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Joan W Berman - One of the best experts on this subject based on the ideXlab platform.
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Dopamine Increases CD14^+CD16^+ Monocyte Transmigration across the Blood Brain Barrier: Implications for Substance Abuse and HIV Neuropathogenesis
Journal of Neuroimmune Pharmacology, 2017Co-Authors: Tina M Calderon, Dionna W Williams, Eliseo A Eugenin, Lillie Lopez, Laura Cheney, Peter J. Gaskill, Mike Veenstra, Kathryn Anastos, Susan Morgello, Joan W BermanAbstract:In human immunodeficiency virus-1 (HIV) infected individuals, substance abuse may accelerate the development and/or increase the severity of HIV associated neurocognitive disorders (HAND). It is proposed that CD14^+CD16^+ monocytes mediate HIV entry into the central nervous system (CNS) and that uninfected and infected CD14^+CD16^+ monocyte transmigration across the blood brain barrier (BBB) contributes to the establishment and propagation of CNS HIV viral reservoirs and chronic neuroinflammation, important factors in the development of HAND. The effects of substance abuse on the frequency of CD14^+CD16^+ monocytes in the peripheral circulation and on the entry of these cells into the CNS during HIV neuropathogenesis are not known. PBMC from HIV infected individuals were analyzed by flow cytometry and we demonstrate that the frequency of peripheral blood CD14^+CD16^+ monocytes in HIV infected substance abusers is increased when compared to those without active substance use. Since drug use elevates extracellular dopamine concentrations in the CNS, we examined the effects of dopamine on CD14^+CD16^+ monocyte transmigration across our in vitro model of the human BBB. The transmigration of this monocyte subpopulation is increased by dopamine and the dopamine receptor agonist, SKF 38393, implicating D1-like dopamine receptors in the increase in transmigration elicited by this neurotransmitter. Thus, elevated extracellular CNS dopamine may be a novel common mechanism by which active substance use increases uninfected and HIV infected CD14^+CD16^+ monocyte transmigration across the BBB. The influx of these cells into the CNS may increase viral seeding and neuroinflammation, contributing to the development of HIV associated neurocognitive impairments.
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jam a and alcam are therapeutic targets to inhibit diapedesis across the bbb of cd14 cd16 monocytes in hiv infected individuals
Journal of Leukocyte Biology, 2015Co-Authors: Dionna W Williams, Kathryn Anastos, Susan Morgello, Joan W BermanAbstract:: Monocyte transmigration across the BBB is a critical step in the development of cognitive deficits termed HAND that affect 40-70% of HIV-infected individuals, even with successful antiretroviral therapy. The monocyte subsets that enter the CNS during HIV infection are not fully characterized. We examined PBMC from HIV-positive individuals from 2 distinct cohorts and enumerated monocyte populations, characterized their transmigration properties across an in vitro human BBB model, and identified surface proteins critical for the entry of these cells into the CNS. We demonstrated that the frequency of peripheral blood CD14(+)CD16(+) and CD14(low)CD16(+) monocytes was increased in HIV-seropositive compared with -seronegative individuals, despite virologic control. We showed that CD14(+)CD16(+) monocytes selectively transmigrated across our BBB model as a result of their increased JAM-A and ALCAM expression. Antibody blocking of these proteins inhibited diapedesis of CD14(+)CD16(+) monocytes but not of T cells from the same HIV-infected people across the BBB. Our data indicate that JAM-A and ALCAM are therapeutic targets to decrease the entry of CD14(+)CD16(+) monocytes into the CNS of HIV-seropositive individuals, contributing to the eradication of neuroinflammation, HAND, and CNS viral reservoirs.
