miRNA-186-5p modulates placental inflammation via Inflammasome activation in gestational diabetes mellitus

Abstract

Inflammasomes are multiprotein complexes that initiate inflammatory responses by activating pro-inflammatory cytokines, playing a crucial role in innate immunity. However, their dysregulation can lead to excessive inflammation, particularly in conditions like gestational diabetes mellitus (GDM), where placental inflammation may adversely affect fetal development and increase the risk of complications. NEK7 (NIMA-related kinase 7) has been identified as a key mediator in inflammasome activation, facilitating the complex assembly and amplifying inflammatory responses. This study aims to investigate the regulatory role of miRNA in inflammasome-mediated placental inflammation through its interaction with NEK7 in the pathophysiology of GDM. In-silico analysis identified that NEK7 is a direct target of miR-186-5p, while PCR analysis demonstrated a significant loss of miR-186-5p expression in GDM placental tissues. Further, the expressions of NEK7, NLRP1, NLRP3, Caspase 1 along with the inflammatory cytokines were significantly elevated in GDM placenta. Furthermore, the correlation analysis demonstrated a significant negative correlation between miR-186-5p and NEK7 expression levels, suggesting that the loss of miR-186-5p may contribute to inflammasome mediated placental inflammation in GDM. Additionally, the overexpression of miR-186-5p decreased the high glucose induced inflammation and the expressions of NEK7, NLRP1 and NLRP3 in BeWo cell line. Therefore, this study concludes that miR-186-5p may attenuate the activation of inflammasome and regulate inflammation via NEK7 in the progression of GDM. Understanding these molecular mechanisms offers valuable insights into potential therapeutic targets aimed at improving pregnancy outcomes in GDM.