O Speaker: Prof. Hee Young Cho

O Affiliation: Dept. of Obstetrics and Gynecology Seoul National University College of Medicine

O Date: Nov. 20, 2024

O Start Time: 4:00 PM

O Title: Preterm Labor and Macrophages: The Potential of Melatonin Treatment

O Abstract:

Preterm birth (PTB) is the parturition of a baby at earlier than 37 weeks of pregnancy in humans, resulting from aberrant early contraction of myometrium due to multifaceted causes. PTB causes the fetal inflammatory response syndrome including perinatal brain injury and prematurity of fetal lung. Current therapies mainly focus on controlling the myometrial contraction, but not much effective and safe. Thus, the development of new therapeutic options and understanding of the underlying molecular mechanism of PTB are prerequisites to ameliorate the fatality of PTB. Although macrophages are the second major population in the maternal-fetal interface (MFI), the roles of macrophages with a wide spectrum of polarity from M1 pro-inflammatory to M2 anti-inflammatory types on the PTB still remain unanswered. Recently, we reported that melatonin prevents not only PTB but also fetal injuries in brain and lung associated with PTB in mice. Thus, the aim of this study was to elucidate the underlying mechanism by which melatonin prevents PTB via modulating macrophage polarization at the MFI. Administration of melatonin considerably reduced the rates of PTB and fetal death, and the expression of acute-inflammatory cytokines in a mouse model of the PTB by an intrauterine injection of lipopolysaccharide (LPS). Moreover, the genes related M2 macrophage were significantly decreased in human patients with PTB. When clodronate liposome was directly given to the uterus of pregnant mice to pharmacologically deplete macrophages, the PTB spontaneously occurred without LPS. Melatonin significantly increased the M2 macrophage population, restoring the M1-biased population of macrophages in the uterus of preterm mice. Furthermore, melatonin significantly reduced secretion of LPS-induced cytokines that could cause muscle contraction. Consistently, melatonin pretreatment in macrophages significantly restored patterns of actin fibers in myometrial cells co-cultured with LPS-treated macrophages and the expression profiles of contraction related factors in the uterus of the preterm birth. Melatonin pretreatment significantly reduced the LPS-induced phosphorylation of p38 MAPK, p65 of NF-kB, and YAP1 (Y357), all of which are related to the M1 features, in macrophages in vitro. Moreover, melatonin pretreatment significantly increased the degradation of YAP1 via increasing the phosphorylation of YAP1 (S127). Interestingly, based on the lack of induction by Yap1-depleted macrophages, LPS failed to induce PTB in most macrophage-specific Yap1-knockout mice, maintaining the balance of M1/M2 ratio in the uterus after LPS injection. Collectively, the imbalanced polarization of macrophages in the uterus could be an underlying pathophysiologic cause of PTB and melatonin restores the imbalanced macrophage polarization, which prevents the myometrial contraction that leads to the PTB.

Using multiple genetic and molecular approaches, we demonstrated melatonin restores the M1-biased macrophage via p38-Yap1 signaling to prevent PTB in a murine model with intrauterine inflammation.

* The seminar will be held offline and online[https://kaist.zoom.us/j/88058197857] simultaneously.

* Closed Caption interpretation service (English) available online (service provided by Zoom)