biological effects of estrogen in lesional skin. The results of proteomic analysis are available via ProteomeXchange with identifier PXD021673.

**Keywords:** psoriasis; proteome analysis; estrogen; menopause

**Citation:** Sobolev, V.; Soboleva, A.; Denisova, E.; Denieva, M.; Dvoryankova, E.; Suleymanov, E.; Zhukova, O.V.; Potekaev, N.; Korsunskaya, I.; Mezentsev, A. Differential Expression of Estrogen-Responsive Genes in Women with Psoriasis. *J. Pers. Med.* **2021**, *11*, 925. https://doi.org/ 10.3390/jpm11090925

Academic Editors: Mircea Tampa, Monica Neagu, Constantin Caruntu and Simona Roxana Georgescu

Received: 14 June 2021 Accepted: 14 September 2021 Published: 17 September 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

#### **1. Introduction**

Psoriasis is an immune-mediated disease that is driven by Th1 and Th17 cells [1]. The incidence of psoriasis is similar in men and women. The mean age at onset of psoriasis presentation ranges between 15 and 20 years of age and the second peak occurs at the ages of 55–60 [2]. It is well-documented that the endogenous factors such as hormonal changes may trigger psoriasis [3]. In women, the severity of psoriasis is influenced by each phase of a woman's life cycle and the disease frequency tends to peak during puberty, postpartum, and menopause. In contrast, the patients' condition often improves during pregnancy [4].

Although puberty is the period of life when the first signs of psoriasis often appear, there is a lack of evidence that female sex hormones trigger the disease. In fact, an increased production of estradiol (E2) and progesterone (PG) during the menstrual cycle has antiinflammatory effects [5]. Moreover, PG shifts the balance between Th<sup>1</sup> and Th<sup>2</sup> responses toward Th<sup>2</sup> [6]. In pregnancy, an increased production of estriol and PG often results in an improvement of symptoms in a majority of psoriasis patients.

However, psoriasis exacerbates in the first months of the postpartum period and the body surface area covered by psoriasis (BSA) significantly increases [7]. There is also a negative correlation between the levels of estrogen (ES) and BSA [4]. Moreover, prolactin (PRL) released by the pituitary gland of the brain stimulates immunity [8]. Respectively, patients with hyperprolactinemia present with many different clinical manifestations, including psoriasis [9]. In addition, there is a correlation of the PRL level and disease severity [9].

In perimenopause, the remaining aging follicles produce less inhibin and ES [10]. Since they are suppressed, the synthesis and secretion of the follicle-stimulating hormone (FSH) and luteinizing hormone (LH) gradually increase and a higher production of FSH stabilizes the level of ES. For this reason, ES can be slightly elevated for a limited period of time. Then, ES drops because there are less ES-producing cells in the ovary and they require more FSH to produce the same amount of ES. Consequently, the level of FSH continues to increase due to an existence of the negative feedback between the synthesis of ES and production of FSH [11], and it is often accompanied by an exacerbation of psoriasis [8].

Our own observations suggest that young women diagnosed with psoriasis have lower ES levels compared to healthy controls [12,13]. In this paper, we aim to identity the genes that could be targeted by ES in the lesional and uninvolved skin of female patients.

#### **2. Materials and Methods**

#### *2.1. Ethics Statement*

All samples were obtained with informed written consent from healthy volunteers and psoriasis patients in accordance with Declaration of Helsinki principles. All protocols were approved by an institutional review board (I.I. Mechnikov Institute of Vaccines and Sera, Moscow, Russia).
