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Dendritic cells (DCs) form a key component of the immune response, as they are involved in the innate and adaptive immunity and in the process of tolerance. Under normal conditions, DCs are absent from the Central Nervous System (CNS), as the blood brain barrier (BBB) restricts their entry. However, DCs have recently been implicated in the pathogenesis of several CNS diseases. The molecular mechanisms that mediate DC trafficking across the BBB are poorly understood. The objectives of this study were to examine the role of endothelial cell adhesion molecules (eCAMs) and their ligands in the process of DC adhesion to the BBB endothelium, and to investigate the participation of DCs in human CNS diseases. To study DC adhesion, DCs were generated in vitro by culturing human blood monocytes in the presence of GM-CSF and IL- 4, and DC maturation was induced by adding inflammatory cytokines (TNF-α, IL-1β, IL-6) and PGE₂. Immature and mature DCs displayed differences in their expression of surface molecules, including eCAM ligands, by flow cytometry. Adhesion to the cerebral endothelium was investigated using an in vitro model of the BBB consisting of primary cultures of human brain microvessel endothelial cells (HBMEC). Immature or mature DCs were incubated with resting or TNF-α-activated HBMEC for up to one hour. Only a few DCs adhered to resting HBMEC, but adhesion was upregulated upon activating HBMEC (p<O.Ol). Moreover, immature DCs adhered to activated HBMEC to a greater extent compared to mature DCs (p<O.OOl). Blocking experiments indicated that the adhesion of both immature and mature DCs to HBMEC was dependent upon ICAM-1-CD18 or ICAM-2-CD18, ICAM-2-DC-SIGN, and PECAM-l PECAM-l interactions. In addition, VCAM-1-VLA-4 interactions mediated the adhesion of immature but not mature DCs to activated HBMEC. Using immunohistochemistry for DC markers, we also examined the presence of DCs in human inflammatory, infectious, and neurodegenerative diseases, stroke and tumours. The results indicate accumulation of DC SIGN—, fascin—, and MHC class Il—expressing DCs in the CNS under most pathological conditions. These findings provide further insight into the mechanisms of neuroinflammation, and highlight the role of DCs and the BBB endothelium in this process.

Dendritic cells (DCs) form a key component of the immune response, as they are involved in the innate and adaptive immunity and in the process of tolerance. Under normal conditions, DCs are absent from the Central Nervous System (CNS), as the blood brain barrier (BBB) restricts their entry. However, DCs have recently been implicated in the pathogenesis of several CNS diseases. The molecular mechanisms that mediate DC trafficking across the BBB are poorly understood. The objectives of this study were to examine the role of endothelial cell adhesion molecules (eCAMs) and their ligands in the process of DC adhesion to the BBB endothelium, and to investigate the participation of DCs in human CNS diseases. To study DC adhesion, DCs were generated in vitro by culturing human blood monocytes in the presence of GM-CSF and IL- 4, and DC maturation was induced by adding inflammatory cytokines (TNF-α, IL-1β, IL-6) and PGE₂. Immature and mature DCs displayed differences in their expression of surface molecules, including eCAM ligands, by flow cytometry. Adhesion to the cerebral endothelium was investigated using an in vitro model of the BBB consisting of primary cultures of human brain microvessel endothelial cells (HBMEC). Immature or mature DCs were incubated with resting or TNF-α-activated HBMEC for up to one hour. Only a few DCs adhered to resting HBMEC, but adhesion was upregulated upon activating HBMEC (p<O.Ol). Moreover, immature DCs adhered to activated HBMEC to a greater extent compared to mature DCs (p<O.OOl). Blocking experiments indicated that the adhesion of both immature and mature DCs to HBMEC was dependent upon ICAM-1-CD18 or ICAM-2-CD18, ICAM-2-DC-SIGN, and PECAM-l PECAM-l interactions. In addition, VCAM-1-VLA-4 interactions mediated the adhesion of immature but not mature DCs to activated HBMEC. Using immunohistochemistry for DC markers, we also examined the presence of DCs in human inflammatory, infectious, and neurodegenerative diseases, stroke and tumours. The results indicate accumulation of DC SIGN—, fascin—, and MHC class Il—expressing DCs in the CNS under most pathological conditions. These findings provide further insight into the mechanisms of neuroinflammation, and highlight the role of DCs and the BBB endothelium in this process.