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JAM-A and ALCAM are therapeutic targets to inhibit diapedesis across the BBB of CD14+CD16+ monocytes in HIV-infected individuals
Journal of Leukocyte Biology, 2014Co-Authors: Dionna W Williams, Kathryn Anastos, Susan Morgello, Joan W BermanAbstract:: Monocyte transmigration across the BBB is a critical step in the development of cognitive deficits termed HAND that affect 40-70% of HIV-infected individuals, even with successful antiretroviral therapy. The monocyte subsets that enter the CNS during HIV infection are not fully characterized. We examined PBMC from HIV-positive individuals from 2 distinct cohorts and enumerated monocyte populations, characterized their transmigration properties across an in vitro human BBB model, and identified surface proteins critical for the entry of these cells into the CNS. We demonstrated that the frequency of peripheral blood CD14(+)CD16(+) and CD14(low)CD16(+) monocytes was increased in HIV-seropositive compared with -seronegative individuals, despite virologic control. We showed that CD14(+)CD16(+) monocytes selectively transmigrated across our BBB model as a result of their increased JAM-A and ALCAM expression. Antibody blocking of these proteins inhibited diapedesis of CD14(+)CD16(+) monocytes but not of T cells from the same HIV-infected people across the BBB. Our data indicate that JAM-A and ALCAM are therapeutic targets to decrease the entry of CD14(+)CD16(+) monocytes into the CNS of HIV-seropositive individuals, contributing to the eradication of neuroinflammation, HAND, and CNS viral reservoirs.
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mechanisms of hiv entry into the cns increased sensitivity of hiv infected cd14 cd16 monocytes to ccl2 and key roles of ccr2 jam a and alcam in diapedesis
PLOS ONE, 2013Co-Authors: Dionna W Williams, Eliseo A Eugenin, Tina M Calderon, Lillie Lopez, Peter J. Gaskill, Susan Morgello, Loreto Carvallotorres, Joan W BermanAbstract:As HIV infected individuals live longer, the prevalence of HIV associated neurocognitive disorders is increasing, despite successful antiretroviral therapy. CD14+CD16+ monocytes are critical to the neuropathogenesis of HIV as they promote viral seeding of the brain and establish neuroinflammation. The mechanisms by which HIV infected and uninfected monocytes cross the blood brain barrier and enter the central nervous system are not fully understood. We determined that HIV infection of CD14+CD16+ monocytes resulted in their highly increased transmigration across the blood brain barrier in response to CCL2 as compared to uninfected cells, which did not occur in the absence of the chemokine. This exuberant transmigration of HIV infected monocytes was due, at least in part, to increased CCR2 and significantly heightened sensitivity to CCL2. The entry of HIV infected and uninfected CD14+CD16+ monocytes into the brain was facilitated by significantly increased surface JAM-A, ALCAM, CD99, and PECAM-1, as compared to CD14+ cells that are CD16 negative. Upon HIV infection, there was an additional increase in surface JAM-A and ALCAM on CD14+CD16+ monocytes isolated from some individuals. Antibodies to ALCAM and JAM-A inhibited the transmigration of both HIV infected and uninfected CD14+CD16+ monocytes across the BBB, demonstrating their importance in facilitating monocyte transmigration and entry into the brain parenchyma. Targeting CCR2, JAM-A, and ALCAM present on CD14+CD16+ monocytes that preferentially infiltrate the CNS represents a therapeutic strategy to reduce viral seeding of the brain as well as the ongoing neuroinflammation that occurs during HIV pathogenesis.
Helen L. Fillmore - One of the best experts on this subject based on the ideXlab platform.
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CD15 and CD15s expression is associated with g1 phase of the cell cycle in glioma cell lines
bioRxiv, 2020Co-Authors: Samah A. Jassam, Zaynah Maherally, Paraskevi Chairta, Geoff Pilkington, Helen L. FillmoreAbstract:Overexpression of the tetrasaccharide carbohydrate epitopes, CD15 and CD15s are associated with non-central nervous system malignancies. While CD15 and CD15s expression is rare in gliomas, recent reports suggest that CD15 may serve as a marker for brain tumour stem-like cells. The aim of this study was to determine if this apparent discrepancy may, in part, be explained by temporal expression of CD15 and CD15s at different phases of the cell cycle. We used flow cytometry, immunocytochemistry and a fluorescence cell cycle indicator (FUCCI) system to examine expression in glioblastoma (GBM) cells (UP-007 and SNB-19) and non-neoplastic astrocytes (SC-1800) synchronised via serum starvation, Hydroxyurea and Nocodazole, respectively. CD15 and CD15s expression was significantly increased in glioma cells synchronised to G1 phase compared with non-synchronised cells (p<0.001). This was supported by qualitative results obtained with the (FUCCI) system. Few studies have considered the possibility of cell-cycle dependent CD15 and CD15s expression which may explain the inconsistencies reported in the literature in terms of expression in glioma stem-like cells where cells are more likely in S phase where CD15 and CD15s expression would be low.
