Sodium Hydrogen Exchanger Regulatory Factor-1 (NHERF1) Regulates Fetal Membrane Inflammation.

Ananth Kumar Kammala,Ramkumar Menon,Talar Kechichian,Hariharan Subramanian,Samantha Sheller-Miller,Enkhtuya Radnaa

doi:10.3390/ijms21207747

Abstract

The fetal inflammatory response, a key contributor of infection-associated preterm birth (PTB), is mediated by nuclear factor kappa B (NF-kB) activation. Na+/H+ exchanger regulatory factor-1 (NHERF1) is an adapter protein that can regulate intracellular signal transduction and thus influence NF-kB activation. Accordingly, NHERF1 has been reported to enhance proinflammatory cytokine release and amplify inflammation in a NF-kB-dependent fashion in different cell types. The objective of this study was to examine the role of NHERF1 in regulating fetal membrane inflammation during PTB. We evaluated the levels of NHERF1 in human fetal membranes from term labor (TL), term not in labor (TNIL), and PTB and in a CD1 mouse model of PTB induced by lipopolysaccharide (LPS). Additionally, primary cultures of fetal membrane cells were treated with LPS, and NHERF1 expression and cytokine production were evaluated. Gene silencing methods using small interfering RNA targeting NHERF1 were used to determine the functional relevance of NHERF1 in primary cultures. NHERF1 expression was significantly (p < 0.001) higher in TL and PTB membranes compared to TNIL membranes, and this coincided with enhanced (p < 0.01) interleukin (IL)-6 and IL-8 expression levels. LPS-treated animals delivering PTB had increased levels of NHERF1, IL-6, and IL-8 compared to phosphate-buffered saline (PBS; control) animals. Silencing of NHERF1 expression resulted in a significant reduction in NF-kB activation and IL-6 and IL-8 production as well as increased IL-10 production. In conclusion, downregulation of NHERF1 increased anti-inflammatory IL-10, and reducing NHERF1 expression could be a potential therapeutic strategy to reduce the risk of infection/inflammation associated with PTB.

Highlights

Pregnancy is a state of immune homeostasis where balanced inflammation at various tissue levels promote fetoplacental growth [1,2,3]
Na+/H+ exchanger regulatory factor-1 (NHERF1) Levels Are Upregulated in Fetal Membranes of term labor (TL) and preterm birth (PTB)
NHERF1 localized in Amnion and chorion layers of fetal membranes, regardless of pregnancy status (Figure 1B); i.e., TL, term not in labor (TNIL) and PTB

Summary

Introduction

Pregnancy is a state of immune homeostasis where balanced inflammation at various tissue levels promote fetoplacental growth [1,2,3]. Increased inflammation and/or an imbalance in immune homeostasis in various intrauterine tissues are among the key mediators of parturition in humans as well as in animals. A multitude of signals from both the mother and fetus coordinate to generate inflammatory mediators. These mediators increase decidual inflammation, cause cervical ripening, and induce contractility of the myometrium on the maternal side as well as lead to a dysfunctional fetal membrane that functions to maintain uterine architecture during pregnancy [6]. Understanding the mechanisms that regulate acute changes in inflammatory mediators is critical to reduce the risk of spontaneous preterm birth (PTB) and preterm premature rupture of membranes (pPROM), two major complications of pregnancy and conditions associated with inflammation [3]

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Conclusion