Spontaneous term labour is associated with increased inflammatory events in the myometrium including cytokine production and leukocyte infiltration. We hypothesized that mechanical stretch of the uterine wall by the growing fetus facilitates peripheral leukocyte transendothelial migration into the term pregnant myometrium through the release of various cytokines. The current study demonstrated that static mechanical stretch directly induces secretion of multiple cytokines and chemokines by human myometrial smooth muscle cells. Stretch-induced cytokines (1) increased vascular permeability; (2) enhanced leukocyte adhesion to the endothelium of the surrounding uterine microvasculature by (3) inducing the expression of endothelial cell adhesion molecules; and (4) directed the transendothelial migration of peripheral neutrophils. Our data provide a direct proof of mechanical regulation in leukocyte recruitment from the uterine blood vessels, which represents a putative mechanism for the leukocyte infiltrate seen in the myometrium during labour and postpartum involution.

Spontaneous term labour is associated with increased inflammatory events in the myometrium including cytokine production and leukocyte infiltration. We hypothesized that mechanical stretch of the uterine wall by the growing fetus facilitates peripheral leukocyte transendothelial migration into the term pregnant myometrium through the release of various cytokines. The current study demonstrated that static mechanical stretch directly induces secretion of multiple cytokines and chemokines by human myometrial smooth muscle cells. Stretch-induced cytokines (1) increased vascular permeability; (2) enhanced leukocyte adhesion to the endothelium of the surrounding uterine microvasculature by (3) inducing the expression of endothelial cell adhesion molecules; and (4) directed the transendothelial migration of peripheral neutrophils. Our data provide a direct proof of mechanical regulation in leukocyte recruitment from the uterine blood vessels, which represents a putative mechanism for the leukocyte infiltrate seen in the myometrium during labour and postpartum involution.

Leukocyte telomere length is an emerging marker for pathologically accelerated cellular aging. First discovered to be associated with aging-related disorders, such as type 2 diabetes mellitus and cardiovascular disease, in young individuals, leukocyte telomeric degeneration is also garnering growing attention in psychiatric illnesses. Comorbid metabolic symptoms and physiological dysregulation observed in schizophrenia patients imply a plausible association between pathological telomere biology and psychosis. Available data on the relationship between leukocyte telomere length and schizophrenia is limited largely to small-sample, cross-sectional studies unable to fully account for the large body of potentially confounding factors on telomere length (psychotropic medication, chronic stress and history of trauma, comorbidities, paternal age, substance use, subject-level variables). The most comprehensive meta-analysis to date reveals a significant trend of shortened telomeres in schizophrenia patients as compared to healthy controls. Some findings suggest a linear relationship between telomeric attrition and disease chronicity/severity. However, overall findings are insufficient to gauge the potential of leukocyte telomere length as a predictive, diagnostic biomarker in this patient population. Future longitudinal studies with carefully controlled covariates are required to verify the promising potential of a new marker for schizophrenia onset and a possible new direction for adjunctive antipsychotic treatment.

Abstract The effects of perioperative filgrastim (rhG-CSF) and surgery per se on the postoperative acute phase reaction were studied by assessing leukocyte functions, cytokine levels and tenascin-C (Tn-C) and procollagen propeptide (PINP, PIIINP) concentrations in different body fluid compartments in patients undergoing gastrointestinal surgery. Thirty consecutive patients were randomized to receive either filgrastim or placebo for five days, starting 12 hours before colorectal surgery. Filgrastim treatment led to marked neutrophilia with decreased neutrophil migration in peripheral blood but not in peritoneal fluid 48 hours postoperatively. Neutrophil phagocytosis and bacterial killing did not differ between the groups. Filgrastim caused increased postoperative expression of neutrophil CD11b/CD18 in blood but not in peritoneal fluid or wound fluid. CD11b/CD18 expression was higher in both wound fluid and peritoneal fluid than in blood in the placebo group. The expression of neutrophil CD62L was higher in blood than in peritoneal fluid or wound fluid in both groups. The serum concentration of interleukin (IL)-8 was lower in the filgrastim group 5 hours postoperatively. The concentrations of IL-1β, IL-6, transforming growth factor (TGF)-β and IL-10 did not differ between the groups. The cytokine levels were markedly higher locally in the wound and in the peritoneal cavity compared to circulating blood. No adverse events attributable to filgrastim were seen. Leukocyte counts, neutrophil and monocyte functions and the levels of IL-6, IL-8 and granulocyte colony-stimulating factor (G-CSF) were measured from 18 patients before and after colorectal surgery. Surgery caused an increase in neutrophil and monocyte counts along with lymphocytopenia. Neutrophil phagocytosis was decreased 4 and 24 hours postoperatively, but normalized after that. A distinct systemic cytokine response was seen postoperatively. In a study with 24 patients, Tn-C concentration increased in wound fluid during the first postoperative week after abdominal surgery. The Tn-C level was markedly higher in wound fluid than in serum.