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CD15 and CD15s expression is associated with G1 phase of the cell cycle in glioma cell lines
2020Co-Authors: Samah A. Jassam, Zaynah Maherally, Paraskevi Chairta, Geoff Pilkington, Helen L. FillmoreAbstract:Overexpression of the tetrasaccharide carbohydrate epitopes, CD15 and CD15s are associated with non-central nervous system malignancies. While CD15 and CD15s expression is rare in gliomas, recent reports suggest that CD15 may serve as a marker for brain tumour stem-like cells. The aim of this study was to determine if this apparent discrepancy may, in part, be explained by temporal expression of CD15 and CD15s at different phases of the cell cycle. We used flow cytometry, immunocytochemistry and a fluorescence cell cycle indicator (FUCCI) system to examine expression in glioblastoma (GBM) cells (UP-007 and SNB-19) and non-neoplastic astrocytes (SC-1800) synchronised via serum starvation, Hydroxyurea and Nocodazole, respectively. CD15 and CD15s expression was significantly increased in glioma cells synchronised to G1 phase compared with non-synchronised cells (p
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Fucosyltransferase 4 and 7 mediates adhesion of non-small cell lung cancer cells to brain-derived endothelial cells and results in modification of the blood–brain-barrier: in vitro investigation of CD15 and CD15s in lung-to-brain metastasis
Journal of Neuro-Oncology, 2019Co-Authors: Samah A. Jassam, Zaynah Maherally, Keyoumars Ashkan, Geoffrey J. Pilkington, Helen L. FillmoreAbstract:Purpose Metastatic non-small cell lung (NSCLC) cancer represents one of the most common types of brain metastasis. The mechanisms involved in how circulating cancer cells transmigrate into brain parenchyma are not fully understood. The aim of this work was to investigate the role of fucosylated carbohydrate epitopes CD15 and sialyated CD15s in cancer adhesion to brain-derived endothelial cells and determine their influence in blood–brain barrier (BBB) disruption Methods Three distinct, independent methods were used to measure brain endothelial integrity and include voltohmmeter (EVOM™), impedance spectroscopy (CellZscope®) and electric cell-substrate impedance sensing system (ECIS™). Two fucosyltransferases (FUT4 and 7) responsible for CD15 and CD15s synthesis were modulated in four human cancer cell lines (three lung cancer and one glioma). Results Overexpression of CD15 or CD15s epitopes led to increase in adhesion of cancer cells to cerebral endothelial cells compared with wild-type and cells with silenced CD15 or CD15s (p
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fucosyltransferase 4 and 7 mediates adhesion of non small cell lung cancer cells to brain derived endothelial cells and results in modification of the blood brain barrier in vitro investigation of CD15 and CD15s in lung to brain metastasis
Journal of Neuro-oncology, 2019Co-Authors: Samah A. Jassam, Zaynah Maherally, Keyoumars Ashkan, Geoffrey J. Pilkington, Helen L. FillmoreAbstract:PURPOSE Metastatic non-small cell lung (NSCLC) cancer represents one of the most common types of brain metastasis. The mechanisms involved in how circulating cancer cells transmigrate into brain parenchyma are not fully understood. The aim of this work was to investigate the role of fucosylated carbohydrate epitopes CD15 and sialyated CD15s in cancer adhesion to brain-derived endothelial cells and determine their influence in blood-brain barrier (BBB) disruption METHODS: Three distinct, independent methods were used to measure brain endothelial integrity and include voltohmmeter (EVOM™), impedance spectroscopy (CellZscope®) and electric cell-substrate impedance sensing system (ECIS™). Two fucosyltransferases (FUT4 and 7) responsible for CD15 and CD15s synthesis were modulated in four human cancer cell lines (three lung cancer and one glioma). RESULTS Overexpression of CD15 or CD15s epitopes led to increase in adhesion of cancer cells to cerebral endothelial cells compared with wild-type and cells with silenced CD15 or CD15s (p < 0.01). This overexpression led to the disruption of cerebral endothelial cell monolayers (p < 0.01). Knockdown of FUT4 and FUT7 in metastatic cancer cells prevented disruption of an in vitro BBB model. Surprisingly, although the cells characterised as 'non-metastatic', they became 'metastatic' -like when cells were forced to over-express either FUT4 or FUT7. CONCLUSIONS Results from these studies suggest that overexpression of CD15 and CD15s could potentiate the transmigration of circulating NSCLC cells into the brain. The clinical significance of these studies includes the possible use of these epitopes as biomarkers for metastasis.
