Neurokinin 3 Receptor and Phosphocholine Transferase

Abstract

C-reactive protein (CRP), an innate immune mediator, is elevated in the circulation prior to symptoms in patients with preeclampsia (PE), a severe hypertensive pregnancy disorder with high mortality and morbidity. However, the specific sources underlying increased CRP and the role of elevated CRP in PE are undefined. Here, we report that circulating CRP levels are significantly increased in a large cohort of normotensive pregnant individuals compared to nulligravid women and is further increased in PE patients. These findings led us to further discover that placental syncytiotrophoblasts are previously unrecognized cellular sources of CRP and underlie elevated CRP in normotensive pregnant women and the additional increase in PE patients. Next, we demonstrated that injection of CRP induces PE features including hypertension (157.08 mmHg CRP treated vs. 118.99 mmHg control), proteinuria (35.0 mg/μg CRP treated vs. 14.1 mg/μg control), kidney and placental damage and increased levels of sFlt-1 in pregnant mice but not nonpregnant mice. We hypothesize that phosphocholine transferase, a placental specific enzyme posttranslationally modifying neurokinin B (NKB), is essential for the pathogenic role of CRP in PE through activation of the neurokinin 3 receptor. Overall, our studies have provided significant new insight regarding the pathogenic role of CRP in PE and highlighted innovative therapeutic strategies.

C-Reactive Protein and Its Role in Preeclampsia

“…Regularly produced in the liver, CRP has also been found in amniotic fluid. This suggested local production sites, which were specified in the current study by Parchim et al 2 As is binds to surface phosphocholine, it activates the complement system.…”

Pathogenesis of Preeclampsia and Therapeutic Approaches Targeting the Placenta

“…The level of CRP, an acute innate immune mediator, is increased in the circulation before the onset of symptoms of PE. CRP production is mainly stimulated by the cytokines IL-6, IL-8, and TNF-α, but the increased levels in PE might be caused by neurokinin B-induced activation of the neurokinin 3 receptor [ 119 ]. The placenta-specific enzyme phosphocholine transferase makes a posttranslational modification of neurokinin B, which ultimately induces the increase in expression of CRP in preeclamptic women.…”

Unactivated leukocyte expression of C-reactive protein is minimal and not dependent on rs1205 genotype

“…Multiple CRP genetic variants are www.nature.com/scientificreports/ associated with these pathologic conditions, implying an in-born propensity. However, the evidence supporting a direct role of CRP as a primary causal agent, rather than acting in a contributory or modifying manner, remains controversial 11,26,27 . There is also countervailing evidence from Mendelian randomization studies, indicating no causal effects of increased serum CRP [28][29][30] .…”

“…Previously we demonstrated an association between rs1205 in the 3′ untranslated region of CRP and severe pre-eclampsia in an American Indian cohort 3 ; and subsequently provided additional evidence for this association and 2 other single nucleotide polymorphisms (SNPs) related to the CRP gene 4 , as have others 5 . While the primary source of circulating CRP appears to be the liver 6 , other tissues, including endothelium 7 , macrophages 8 , kidney 9 , brain 10 , and placenta 11 are also thought to secrete CRP, although often under various stimulating conditions. Evidence for leukocyte expression of CRP has been contentious due to difficulties with non-specific antibody detection 12,13 , differing real-time quantitative polymerase chain reaction (RT-qPCR) protocols, as well as characteristics of the CRP gene that complicate primer design for RT-qPCR.…”