Plexin-B2 Negatively Regulates Macrophage Motility, Rac, and Cdc42 Activation

Plexins are cell surface receptors widely studied in the nervous system, where they mediate migration and morphogenesis though the Rho family of small GTPases. More recently, plexins have been implicated in immune processes including cell-cell interaction, immune activation, migration, and cytokine production. Plexin-B2 facilitates ligand induced cell guidance and migration in the nervous system, and induces cytoskeletal changes in overexpression assays through RhoGTPase. The function of Plexin-B2 in the immune system is unknown. This report shows that Plexin-B2 is highly expressed on cells of the innate immune system in the mouse, including macrophages, conventional dendritic cells, and plasmacytoid dendritic cells. However, Plexin-B2 does not appear to regulate the production of proinflammatory cytokines, phagocytosis of a variety of targets, or directional migration towards chemoattractants or extracellular matrix in mouse macrophages. Instead, Plxnb2−/− macrophages have greater cellular motility than wild type in the unstimulated state that is accompanied by more active, GTP-bound Rac and Cdc42. Additionally, Plxnb2−/− macrophages demonstrate faster in vitro wound closure activity. Studies have shown that a closely related family member, Plexin-B1, binds to active Rac and sequesters it from downstream signaling. The interaction of Plexin-B2 with Rac has only been previously confirmed in yeast and bacterial overexpression assays. The data presented here show that Plexin-B2 functions in mouse macrophages as a negative regulator of the GTPases Rac and Cdc42 and as a negative regulator of basal cell motility and wound healing

Neuregulin-1 Regulates Cell Adhesion via an ErbB2/Phosphoinositide-3 Kinase/Akt-Dependent Pathway: Potential Implications for Schizophrenia and Cancer

Neuregulin-1 (NRG1) is a putative schizophrenia susceptibility gene involved extensively in central nervous system development as well as cancer invasion and metastasis. Using a B lymphoblast cell model, we previously demonstrated impairment in NRG1alpha-mediated migration in cells derived from patients with schizophrenia as well as effects of risk alleles in NRG1 and catechol-O-methyltransferase (COMT), a second gene implicated both in schizophrenia susceptibility and in cancer.Here, we examine cell adhesion, an essential component process of cell motility, using an integrin-mediated cell adhesion assay based on an interaction between ICAM-1 and the CD11a/CD18 integrin heterodimer expressed on lymphoblasts. In our assay, NRG1alpha induces lymphoblasts to assume varying levels of adhesion characterized by time-dependent fluctuations in the firmness of attachment. The maximum range of variation in adhesion over sixty minutes correlates strongly with NRG1alpha-induced migration (r(2) = 0.61). NRG1alpha-induced adhesion variation is blocked by erbB2, PI3K, and Akt inhibitors, but not by PLC, ROCK, MLCK, or MEK inhibitors, implicating the erbB2/PI3K/Akt1 signaling pathway in NRG1-stimulated, integrin-mediated cell adhesion. In cell lines from 20 patients with schizophrenia and 20 normal controls, cells from patients show a significant deficiency in the range of NRG1alpha-induced adhesion (p = 0.0002). In contrast, the response of patient-derived cells to phorbol myristate acetate is unimpaired. The COMT Val108/158Met genotype demonstrates a strong trend towards predicting the range of the NRG1alpha-induced adhesion response with risk homozygotes having decreased variation in cell adhesion even in normal subjects (p = 0.063).Our findings suggest that a mechanism of the NRG1 genetic association with schizophrenia may involve the molecular biology of cell adhesion

Expression of pertussis toxin adenosine diphosphate-ribosyltransferase in a T-cell hybridoma reduces metastatic capacity