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p13 13 trans endothelial migration of non small cell lung cancer cells role of CD15 and CD15s in brain metastasis
Neuro-oncology, 2016Co-Authors: Samah A. Jassam, Zaynah Maherally, Keyoumars Ashkan, Helen L. Fillmore, Geoff PilkingtonAbstract:Introduction: Metastatic non-small cell lung cancer represents the most common cause of brain metastasis in adults. Interaction between circulating cancer cells and brain endothelial cells play a key role in brain metastasis, but their underlining molecular mechanisms are still not fully understood. The CD15 and CD15s epitopes function as cell adhesion molecules and are known to be correlated with metastasis in non-CNS cancers. This study aims to investigate the role of CD15 and CD15s in cancer cell adhesion and trans-endothelial migration during metastasis to the brain by perturbing the expression of the fucosyltransferases responsible for the synthesis of these epitopes.
Samah A. Jassam - One of the best experts on this subject based on the ideXlab platform.
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CD15 and CD15s expression is associated with g1 phase of the cell cycle in glioma cell lines
bioRxiv, 2020Co-Authors: Samah A. Jassam, Zaynah Maherally, Paraskevi Chairta, Geoff Pilkington, Helen L. FillmoreAbstract:Overexpression of the tetrasaccharide carbohydrate epitopes, CD15 and CD15s are associated with non-central nervous system malignancies. While CD15 and CD15s expression is rare in gliomas, recent reports suggest that CD15 may serve as a marker for brain tumour stem-like cells. The aim of this study was to determine if this apparent discrepancy may, in part, be explained by temporal expression of CD15 and CD15s at different phases of the cell cycle. We used flow cytometry, immunocytochemistry and a fluorescence cell cycle indicator (FUCCI) system to examine expression in glioblastoma (GBM) cells (UP-007 and SNB-19) and non-neoplastic astrocytes (SC-1800) synchronised via serum starvation, Hydroxyurea and Nocodazole, respectively. CD15 and CD15s expression was significantly increased in glioma cells synchronised to G1 phase compared with non-synchronised cells (p<0.001). This was supported by qualitative results obtained with the (FUCCI) system. Few studies have considered the possibility of cell-cycle dependent CD15 and CD15s expression which may explain the inconsistencies reported in the literature in terms of expression in glioma stem-like cells where cells are more likely in S phase where CD15 and CD15s expression would be low.
