Placental CX3CL1 is Deregulated by Angiotensin II and Contributes to a Pro-Inflammatory Trophoblast-Monocyte Interaction

Abstract

CX3CL1, which is a chemokine involved in many aspects of human pregnancy, is a membrane-bound chemokine shed into circulation as a soluble isoform. Placental CX3CL1 is induced by inflammatory cytokines and is upregulated in severe early-onset preeclampsia. In this study, the hypothesis was addressed whether angiotensin II can deregulate placental CX3CL1 expression, and whether CX3CL1 can promote a pro-inflammatory status of monocytes. qPCR analysis of human placenta samples (n = 45) showed stable expression of CX3CL1 and the angiotensin II receptor AGTR1 throughout the first trimester, but did not show a correlation between both or any influence of maternal age, BMI, and gestational age. Angiotensin II incubation of placental explants transiently deregulated CX3CL1 expression, while the angiotensin II receptor antagonist candesartan reversed this effect. Overexpression of recombinant human CX3CL1 in SGHPL-4 trophoblasts increased adhesion of THP-1 monocytes and significantly increased IL8, CCL19, and CCL13 in co-cultures with human primary monocytes. Incubation of primary monocytes with CX3CL1 and subsequent global transcriptome analysis of CD16+ subsets revealed 81 upregulated genes, including clusterin, lipocalin-2, and the leptin receptor. Aldosterone synthase, osteopontin, and cortisone reductase were some of the 66 downregulated genes present. These data suggest that maternal angiotensin II levels influence placental CX3CL1 expression, which, in turn, can affect monocyte to trophoblast adhesion. Release of placental CX3CL1 could promote the pro-inflammatory status of the CD16+ subset of maternal monocytes.

The potential association between a new angiogenic marker fractalkine and a placental vascularization in preeclampsia

“…The median gestational age (weeks of gestation) for ultrasound examination in Group 1 (median 33; IQR [31][32][33][34] was not different in comparison to Group 2 (median 31; IQR 31-32), p = 0.3 The observed changes in Doppler parameters in Group 2, compared to Group 1, were distinctive for reduced placental blood flow. We observed increased UA PI percentile (median 58.0; IQR 32.0-86.0), decreased MCA PI percentile (mean 27.0 ± 19.9), and lower CPR percentile (median 21.5; IQR 6.0-45.0) in Group 2 (preeclampsia), compared to Group 1 (normotensive), (median 23.0; IQR 17.0-44.0), (mean 45.1 ± 28.7) and (median 61.5; IQR 35.0-79.5), p = 0.003, p = 0.02, p = 0.007, respectively.…”

Role of the Monocyte–Macrophage System in Normal Pregnancy and Preeclampsia

“…It is assumed that the placenta plays a leading role in this process. Monocytes, circulating with the blood through placental lacunae, come into contact with syncytiotrophoblast which can activate them towards pro-inflammatory phenotype [27,28]. In addition to the direct contacts, monocytes can be activated indirectly by cytokines [29,30], by microvesicles and exosomes released from syncytiotrophoblast into the maternal blood [31,32,33,34] and by pregnancy hormones, e.g., estrogens.…”

Maternal Platelets—Friend or Foe of the Human Placenta?

“…In addition to P-selectin and PSGL-1, the chemokine CX3CL1 (also referred to as fractalkine) and its receptor CX3CR1 are directly involved in the platelet–monocyte complex formation [82]. Importantly, the fractalkine/CX3CR1 axis has been shown to mediate monocyte to trophoblast adhesion [83,84], and fractalkine is increased in placentas from severe early-onset PE [85], possibly contributing to increased adhesion of platelet-monocyte aggregates. In nonpregnant women and healthy control pregnancies, only low percentages of monocytes associated with platelets are detected, while the proportion of circulating platelet-monocyte aggregates are significantly increased in women with preeclampsia [86].…”