Trophoblast Contact Deactivates Human Neutrophils

Abstract

Trophoblasts are fetal epithelial cells that form an interface between mother and offspring. To evaluate their anti-inflammatory capacity, we tested the hypothesis that trophoblasts deactivate neutrophils using single-cell assays. Several biophysical (Ca2+ and NAD(P)H oscillation frequency) and physiological (oxidant production) markers of activated neutrophils revert to a nonactivated phenotype as activated cells make contact with trophoblasts. Indistinguishable results were obtained using syncytiotrophoblasts and in experiments using trophoblasts and neutrophils from the same mother to recapitulate the semiallogeneic system. These changes suggest reduced hexose monophosphate shunt (HMS) activity. We discovered that two metabolic regulatory points, glucose transport and HMS enzyme trafficking, are affected by trophoblasts. This restriction in HMS activity deactivates neutrophils, thereby limiting oxidative DNA damage within trophoblasts.

The hexosamine biosynthesis pathway negatively regulates IL-2 production by Jurkat T cells

“…In contrast to conventional approaches relying upon rational structure-based drug design or proteomic screening methods, our approach has been to analyze sites of intersection between metabolic and signaling circuitry to identify control or "choke" points that influence immune cell physiology. For example, we have identified epigenetic metabolic regulatory mechanisms such as the translocation of cytosolic enzymes and the inhibition of glucose transport that influence leukocyte activation [3][4][5]. In the present work, we have extended this strategic approach to lymphocyte activation.…”

“…NAD(P)H autofluorescence is a well-established noninvasive method to study cell and tissue metabolism [3]. An LED operating at 365nm (Rapp ElectroOptic, Wedel, Germany) was used for excitation to minimize illumination noise (both intensity fluctuations and out-ofband illumination noise).…”

“…Nonetheless, metabolism is frequently overlooked or only seen as a power supply, not a regulatory mechanism. For example, leukocyte activation is regulated by glucose transport [1][2][3] and the spatial location of enzymes constituting the hexose monophosphate shunt [4,5]. Another important metabolic regulatory pathway is the hexosamine biosynthesis pathway (HBP), although only 1-3% of the glucose entering a cell is shunted into this pathway.…”

A primate subfamily of galectins expressed at the maternal–fetal interface that promote immune cell death

“…At the villous trophoblast-blood barrier, the syncytiotrophoblast apical membrane is densely covered with glycoproteins that may confer tolerance (e.g., Fas-ligand/CD178) (8). Indeed, this glycosylated trophoblast membrane inhibits activated maternal leukocytes (9,10) and affects compatibility between mother and offspring (11).…”

Glucose initially inhibits and later stimulates blood ROS generation

“…Of particular interest is the diabetic patient in pregnancy, where increased ROS generation can threaten the health of mother and unborn [34]. Interestingly, the healthy placenta produces large quantities of the macrophage derived plasminogen activator inhibitor (PAI)-2, a suppressor of fetal rejection and autoimmunity [35,36]. A physiologic drug "PAI-2" could replace glucocorticoids with dangerous side reactions [37].…”