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CD15 and CD15s expression is associated with G1 phase of the cell cycle in glioma cell lines
2020Co-Authors: Samah A. Jassam, Zaynah Maherally, Paraskevi Chairta, Geoff Pilkington, Helen L. FillmoreAbstract:Overexpression of the tetrasaccharide carbohydrate epitopes, CD15 and CD15s are associated with non-central nervous system malignancies. While CD15 and CD15s expression is rare in gliomas, recent reports suggest that CD15 may serve as a marker for brain tumour stem-like cells. The aim of this study was to determine if this apparent discrepancy may, in part, be explained by temporal expression of CD15 and CD15s at different phases of the cell cycle. We used flow cytometry, immunocytochemistry and a fluorescence cell cycle indicator (FUCCI) system to examine expression in glioblastoma (GBM) cells (UP-007 and SNB-19) and non-neoplastic astrocytes (SC-1800) synchronised via serum starvation, Hydroxyurea and Nocodazole, respectively. CD15 and CD15s expression was significantly increased in glioma cells synchronised to G1 phase compared with non-synchronised cells (p
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Fucosyltransferase 4 and 7 mediates adhesion of non-small cell lung cancer cells to brain-derived endothelial cells and results in modification of the blood–brain-barrier: in vitro investigation of CD15 and CD15s in lung-to-brain metastasis
Journal of Neuro-Oncology, 2019Co-Authors: Samah A. Jassam, Zaynah Maherally, Keyoumars Ashkan, Geoffrey J. Pilkington, Helen L. FillmoreAbstract:Purpose Metastatic non-small cell lung (NSCLC) cancer represents one of the most common types of brain metastasis. The mechanisms involved in how circulating cancer cells transmigrate into brain parenchyma are not fully understood. The aim of this work was to investigate the role of fucosylated carbohydrate epitopes CD15 and sialyated CD15s in cancer adhesion to brain-derived endothelial cells and determine their influence in blood–brain barrier (BBB) disruption Methods Three distinct, independent methods were used to measure brain endothelial integrity and include voltohmmeter (EVOM™), impedance spectroscopy (CellZscope®) and electric cell-substrate impedance sensing system (ECIS™). Two fucosyltransferases (FUT4 and 7) responsible for CD15 and CD15s synthesis were modulated in four human cancer cell lines (three lung cancer and one glioma). Results Overexpression of CD15 or CD15s epitopes led to increase in adhesion of cancer cells to cerebral endothelial cells compared with wild-type and cells with silenced CD15 or CD15s (p
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fucosyltransferase 4 and 7 mediates adhesion of non small cell lung cancer cells to brain derived endothelial cells and results in modification of the blood brain barrier in vitro investigation of CD15 and CD15s in lung to brain metastasis
Journal of Neuro-oncology, 2019Co-Authors: Samah A. Jassam, Zaynah Maherally, Keyoumars Ashkan, Geoffrey J. Pilkington, Helen L. FillmoreAbstract:PURPOSE Metastatic non-small cell lung (NSCLC) cancer represents one of the most common types of brain metastasis. The mechanisms involved in how circulating cancer cells transmigrate into brain parenchyma are not fully understood. The aim of this work was to investigate the role of fucosylated carbohydrate epitopes CD15 and sialyated CD15s in cancer adhesion to brain-derived endothelial cells and determine their influence in blood-brain barrier (BBB) disruption METHODS: Three distinct, independent methods were used to measure brain endothelial integrity and include voltohmmeter (EVOM™), impedance spectroscopy (CellZscope®) and electric cell-substrate impedance sensing system (ECIS™). Two fucosyltransferases (FUT4 and 7) responsible for CD15 and CD15s synthesis were modulated in four human cancer cell lines (three lung cancer and one glioma). RESULTS Overexpression of CD15 or CD15s epitopes led to increase in adhesion of cancer cells to cerebral endothelial cells compared with wild-type and cells with silenced CD15 or CD15s (p < 0.01). This overexpression led to the disruption of cerebral endothelial cell monolayers (p < 0.01). Knockdown of FUT4 and FUT7 in metastatic cancer cells prevented disruption of an in vitro BBB model. Surprisingly, although the cells characterised as 'non-metastatic', they became 'metastatic' -like when cells were forced to over-express either FUT4 or FUT7. CONCLUSIONS Results from these studies suggest that overexpression of CD15 and CD15s could potentiate the transmigration of circulating NSCLC cells into the brain. The clinical significance of these studies includes the possible use of these epitopes as biomarkers for metastasis.
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p13 13 trans endothelial migration of non small cell lung cancer cells role of CD15 and CD15s in brain metastasis
Neuro-oncology, 2016Co-Authors: Samah A. Jassam, Zaynah Maherally, Keyoumars Ashkan, Helen L. Fillmore, Geoff PilkingtonAbstract:Introduction: Metastatic non-small cell lung cancer represents the most common cause of brain metastasis in adults. Interaction between circulating cancer cells and brain endothelial cells play a key role in brain metastasis, but their underlining molecular mechanisms are still not fully understood. The CD15 and CD15s epitopes function as cell adhesion molecules and are known to be correlated with metastasis in non-CNS cancers. This study aims to investigate the role of CD15 and CD15s in cancer cell adhesion and trans-endothelial migration during metastasis to the brain by perturbing the expression of the fucosyltransferases responsible for the synthesis of these epitopes.