T-cell hybridomas are highly metastatic, and their in vitro invasiveness correlates with metastatic capacity. Invasion is blocked by pertussis toxin (PT), which adenosine diphosphate (ADP)-ribosylates G1-proteins, and we have provided evidence that the PT-sensitive signal stimulates leukocyte function-associated antigen-1 (LFA-1)-mediated adhesion required for invasion. PT pretreatment of TAM2D2 T-cell hybridoma cells reduced metastasis, but only to a limited extent. In the present study, we have transfected the cDNA of the PT ADP-ribosyltransferase S1 subunit into TAM2D2 cells to abrogate G1-protein function permanently. We report here a substantial reduction in the metastatic capacity of two transfectants, S05 and S09, in which 88% and 95% of the G1-proteins was ADP-ribosylated. Two-thirds of the mice injected with S09 cells were tumor-free. Metastasis to the liver was almost completely prevented and less metastases were formed in the spleen and kidneys. Metastasis formation by S05 cells in liver and spleen was much reduced, but in lymph nodes and peritoneal tissues, metastases occurred with a frequency similar to that of controls. We conclude that G1-proteins play an important role in T-cell hybridoma metastasis. We propose that the reduction in metastasis is due to diminished entry of tumor cells from the blood into tissues.</jats:p

Streamlined Classification of Psychopathological Hand Disorders: a Literature Review

In the surgical hand clinic, psychopathological hand disorders can be sorted into one of the following four categories: (1) factitious wound creation and manipulation; (2) factitious edema; (3) psychopathological dystonias, and (4) psychopathological sensory abnormalities and psychopathological Complex Regional Pain Syndrome. This article introduces these four categories. Pertinent literature that includes descriptions of each category’s syndromes and diseases, demographic and psychological profiles, differential diagnoses, and appropriate treatment recommendations is reviewed

PEOPLE WITH MILD HEMOPHILIA ARE AT RISK OF JOINT DISEASE: THE NATIONWIDE COHORT HIN-6 STUDY

Clinical data on people with mild hemophilia (mPwH) is important to guide their treatment but remains scarce worldwide. In addition, since modern hemophilia therapies can turn severe phenotypes into mild or normal ones, knowing the clinical, therapeutical, and outcomes data of mPwH becomes essential as a proxy of these treatments. We described mPwH who participated in the 6th version of the Hemophilia in the Netherlands (HiN-6) cross-sectional nationwide study. Male mPwH (lowest plasmatic factor activity 5.1%‒40.0%) answered a questionnaire about their disease, treatment, and outcomes, in 2019. Questionnaires were elaborated according to age: younger than 12-years (children and responded by their parents/caregivers), between 12- and 17.9-years (adolescents), and 18-years or older (adults). A total of 387 mPwH responded to the questionnaires. Their median (Interquartile Range; IQR) age was 49.0-years (26.0‒62.0), 340 (87.8%) were adults, 29 (7.5%) had past or current inhibitors, 197 (50.9%) had ever been treated with any clotting product, and 12 (3.1%) were currently on prophylaxis. Approximately 74% reported they perceived their disease was not serious or not serious at all, and the different activity groups responded similarly. Recent bleed at any site was reported by 24/47 (51.1%) non-adults, related to the previous quarter, and 96/340 (28.2%) adults, related to the previous year. Joint impairment was reported for 180 joints (22 perceived as severe) by 50/387 (12.9%) mPwH. Age at first hemarthrosis was 10.0 years [5.0‒16.0] among 97 (25%) mPwH. Lifetime hospitalization due to joint surgery was reported by 31/358 (8.7%) mPwH. The analyses of PROMIS29 and RAND-26 (quality of life), and HAL (functional abilities) indicated good quality of life and functional abilities. mPwH who participated in the HiN-6 Study reported good social functioning and a non-impactant disease in their lives, although bleeds, joint impairment, and need for joint surgeries still occur

Genetic Lineage Tracing of Lymphatic Endothelial Cells in Mice

Lineage tracing allows for identification of all progeny produced by a single cell or groups of cells and can thus be used to assess developmental fate of cells. Here we focus on one of the most widely used lineage tracing approaches that utilize the Cre/loxP system for site-specific genetic recombination in studying the developmental origins of lymphatic endothelial cells (LECs) in the mouse embryo. We discuss general considerations for a successful Cre/loxP based lineage tracing experiment and provide information about strains that are available for genetic lineage tracing of LECs. A protocol for lineage tracing analysis of the lymphatic vasculature by whole-mount immunofluorescence in two embryonic tissues, the skin and the mesentery, is also provided.</p