The placenta responds to adverse environmental conditions by adapting its capacity for substrate transfer to maintain fetal growth and development. Early-onset hypoxia effects on placental morphology and activation of the unfolded protein response (UPR) were determined using an established rat model in which fetal growth restriction is minimized. We further established whether maternal treatment with a mitochondria-targeted antioxidant (MitoQ) confers protection during hypoxic pregnancy. Wistar dams were exposed to normoxia (21% O2) or hypoxia (13% to 14% O2) from days 6 to 20 of pregnancy with and without MitoQ treatment (500 μmol/L in drinking water). On day 20, animals were euthanized and weighed, and the placentas from male fetuses were processed for stereology to assess morphology. UPR activation in additional cohorts of frozen placentas was determined with Western blot analysis. Neither hypoxic pregnancy nor MitoQ treatment affected fetal growth. Hypoxia increased placental volume and the fetal capillary surface area and induced mitochondrial stress as well as the UPR, as evidenced by glucose-regulated protein 78 and activating transcription factor (ATF) 4 protein up-regulation. MitoQ treatment in hypoxic pregnancy increased placental maternal blood space surface area and volume and prevented the activation of mitochondrial stress and the ATF4 pathway. The data suggest that mitochondria-targeted antioxidants may be beneficial in complicated pregnancy via mechanisms protecting against placental stress and enhancing placental perfusion.

Extracellular vesicles are a heterogeneous family of vesicles, generated from different subcellular compartments and released into the extracellular space. Composed of a lipid bilayer encompassing both soluble cytosolic material and nuclear components, these organelles have been recently described as novel regulators of intercellular communication between adjacent and remote cells. Due to their diversified composition and biological content, they portray specific signatures of cellular activation and pathological processes, their potential as diagnostic and prognostic biomarkers has raised significant interest in cardiovascular diseases. Circulating vesicles, especially those released from platelets, leukocytes, and endothelial cells are found to play a critical role in activating several fundamental cells within the vasculature, including endothelial cells and vascular smooth muscle cells. Their intrinsic activity and immunomodulatory properties lends them to not only promote vascular inflammation, but also enhance tissue regeneration, vascular repair, and indeed resolution. In this review we aim to recapitulate the recent findings concerning the roles played by EVs that originate from different circulating cells, with particular reference to their action on the endothelium. We focus herein, on the interaction of platelet and leukocyte EVs with the endothelium. In addition, their potential biological function in promoting tissue resolution and vascular repair will also be discussed.

SummaryMacrophages are central in orchestrating the clearance of apoptotic cells and cellular debris during inflammation, with the mechanism(s) regulating this process remaining of interest. Herein, we found that the n-3 docosapentaenoic acid-derived protectin (PDn-3 DPA) biosynthetic pathway regulated the differentiation of human monocytes, altering macrophage phenotype, efferocytosis, and bacterial phagocytosis. Using lipid mediator profiling, human primary cells and recombinant enzymes we found that human 15-lipoxygenases initiate the PDn-3 DPA pathway catalyzing the formation of an allylic epoxide. The complete stereochemistry of this epoxide was determined using stereocontrolled total organic synthesis as 16S,17S-epoxy-7Z,10Z,12E,14E,19Z-docosapentaenoic acid (16S,17S-ePDn-3 DPA). This intermediate was enzymatically converted by epoxide hydrolases to PD1n-3 DPA and PD2n-3 DPA, with epoxide hydrolase 2 converting 16S,17S-ePDn-3 DPA to PD2n-3 DPA in human monocytes. Taken together these results establish the PDn-3 DPA biosynthetic pathway in human monocytes and macrophages and its role in regulating macrophage resolution responses.

Summary The migration of neutrophils from the blood circulation to sites of infection or injury is a key immune response and requires the breaching of endothelial cells (ECs) that line the inner aspect of blood vessels. Unregulated neutrophil transendothelial cell migration (TEM) is pathogenic, but the molecular basis of its physiological termination remains unknown. Here, we demonstrated that ECs of venules in inflamed tissues exhibited a robust autophagic response that was aligned temporally with the peak of neutrophil trafficking and was strictly localized to EC contacts. Genetic ablation of EC autophagy led to excessive neutrophil TEM and uncontrolled leukocyte migration in murine inflammatory models, while pharmacological induction of autophagy suppressed neutrophil infiltration into tissues. Mechanistically, autophagy regulated the remodeling of EC junctions and expression of key EC adhesion molecules, facilitating their intracellular trafficking and degradation. Collectively, we have identified autophagy as a modulator of EC leukocyte trafficking machinery aimed at terminating physiological inflammation.

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Neutrophil trafficking is a key component of the inflammatory response. Here, we have investigated the role of the immunomodulatory lectin Galectin‐9 (Gal‐9) on neutrophil recruitment. Our data indicate that Gal‐9 is upregulated in the inflamed vasculature of RA synovial biopsies and report the release of Gal‐9 into the extracellular environment following endothelial cell activation. siRNA knockdown of endothelial Gal‐9 resulted in reduced neutrophil adhesion and neutrophil recruitment was significantly reduced in Gal‐9 knockout mice in a model of zymosan‐induced peritonitis. We also provide evidence for Gal‐9 binding sites on human neutrophils; Gal‐9 binding induced neutrophil activation (increased expression of β2 integrins and reduced expression of CD62L). Intra‐vital microscopy confirmed a pro‐recruitment role for Gal‐9, with increased numbers of transmigrated neutrophils following Gal‐9 administration. We studied the role of both soluble and immobilized Gal‐9 on human neutrophil recruitment. Soluble Gal‐9 significantly strengthened the interaction between neutrophils and the endothelium and inhibited neutrophil crawling on ICAM‐1. When immobilized, Gal‐9 functioned as an adhesion molecule and captured neutrophils from the flow. Neutrophils adherent to Gal‐9 exhibited a spread/activated phenotype that was inhibited by CD18 and CD44 neutralizing antibodies, suggesting a role for these molecules in the pro‐adhesive effects of Gal‐9. Our data indicate that Gal‐9 is expressed and released by the activated endothelium and functions both in soluble form and when immobilized as a neutrophil adhesion molecule. This study paves the way for further investigation of the role of Gal‐9 in leukocyte recruitment in different inflammatory settings.

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Inflammation is linked with carcinogenesis in many types of cancer including colorectal cancer (CRC). Aspirin is recommended for the prevention of CRC, although the mechanism(s) mediating its immunomodulatory actions remain incompletely understood. Here, we demonstrate that aspirin increased concentrations of the immune-regulatory aspirin-triggered specialized proresolving mediators (AT-SPMs), including AT-lipoxin A 4 and AT-resolvin D1, in colonic tissues during inflammation-associated CRC (I-CRC). Aspirin also down-regulated the expression of the checkpoint protein programmed cell death protein-1 in macrophages and CD8 + T cells from the colonic mucosa. Inhibition of AT-SPM biosynthesis or knockout of the AT-SPM receptor Alx/Fpr2 reversed the immunomodulatory actions of aspirin on macrophages and CD8 + T cells and abrogated its protective effects during I-CRC. Furthermore, treatment of mice with AT-SPM recapitulated the immune-directed actions of aspirin during I-CRC. Together, these findings elucidate a central role for AT-SPM in mediating the immune-directed actions of aspirin in regulating I-CRC progression.