Dionna W Williams - One of the best experts on this subject based on the ideXlab platform.
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Dopamine Increases CD14^+CD16^+ Monocyte Transmigration across the Blood Brain Barrier: Implications for Substance Abuse and HIV Neuropathogenesis
Journal of Neuroimmune Pharmacology, 2017Co-Authors: Tina M Calderon, Dionna W Williams, Eliseo A Eugenin, Lillie Lopez, Laura Cheney, Peter J. Gaskill, Mike Veenstra, Kathryn Anastos, Susan Morgello, Joan W BermanAbstract:In human immunodeficiency virus-1 (HIV) infected individuals, substance abuse may accelerate the development and/or increase the severity of HIV associated neurocognitive disorders (HAND). It is proposed that CD14^+CD16^+ monocytes mediate HIV entry into the central nervous system (CNS) and that uninfected and infected CD14^+CD16^+ monocyte transmigration across the blood brain barrier (BBB) contributes to the establishment and propagation of CNS HIV viral reservoirs and chronic neuroinflammation, important factors in the development of HAND. The effects of substance abuse on the frequency of CD14^+CD16^+ monocytes in the peripheral circulation and on the entry of these cells into the CNS during HIV neuropathogenesis are not known. PBMC from HIV infected individuals were analyzed by flow cytometry and we demonstrate that the frequency of peripheral blood CD14^+CD16^+ monocytes in HIV infected substance abusers is increased when compared to those without active substance use. Since drug use elevates extracellular dopamine concentrations in the CNS, we examined the effects of dopamine on CD14^+CD16^+ monocyte transmigration across our in vitro model of the human BBB. The transmigration of this monocyte subpopulation is increased by dopamine and the dopamine receptor agonist, SKF 38393, implicating D1-like dopamine receptors in the increase in transmigration elicited by this neurotransmitter. Thus, elevated extracellular CNS dopamine may be a novel common mechanism by which active substance use increases uninfected and HIV infected CD14^+CD16^+ monocyte transmigration across the BBB. The influx of these cells into the CNS may increase viral seeding and neuroinflammation, contributing to the development of HIV associated neurocognitive impairments.
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jam a and alcam are therapeutic targets to inhibit diapedesis across the bbb of cd14 cd16 monocytes in hiv infected individuals
Journal of Leukocyte Biology, 2015Co-Authors: Dionna W Williams, Kathryn Anastos, Susan Morgello, Joan W BermanAbstract:: Monocyte transmigration across the BBB is a critical step in the development of cognitive deficits termed HAND that affect 40-70% of HIV-infected individuals, even with successful antiretroviral therapy. The monocyte subsets that enter the CNS during HIV infection are not fully characterized. We examined PBMC from HIV-positive individuals from 2 distinct cohorts and enumerated monocyte populations, characterized their transmigration properties across an in vitro human BBB model, and identified surface proteins critical for the entry of these cells into the CNS. We demonstrated that the frequency of peripheral blood CD14(+)CD16(+) and CD14(low)CD16(+) monocytes was increased in HIV-seropositive compared with -seronegative individuals, despite virologic control. We showed that CD14(+)CD16(+) monocytes selectively transmigrated across our BBB model as a result of their increased JAM-A and ALCAM expression. Antibody blocking of these proteins inhibited diapedesis of CD14(+)CD16(+) monocytes but not of T cells from the same HIV-infected people across the BBB. Our data indicate that JAM-A and ALCAM are therapeutic targets to decrease the entry of CD14(+)CD16(+) monocytes into the CNS of HIV-seropositive individuals, contributing to the eradication of neuroinflammation, HAND, and CNS viral reservoirs.
