Abstract
Objective Inflammation and hypoxia activate the fractalkine (CX3CL1) receptor (CX3CR1)-related signaling pathway. Tumor necrosis factor alpha (TNFα) induces CX3CL1, influencing a mechanism of CX3CL1 autoregulation by CX3CR1 expression. We compared spontaneous and lipopolysaccharide (LPS)-induced CX3CL1 and TNFα production by human placenta under normoxic vs. hypoxic conditions, with respect to CX3CR1 expression and its functional status.MethodsPlacental lobules of term placentae (N = 24) were perfused extracorporeally. CX3CL1 and TNFα concentrations were measured in the perfusion fluid by ELISA. LPS, anti-CX3CR1 antibodies and pirfenidone were used in respective subgroups. After perfusion, CX3CR1 expression was estimated in placental tissue using quantitative immunohistochemistry, and the final results were adjusted for the mean microvascular density.ResultsThe highest increase in CX3CL1 concentration in response to LPS was observed in hypoxia (p < 0.05). Unlike in normoxia, anti-CX3CR1 administration in hypoxia significantly reduced the LPS-evoked response. CX3CR1 expression was augmented by hypoxia and reached 260.9 ± 41 (% ±SEM) of the reference value in normoxia. Positive immunostaining for CX3CR1 corresponded to the vascular endothelium. Pirfenidone inhibited hypoxia + LPS-related increase in TNFα production and prevented the up-regulation of CX3CR1.ConclusionThe modulatory influence of TNFα on CX3CR1 expression in hypoxia and CX3CL1/CX3CR1 interaction may serve as a compensatory mechanism to preserve or augment the pro-inflammatory course of intercellular interactions in placental endothelium.
Highlights
Because placental vessels lack autonomic innervation, circulating and locally produced humoral factors must play a crucial role in communication between the compartments of the utero-placento-fetal unit [1]
The highest increase in CX3CL1 concentration in response to LPS was observed in hypoxia (p \ 0.05)
CX3CR1 expression was augmented by hypoxia and reached 260.9 ± 41 (% ±SEM) of the reference value in normoxia
Summary
Because placental vessels lack autonomic innervation, circulating and locally produced humoral factors must play a crucial role in communication between the compartments of the utero-placento-fetal unit [1]. Chemokines form a superfamily of cytokines whose major roles involve the modulation of immune response and the guidance of migrating leukocytes towards or away from chemotactic factors, which act as either chemoattractants or chemorepellents, respectively [3]. The main roles of membrane-bound CX3CL1 include the promotion of leukocyte binding and adhesion and activation of target cells, whereas the soluble chemokine domain of human CX3CL1 is chemotactic for natural killer cells, T cells and monocytes but not neutrophils. This dual function as an adhesive compound and chemoattractant distinguishes CX3CL1 from other chemokines [5, 7]
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