EXPRESSION OF FOXO1, FOXO3 AND BECN1 GENES IN PERIPHERAL BLOOD LEUKOCYTES IN CHRONIC COURSE OF PULMONARY SARCOIDOSIS

Abstract

Among the FOXO (Forkhead box O) family proteins, which are the most studied and widely represented in various human organs and tissues, transcription factors FOXO1 and FOXO3 are of special importance. Numerous studies evidence about their crucial role in maintaining cell metabolism and homeostasis, as well as in the pathogenesis of various pathological conditions. The involvement of the FOXO-signaling pathway in the pathogenesis of pulmonary sarcoidosis is also confirmed by RNA sequencing data. FOXO activation is related to the regulation of autophagy processes, the disruption of which is noted in pulmonary sarcoidosis, a systemic immunoinflammatory disease of unknown etiology, characterized by the formation of epithelioid cell granulomas in various organs, primarily in the lungs. The study was aimed at investigating expression of FOXO1, FOXO3 and BECLN1 genes in peripheral blood leukocytes from patients with chronic pulmonary sarcoidosis compared with apparently healthy donors (control). It is shown that the expression of transcription factors FOXO1 and FOXO3 genes is significantly higher in peripheral blood leukocytes (PBL) from patients with pulmonary sarcoidosis stage II, with chronic course (stabilization of the condition), in the absence of therapy compared to the control (p<0,01 and p<0,001).  The PBL BECN1 gene mRNA level from patients with chronic pulmonary sarcoidosis is also higher compared to control group. Correlation analysis revealed a close positive relation between the expression of FOXO1, FOXO3 and BECN1 genes, with Spearman rank correlation coefficients comprising 0.69 (FOXO1/BECN1) and 0.61 (FOXO3/BECN1) (p=0.0002 and p=0.0016, respectively). Thus, in stage II pulmonary sarcoidosis patients without therapy, FOXO1/3 activation is likely associated with upregulated BECN1 gene expression encoding the autophagy protein BECLIN1 (ATG6). Numerous molecular genetic markers that contribute to the risk of pulmonary sarcoidosis have been identified. Studying the underlying molecular mechanisms is essential to better understand the disease pathogenesis not only allowing to gain insight into the clinical symptomatology but also to predict the disease outcome. In addition, increased knowledge on pathogenesis contributes to developing more targeted, effective and safe treatment methods for pulmonary sarcoidosis, taking into account individual characteristics of each patient's health status.