Regulation of Apoptosis and Innate Immune Stimuli in Inflammation-Induced Preterm Labor

Abstract

An innate immune response is required for successful implantation and placentation. This is regulated in part by a2 isoform of V-ATPase (a2V) and the concurrent infiltration of M1 (inflammatory) and M2 (anti-inflammatory) macrophages to the uterus and placenta. The objective of present study was to identify the role of a2V during inflammation-induced preterm labor in mice and its relationship to the regulation of apoptosis and innate immune responses. Using a mouse model of infection-induced preterm delivery, gestational tissues were collected 8 hrs after intrauterine inoculation on day 14.5 of pregnancy with either saline or peptidoglycan (PGN, a toll-like receptor (TLR) 2 agonist) and polyinosinic:cytidylic acid (poly(I:C), a TLR3 agonist), modeling Gram positive bacterial and viral infections, respectively. Expression of a2V decreased significantly in the placenta, uterus, and fetal membranes during PGN+poly(I:C) induced preterm labor. Expression of iNOS was significantly upregulated in PGN+poly(I:C) treated placenta and uterus. PGN+poly(I:C) treatment disturbed adherens junction proteins and increased apoptotic cell death via extrinsic pathway of apoptosis among uterine decidual cells and spongiotrophoblast. F4/80+ macrophages were increased and polarization was skewed in PGN+poly(I:C) treated uterus toward double positive CD11c+ (M1) and CD206+ (M2) cells, which are critical for the clearance of dying cells and rapid resolution of inflammation. Expression of Nlrp3 and activation of caspase-1 was increased in PGN+poly(I:C) treated uterus which could induce pyroptosis. These results suggest that double hit of PGN+poly(I:C) induces preterm labor via reduction of a2V expression and simultaneous activation of apoptosis and inflammatory processes.

Future directions of clinical laboratory evaluation of pregnancy

“…84 Our study of macrophage phenotypes showed that during preterm labor induced by double hit of PGN1poly(I : C), increased the number of macrophages (F4/ 801) that were double-positive for CD11c and CD206. 26 Wentworth et al 85 has demonstrated these double positive CD11c…”

“…We focused on one of the crucial enzyme which, in part, regulates innate response is Vacuolar ATPase (V-ATPase). 26 V-ATPase is a multisubunit enzyme which is responsible for regulating the acidic environment of intracellular organelles and the extracellular environment via ATP hydrolysis. Its expression in round spermatids was first demonstrated by Wada and colleagues.…”

“…71 We and others have demonstrated that the combined activation of Toll-like receptor 2 (TLR2) and TLR3 using peptidoglycan (PGN) and polyinosinic : cytidylic acid (poly(I : C)) yields a dramatic synergy in the labor response and expression of inflammatory mediators in gestational tissues. 26,[71][72][73][74] Such combined stimulation might occur in nature in at least four scenarios: (i) engagement of TLR4; (ii) activation of both TLR3 and another TLR simultaneously by a single organism (e.g., murine cytomegalovirus, herpes simplex virus and Schistosoma mansoni; 75,76 (iii) superinfection, in which a host is infected simultaneously by more than one microorganism, such as a virus and a bacterium; 77 and (iv) activation of TLRs by one of several known, endogenously produced TLR ligands together with an exogenous pathogen. 78,79 PRETERM LABOR AND PYROPTOSIS Caspase-1 plays a central role in various inflammatory diseases as a protease that activates the pro-inflammatory cytokines proIL-1beta and proIL-18.…”

“…80 We have recently shown that a 'double hit' of PGN1poly(I : C) induces expression of NLRP3 (NACHT, LRR and PYD domains-containing protein 3)and activation of caspase-1 which could induce pyroptosis and simultaneously the activation of apoptosis and inflammatory processes, which leads to preterm labor (Figure 1). 26 It might possible that this simultaneous activation of apoptosis and inflammatory is linked with reduction of a2 isoform of VATPase. We have also demonstrated that reproductive tissue had increased apoptotic death via extrinsic pathway of apoptosis (Figure 1).…”

“…We have also demonstrated that reproductive tissue had increased apoptotic death via extrinsic pathway of apoptosis (Figure 1). 26 Others have shown increased apoptotic cell death at the fetomaternal interphase during preterm labor. levels of the a2 isoform of vacuolar ATPase can result in preterm labor and could be biomarkers.…”