Depletion of polymorphonuclear leukocytes has no effect on preterm delivery in a mouse model of Escherichia coli-induced labor

Abstract

Objective To investigate the role of polymorphonuclear leukocytes (PMNs) in a mouse model of E. coli-induced labor. Study Design Intraperitoneal injection of rabbit anti-mouse PMN antiserum or control was performed in CD-1 mice 29 hours and 5 hours prior to laparotomy and intrauterine injection of either killed E. coli or phosphate buffered saline on Day 14.5 of pregnancy. Preterm delivery was defined as delivery of at least one pup within 48 hours. Circulating leukocyte counts were determined manually or by flow cytometry at the time of surgery and 8, 24 and 48 hours afterwards. Maternal and fetal tissues were analyzed in a separate group of animals 8 hours after surgery. Results Pre-treatment with anti-PMN antiserum significantly decreased the numbers of circulating leukocytes and the proportion of neutrophils among all leukocytes by 70–80% at surgery and at least 8 hours thereafter. Neutrophil depletion significantly reduced two markers of neutrophil activation in uterus and placenta (neutrophil elastase and myeloperoxidase activity) and neutrophil infiltration into gestational tissues in bacterially treated animals to baseline (control) levels, but did not affect preterm birth rates. The large E. coli-induced increases in uterine inflammatory markers (interleukin 1β, tumor necrosis factor, CCL5, cyclooxygenase 2) were not affected or were only minimally affected by neutrophil depletion. Conclusions Although PMN antiserum reduces both neutrophil number and activity, it does not diminish sensitivity to bacterially induced delivery or meaningfully alter the expression of inflammatory markers in the mouse model. Preterm birth and inflammation in this model are not likely to depend on neutrophil function.

TNF-Signaling Modulates Neutrophil-Mediated Immunity at the Feto-Maternal Interface During LPS-Induced Intrauterine Inflammation

“…According to a multi-center biomarker study of IUI, when compared to human data, the IL-6 levels in the AF in our study would be categorized as "severe inflammation" (28). Contrary to our data, studies in mice did not show a benefit to neutrophil depletion in protecting against LPS induced PTL (29,30). However, these mice had increased systemic concentrations of myeloid hematopoietic progenitors and myelopoietic cytokines G-CSF, IL-23, and IL-17 (31), presumably due to a "neurostat" mechanism sensing neutrophil depletion.…”

Immunobiology of Acute Chorioamnionitis

“…Neutrophilderived pro-inflammatory mediators can trigger preterm labor and matrix metalloproteinases (MMPs) can weaken the collagen scaffolding, resulting in preterm rupture of membranes (156)(157)(158). However, studies in mice with systemic neutrophil depletion did not protect against inflammation-induced preterm birth (159,160). Although the reasons for the apparent contradiction are not clear, neutrophil depletion in mice causes a systemic up-regulation of G-CSF, IL-17, and IL-23, leading to hyper-cellular bone marrow as a homeostatic "neutrostat" mechanism to restore the blood neutrophil pool (161,162).…”

Distinct Roles of Cervical Epithelia and Stroma in Pregnancy and Parturition

“…However, two independent studies have demonstrated that depletion of neutrophils in mice treated with LPS did not prevent PTB, suggesting that infection-induced PTB does not require neutrophil infiltration. 78,79 Ongoing studies to understand the role of immune cells and inflammation in term and preterm cervical remodeling may provide insight into the distinct mechanisms that drive the prostaglandin-dependent and prostaglandin-independent pathways of cervical remodeling.…”