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JAM-A and ALCAM are therapeutic targets to inhibit diapedesis across the BBB of CD14+CD16+ monocytes in HIV-infected individuals
Journal of Leukocyte Biology, 2014Co-Authors: Dionna W Williams, Kathryn Anastos, Susan Morgello, Joan W BermanAbstract:: Monocyte transmigration across the BBB is a critical step in the development of cognitive deficits termed HAND that affect 40-70% of HIV-infected individuals, even with successful antiretroviral therapy. The monocyte subsets that enter the CNS during HIV infection are not fully characterized. We examined PBMC from HIV-positive individuals from 2 distinct cohorts and enumerated monocyte populations, characterized their transmigration properties across an in vitro human BBB model, and identified surface proteins critical for the entry of these cells into the CNS. We demonstrated that the frequency of peripheral blood CD14(+)CD16(+) and CD14(low)CD16(+) monocytes was increased in HIV-seropositive compared with -seronegative individuals, despite virologic control. We showed that CD14(+)CD16(+) monocytes selectively transmigrated across our BBB model as a result of their increased JAM-A and ALCAM expression. Antibody blocking of these proteins inhibited diapedesis of CD14(+)CD16(+) monocytes but not of T cells from the same HIV-infected people across the BBB. Our data indicate that JAM-A and ALCAM are therapeutic targets to decrease the entry of CD14(+)CD16(+) monocytes into the CNS of HIV-seropositive individuals, contributing to the eradication of neuroinflammation, HAND, and CNS viral reservoirs.
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mechanisms of hiv entry into the cns increased sensitivity of hiv infected cd14 cd16 monocytes to ccl2 and key roles of ccr2 jam a and alcam in diapedesis
PLOS ONE, 2013Co-Authors: Dionna W Williams, Eliseo A Eugenin, Tina M Calderon, Lillie Lopez, Peter J. Gaskill, Susan Morgello, Loreto Carvallotorres, Joan W BermanAbstract:As HIV infected individuals live longer, the prevalence of HIV associated neurocognitive disorders is increasing, despite successful antiretroviral therapy. CD14+CD16+ monocytes are critical to the neuropathogenesis of HIV as they promote viral seeding of the brain and establish neuroinflammation. The mechanisms by which HIV infected and uninfected monocytes cross the blood brain barrier and enter the central nervous system are not fully understood. We determined that HIV infection of CD14+CD16+ monocytes resulted in their highly increased transmigration across the blood brain barrier in response to CCL2 as compared to uninfected cells, which did not occur in the absence of the chemokine. This exuberant transmigration of HIV infected monocytes was due, at least in part, to increased CCR2 and significantly heightened sensitivity to CCL2. The entry of HIV infected and uninfected CD14+CD16+ monocytes into the brain was facilitated by significantly increased surface JAM-A, ALCAM, CD99, and PECAM-1, as compared to CD14+ cells that are CD16 negative. Upon HIV infection, there was an additional increase in surface JAM-A and ALCAM on CD14+CD16+ monocytes isolated from some individuals. Antibodies to ALCAM and JAM-A inhibited the transmigration of both HIV infected and uninfected CD14+CD16+ monocytes across the BBB, demonstrating their importance in facilitating monocyte transmigration and entry into the brain parenchyma. Targeting CCR2, JAM-A, and ALCAM present on CD14+CD16+ monocytes that preferentially infiltrate the CNS represents a therapeutic strategy to reduce viral seeding of the brain as well as the ongoing neuroinflammation that occurs during HIV pathogenesis.
Keyoumars Ashkan - One of the best experts on this subject based on the ideXlab platform.
