Frontiers in immunology
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Frontiers in immunology · Jan 2018
Differential Mechanisms of Septic Human Pulmonary Microvascular Endothelial Cell Barrier Dysfunction Depending on the Presence of Neutrophils.
Sepsis is characterized by injury of pulmonary microvascular endothelial cells (PMVEC) leading to barrier dysfunction. Multiple mechanisms promote septic PMVEC barrier dysfunction, including interaction with circulating leukocytes and PMVEC apoptotic death. Our previous work demonstrated a strong correlation between septic neutrophil (PMN)-dependent PMVEC apoptosis and pulmonary microvascular albumin leak in septic mice in vivo; however, this remains uncertain in human PMVEC. ⋯ Moreover, inhibition of caspase 3, 8, or 9 in PMN-PMVEC cocultures also reduced septic PMVEC barrier dysfunction whereas inhibition of caspase 1 had no effect. Our data demonstrate that human PMVEC barrier dysfunction under septic conditions in vitro (cytomix stimulation) is clearly caspase-dependent, but the mechanism differs depending on the presence of PMN. In isolated PMVEC, apoptosis contributes to septic barrier dysfunction, whereas PMN presence enhances caspase-dependent septic PMVEC barrier dysfunction independently of PMVEC apoptosis.
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Frontiers in immunology · Jan 2018
Novel Role for PD-1:PD-L1 as Mediator of Pulmonary Vascular Endothelial Cell Functions in Pathogenesis of Indirect ARDS in Mice.
Deficiency of the co-inhibitory receptor, Programmed cell death receptor (PD)-1, provides a survival benefit in our murine shock/sepsis model for the development of indirect acute respiratory distress syndrome (iARDS). Further, of clinical significance, patients that develop ARDS express increased PD-1 on their blood leukocytes. While PD-1 expression and its regulatory role have been associated with mainly T-cell responses, the contribution of its primary ligand, PD-L1, broadly expressed on non-immune cells such as lung endothelial cells (ECs) as well as immune cells, is less well-understood. ⋯ However, PD-L1 deficiency, unlike PD-1, significantly decreased EC activation through the Angiopoietin/Tie2 pathway in our iARDS mice. Additionally, while PD-1 gene deficiency was associated with decreased neutrophil influx in our iARDS mice, EC monolayers derived from PD-L1 deficient mice showed increased expression of EC junction proteins in response to ex vivo TNF-α stimulation. Together, these data suggest that ligation of PD-1:PD-L1 may play a novel role(s) in the maintenance of pulmonary EC barrier regulation, beyond that of the classic regulation of the leukocyte tolerogenic immune response, which may account for its pathogenic actions in iARDS.
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Frontiers in immunology · Jan 2018
Host Defense Peptide LL-37-Mediated Chemoattractant Properties, but Not Anti-Inflammatory Cytokine IL-1RA Production, Is Selectively Controlled by Cdc42 Rho GTPase via G Protein-Coupled Receptors and JNK Mitogen-Activated Protein Kinase.
The human host defense peptide LL-37 promotes immune activation such as induction of chemokine production and recruitment of leukocytes. Conversely, LL-37 also mediates anti-inflammatory responses such as production of anti-inflammatory cytokines, e.g., IL-1RA, and the control of pro-inflammatory cytokines, e.g., TNF. The mechanisms regulating these disparate immunomodulatory functions of LL-37 are not completely understood. ⋯ We demonstrate that LL-37 facilitates chemokine production and leukocyte recruitment engaging Cdc42/Rac1 Rho GTPase via GPCR and the JNK MAPK pathway. In contrast, LL-37-mediated anti-inflammatory cytokine IL-1RA production is independent of either Rho or Ras GTPase. The results of this study suggest that Cdc42 Rho GTPase may be the molecular switch that controls the opposing functions of LL-37 in the process of inflammation.
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Frontiers in immunology · Jan 2018
Intestinal Microbiota at Engraftment Influence Acute Graft-Versus-Host Disease via the Treg/Th17 Balance in Allo-HSCT Recipients.
Animal models have indicated that intestinal microbiota influence acute graft-versus-host disease (aGVHD) by modulating immune homeostasis. But, in humans, the mechanism by which the microbiota induces aGVHD remains unclear. In this study, we investigated the relationship between the intestinal microbiota and T cell subsets in patients who undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT) to explore the mechanism by which microbiota induced aGVHD. ⋯ The level of acetylated H3 in CD4+ T cells was not only correlated with Lachnospiraceae/Ruminococcaceae, but also with the Treg/Th17 ratio (r = 0.354; p = 0.001). In conclusions, our results suggest that decreased Lachnospiraceae and Ruminococcaceae and increased Enterobacteriaceae, correlate with a Treg/Th17 imbalance, which might be through acetylated H3 in CD4+ T cells. These findings suggest that intestinal microbiota might induce aGVHD by influencing the Treg/Th17 balance.
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Frontiers in immunology · Jan 2018
Genetic Association of Pulmonary Surfactant Protein Genes, SFTPA1, SFTPA2, SFTPB, SFTPC, and SFTPD With Cystic Fibrosis.
Surfactant proteins (SP) are involved in surfactant function and innate immunity in the human lung. Both lung function and innate immunity are altered in CF, and altered SP levels and genetic association are observed in Cystic Fibrosis (CF). We hypothesized that single nucleotide polymorphisms (SNPs) within the SP genes associate with CF or severity subgroups, either through single SNP or via SNP-SNP interactions between two SNPs of a given gene (intragenic) and/or between two genes (intergenic). ⋯ The results showed (a) Two SNPs, SFTPB rs7316 (p = 0.0083) and SFTPC rs1124 (p = 0.0154), each associated with CF. (b) Three intragenic SNP-SNP interactions, SFTPB (rs2077079, rs3024798), and SFTPA1 (rs1136451, rs1059057 and rs4253527), associated with CF. (c) A total of 34 intergenic SNP-SNP interactions among the 4 SP genes to be associated with CF. (d) No SNP-SNP interaction was observed between SFTPA1 or SFTPA2 and SFTPD. (e) Equal number of SNP-SNP interactions were observed between SFTPB and SFTPA1/SFTPA2 (n = 7) and SP-B and SFTPD (n = 7). (f) SFTPC exhibited significant SNP-SNP interactions with SFTPA1/SFTPA2 (n = 11), SFTPB (n = 4) and SFTPD (n = 3). (g) A single SFTPB SNP was associated with mild CF after Bonferroni correction, and several intergenic interactions that are associated (p < 0.01) with either mild or moderate/severe CF were observed. These collectively indicate that complex SNP-SNP interactions of the SP genes may contribute to the pulmonary disease in CF patients. We speculate that SPs may serve as modifiers for the varied progression of pulmonary disease in CF and/or its severity.