Neutrophils induce proangiogenic T cells with a regulatory phenotype in pregnancy

Although neutrophils are known to be fundamental in controlling innate immune responses, their role in regulating adaptive immunity is just starting to be appreciated. We report that human neutrophils exposed to pregnancy hormones progesterone and estriol promote the establishment of maternal tolerance through the induction of a population of CD4$^{+}$ T cells displaying a GARP$^{+}$CD127$^{Io}$FOXP3$^{+}$ phenotype following antigen activation. Neutrophil-induced T (niT) cells produce IL-10, IL-17, and VEGF and promote vessel growth in vitro. Neutrophil depletion during murine pregnancy leads to abnormal development of the fetal-maternal unit and reduced empbryo development, with placental architecture displaying poor trophoblast invasion and spiral artery development in the maternal decidua, accompanied by significantly attenuated niT cell numbers in draining lymph nodes. Using CD45 congenic cells, we show that induction of niT cells and their regulatory function occurs via transfer of apoptotic neutrophil-derived proteins, including forkhead box protein 1 (FOXO1), to T cells. Unlike in women with healthy pregnancies, neutrophils from blood and placental samples of preeclamptic women fail to induce niT cells as a direct consequence of their inability to transfer FOXO1 to T cells. Finally, neutrophil-selective FOXO1 knockdown leads to defective placentation and compromised embryo development, similar to that resulting from neutrophil depletion. These data define a nonredundant function of neutrophil-T cell interactions in the regulation of vascularization at the maternal-fetal interface.S.N. and M.P. were supported by the Wellcome Trust (Programme 086867/Z/08/Z). F.M.M.-B. is supported by the British Heart Foundation (CH/15/2/32064). D.J.W. is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. S.H.P.F. is a Research Fellow at CNPq. This work is part of the research themes contributing to the translational research portfolio of Barts and the London Cardiovascular Biomedical Research Unit, which is supported and funded by the National Institutes of Health Research

Envenomations by Bothrops and Crotalus Snakes Induce the Release of Mitochondrial Alarmins

Skeletal muscle necrosis is a common manifestation of viperid snakebite envenomations. Venoms from snakes of the genus Bothrops, such as that of B. asper, induce muscle tissue damage at the site of venom injection, provoking severe local pathology which often results in permanent sequelae. In contrast, the venom of the South American rattlesnake Crotalus durissus terrificus, induces a clinical picture of systemic myotoxicity, i.e., rhabdomyolysis, together with neurotoxicity. It is known that molecules released from damaged muscle might act as ‘danger’ signals. These are known as ‘alarmins’, and contribute to the inflammatory reaction by activating the innate immune system. Here we show that the venoms of B. asper and C. d. terrificus release the mitochondrial markers mtDNA (from the matrix) and cytochrome c (Cyt c) from the intermembrane space, from ex vivo mouse tibialis anterior muscles. Cyt c was released to a similar extent by the two venoms whereas B. asper venom induced the release of higher amounts of mtDNA, thus reflecting hitherto some differences in their pathological action on muscle mitochondria. At variance, injection of these venoms in mice resulted in a different time-course of mtDNA release, with B. asper venom inducing an early onset increment in plasma levels and C. d. terrificus venom provoking a delayed release. We suggest that the release of mitochondrial ‘alarmins’ might contribute to the local and systemic inflammatory events characteristic of snakebite envenomations

In vivo characterization of Lopap, a prothrombin activator serine protease from the Lonomia obliqua caterpillar venom

Increasing occurrence of hemorrhagic syndrome in man, caused by contact with Lonomia obliqua caterpillars, has been reported in Southern Brazil in the past 10 years. the L. obliqua venom causes a severe consumptive coagulopathy, which can lead to hemorrhagic syndrome. L. obliqua prothrombin activator protease (Lopap) is a 69-kDa prothrombin activator serine protease isolated from L. obliqua caterpillar bristle extract, which is able to evoke thrombus formation, unclottable blood, and fibrinogen depletion when injected into the blood stream of rats. the purified protein generated thrombin from prothrombin, able to clot purified human fibrinogen and plasma. A decrease in platelet count and inhibition of collagen-induced platelet aggregation were observed, as well as leukocyte infiltration in the lungs. Ln addition, we observed congestion and hemorrhage in renal glomeruli and necrosis in renal distal tubules. These data support the hypothesis that Lopap contributes to the clinical syndrome caused by human contact with L. obliqua, most probably through prothrombin activation, resulting in a consumption coagulopathy. (C) 2001 Elsevier B.V. All rights reserved.FAPESP, Biochem & Biophys Lab, Butantan Inst, Ctr Appl Toxinol,CEPID, BR-05503900 São Paulo, BrazilFAPESP, Lab Immunochem, Butantan Inst, Ctr Appl Toxinol,CEPID, BR-05503900 São Paulo, BrazilUniv São Paulo, Dept Microbiol, Inst Biomed Sci, São Paulo, BrazilButantan Inst, Lab Pathophysiol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biochem & Mol Biol, São Paulo, BrazilUniversidade Federal de São Paulo, Discipline Immunol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biochem & Mol Biol, São Paulo, BrazilUniversidade Federal de São Paulo, Discipline Immunol, São Paulo, BrazilWeb of Scienc

Injuries to the mesenteric microcirculation due to bacterial translocation

Universidade Federal de São Paulo, Dept Pediat, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Microbiol, São Paulo, BrazilInst Butantan, Intravital Unit, Butantan, BrazilUniversidade Federal de São Paulo, Dept Pediat, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Microbiol, São Paulo, BrazilWeb of Scienc