Complement Activation Triggers Metalloproteinases Release Inducing Cervical Remodeling and Preterm Birth in Mice

Abstract

Inflammation is frequently linked to preterm delivery (PTD). Here, we tested the hypothesis that complement activation plays a role in cervical remodeling and PTD. We studied two mouse models of inflammation-induced PTD. The first model was induced by vaginal administration of lipopolysaccharide (LPS) and the second one by administration of progesterone antagonist RU486. Increased cervical C3 deposition and macrophages infiltration and increased serum C3adesArg and C5adesArg levels were observed in both models when compared to gestational age matched controls. A significant increase in collagen degradation, matrix metalloproteinase 9 (MMP-9) activity and tissue distensibility was observed in the cervix in both models. Mice deficient in complement receptor C5a did not show increased MMP-9 activity and cervical remodeling and did not deliver preterm in response to LPS or RU486, suggesting a role for C5aR in the cervical changes that precede PTD. In vitro studies show that macrophages release MMP-9 in response to C5a. Progesterone diminished the amount of C5aR on the macrophages surface, inhibited the release of MMP-9 and prevented PTD. In addition, macrophages depletion also prevented cervical remodeling and PTD in LPS-treated mice. Our studies show that C5a-C5aR interaction is required for MMP-9 release from macrophages, and the cervical remodeling that leads to PTD. Complement inhibition and supplementation with progesterone may be good therapeutic options to prevent this serious pregnancy complication. Premature birth/delivery (PTD) is one of the most significant causes of perinatal mortality and morbidity in developed countries. Preterm infants suffer morbidities including respiratory distress, intraventricular hemorrhage, and cerebral palsy, among other serious diseases.1 These outcomes can have a life-long impact and more than $25 billion is spent each year to take care of these infants. Investigations to define the causes of PTD remain a challenge in the obstetrical field. Preterm labor is a multistage biochemical and biophysical process, during which changes in the myometrium and the cervix occur.The uterine cervix is a complex organ that undergoes extensive changes through gestation and parturition. These changes are a common first step in preterm parturition.2 As a gatekeeper for pregnancy, the cervix is a structural barrier that keeps the fetus inside the uterus until the end of gestation. Collagens, elastin, proteoglycans, and hyaluronate are responsible for the full tensile strength of the cervix.2 Ripening of the cervix is an important biological and clinical event required for a normal parturition. The process is gradual during pregnancy, with a fast final remodeling of the cervix before parturition. Increased collagen degradation and synthesis, and high activity of collagenases have been observed in the human cervix during final ripening.

Prevention of preterm birth: Harnessing science to address the global epidemic

“…Similar signaling cascades may be activated by noninfectious inflammation, triggered by damage-associated molecular patterns (DAMPs), which activate signals such as the receptor for advanced glycation end products (RAGE) and resulting in the production of parturition-triggering cytokines (49). Inflammatory mediators also activate complement, which contributes to cervical remodeling and PTB (50). These diverse pathways converge on a set of well-established labor-inducing inflammatory mediators, such as prostaglandins.…”

Protein Microarrays and Midtrimester Amniotic Fluids: A Novel Approach for the Diagnosis of Early Intrauterine Inflammation Related to Preterm Delivery

“…membranes, lead to a decreased tensile strength ofthe chorioamniotic membrane, suggesting a correlation between increased levels of these molecules and the risk of PPROM and PTD (10)(11)(12). The detection of intrauterine inflammation as early PTD risk factor is based not only on the search of relevant AF markers, but also on the choice of the most appropriate diagnostic tool.…”

Future directions of clinical laboratory evaluation of pregnancy

“…83 Depletion of macrophages prevented cervical remodeling and preterm delivery in lipopolysaccharide-treated mice. 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…”