An Emerging Role of Endometrial Inflammasome in Reproduction: New Therapeutic Approaches.

Abstract

One of the common complications of pregnancy is spontaneous pregnancy loss which occurs in an estimated 5- 15% of pregnancies. Of all women 1%-5% suffer from Recurrent Pregnancy Loss (RPL). Despite the fact that RPL has been associated to various anatomic, hormonal, immune, hematologic, and genetic defects, in 30% of the patients, screening tests included in the RPL workup may have negative results. Recently, we demonstrated a significant increased activation of endometrial NALP-3 inflammasome, and a caspase-1 dependent secretion of IL-18 and IL-1β in the endometrial tissues obtained from RPL women compared with a fertile women group. The inflammasome has emerged as a key player in innate immunity and inflammation. An abnormal inflammasome activation, in absence of detectable infectious causes, might be one of the molecular mechanisms involved in establishing an unreceptive endometrium, potentially leading to early fetal loss. Upon activation, this multiprotein complex makes possible the caspase- 1-mediated proteolytic processing of proinflammatory cytokines generating their respective mature secretory forms. The understanding of molecular modulation of inflammasome associated pathways is critical for drug design, development and delivery. To date many promising inhibitors of inflammasome complex activation have been described, such as MCC950, β-Hydroxybutyrate or Micro RNAs that affect NALP3 expression and activation. Furthermore, several herbal extracts and its bioactive constituents have shown to be effective in inflammatory response mediated by NLRP3 inflammasome activation. Nevertheless all these molecules represent a significant progress toward developing therapies that target IL-18 and IL-1β secretion in a variety of diseases.