Avaliação da modulação hormonal na expressão de microRNAs em macrófagos inoculados com Staphylococcus aureus

Abstract

Introduction: MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally, playing an essential role in various biological processes, including immune system development and function. On the other hand, the steroid hormones 5α-dihydrotestosterone (DHT) and 17β-estradiol (E2) modulate the immune system by interacting with their nuclear receptors, influencing the sexual dimorphism of immune responses. Staphylococcus aureus (S. aureus) is an opportunistic bacterium present in the human microbiota that can cause severe infections such as bacteremia, pneumonia, and septicemia. Understanding how sex hormones affect immune responses via miRNAs may contribute to the development of more effective therapeutic approaches. However, current literature lacks integrative studies that clarify how these hormones influence miRNA expression during immune responses to pathogens such as S. aureus. Objective: To investigate the effects of hormonal modulation by DHT and E2 on the expression of microRNAs in human macrophages inoculated with Staphylococcus aureus. Methods: Macrophages were differentiated from PBMCs isolated from three male and three female volunteers. The cells were inoculated with S. aureus for 24 hours and treated with E2 or DHT for the same period. Cytokine quantification (TNF-α, IL-10, IL-6, and IL-1β) was performed using ELISA, while miRNA expression was analyzed by qPCR. Results: Treatment with E2 and DHT significantly reduced TNF-α and IL-1β production in both sexes. 15 out of the 16 microRNAs analyzed in this study showed differential expression patterns between the experimental groups of males and females, with particular emphasis on miR-29b, whose expression may be modulated by progesterone in this context. The heatmap identified six differentially expressed microRNAs in response to infection and hormonal modulation (miR-15, -107, -21, -128, -24, -147b, and -92a), including molecules that are still understudied in infectious or hormonal contexts, such as miR-107 and miR-128. Furthermore, correlations between microRNA expression and cytokine production varied significantly between sexes and across experimental conditions, reflecting the complexity of the interaction between sex hormones and miRNA-mediated immune regulation. Conclusion: This study contributes to the understanding of the relationship between sex hormones, microRNAs, and the immune response during S. aureus infection, providing novel evidence of the modulation of inflammatory microRNAs by E2 and DHT in human macrophages. The data highlight the impact of sexual dimorphism in regulating the inflammatory response and reinforce the potential of miRNAs as biomarkers or therapeutic targets. Expanding this knowledge may drive advances in personalized medicine by enabling the development of more effective therapeutic strategies for bacterial infections and inflammatory diseases.