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Fucosyltransferase 4 and 7 mediates adhesion of non-small cell lung cancer cells to brain-derived endothelial cells and results in modification of the blood–brain-barrier: in vitro investigation of CD15 and CD15s in lung-to-brain metastasis
Journal of Neuro-Oncology, 2019Co-Authors: Samah A. Jassam, Zaynah Maherally, Keyoumars Ashkan, Geoffrey J. Pilkington, Helen L. FillmoreAbstract:Purpose Metastatic non-small cell lung (NSCLC) cancer represents one of the most common types of brain metastasis. The mechanisms involved in how circulating cancer cells transmigrate into brain parenchyma are not fully understood. The aim of this work was to investigate the role of fucosylated carbohydrate epitopes CD15 and sialyated CD15s in cancer adhesion to brain-derived endothelial cells and determine their influence in blood–brain barrier (BBB) disruption Methods Three distinct, independent methods were used to measure brain endothelial integrity and include voltohmmeter (EVOM™), impedance spectroscopy (CellZscope®) and electric cell-substrate impedance sensing system (ECIS™). Two fucosyltransferases (FUT4 and 7) responsible for CD15 and CD15s synthesis were modulated in four human cancer cell lines (three lung cancer and one glioma). Results Overexpression of CD15 or CD15s epitopes led to increase in adhesion of cancer cells to cerebral endothelial cells compared with wild-type and cells with silenced CD15 or CD15s (p
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fucosyltransferase 4 and 7 mediates adhesion of non small cell lung cancer cells to brain derived endothelial cells and results in modification of the blood brain barrier in vitro investigation of CD15 and CD15s in lung to brain metastasis
Journal of Neuro-oncology, 2019Co-Authors: Samah A. Jassam, Zaynah Maherally, Keyoumars Ashkan, Geoffrey J. Pilkington, Helen L. FillmoreAbstract:PURPOSE Metastatic non-small cell lung (NSCLC) cancer represents one of the most common types of brain metastasis. The mechanisms involved in how circulating cancer cells transmigrate into brain parenchyma are not fully understood. The aim of this work was to investigate the role of fucosylated carbohydrate epitopes CD15 and sialyated CD15s in cancer adhesion to brain-derived endothelial cells and determine their influence in blood-brain barrier (BBB) disruption METHODS: Three distinct, independent methods were used to measure brain endothelial integrity and include voltohmmeter (EVOM™), impedance spectroscopy (CellZscope®) and electric cell-substrate impedance sensing system (ECIS™). Two fucosyltransferases (FUT4 and 7) responsible for CD15 and CD15s synthesis were modulated in four human cancer cell lines (three lung cancer and one glioma). RESULTS Overexpression of CD15 or CD15s epitopes led to increase in adhesion of cancer cells to cerebral endothelial cells compared with wild-type and cells with silenced CD15 or CD15s (p < 0.01). This overexpression led to the disruption of cerebral endothelial cell monolayers (p < 0.01). Knockdown of FUT4 and FUT7 in metastatic cancer cells prevented disruption of an in vitro BBB model. Surprisingly, although the cells characterised as 'non-metastatic', they became 'metastatic' -like when cells were forced to over-express either FUT4 or FUT7. CONCLUSIONS Results from these studies suggest that overexpression of CD15 and CD15s could potentiate the transmigration of circulating NSCLC cells into the brain. The clinical significance of these studies includes the possible use of these epitopes as biomarkers for metastasis.
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p13 13 trans endothelial migration of non small cell lung cancer cells role of CD15 and CD15s in brain metastasis
Neuro-oncology, 2016Co-Authors: Samah A. Jassam, Zaynah Maherally, Keyoumars Ashkan, Helen L. Fillmore, Geoff PilkingtonAbstract:Introduction: Metastatic non-small cell lung cancer represents the most common cause of brain metastasis in adults. Interaction between circulating cancer cells and brain endothelial cells play a key role in brain metastasis, but their underlining molecular mechanisms are still not fully understood. The CD15 and CD15s epitopes function as cell adhesion molecules and are known to be correlated with metastasis in non-CNS cancers. This study aims to investigate the role of CD15 and CD15s in cancer cell adhesion and trans-endothelial migration during metastasis to the brain by perturbing the expression of the fucosyltransferases responsible for the synthesis of these epitopes.
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PO56EXPRESSION OF CD15 AND CD15S IS CORRELATED WITH GLIOMA CELL ARREST AT G1-PHASE
Neuro-Oncology, 2015Co-Authors: Samah A. Jassam, Zaynah Maherally, Keyoumars Ashkan, Helen L. Fillmore, Paraskevi Chairta, Geoffrey J. PilkingtonAbstract:INTRODUCTION: CD15 and CD15s are cell surface epitopes, known for their ability to bind specific ligands. They are over-expressed on many non-central nervous system (CNS) cancers. Few reports show CD15 expression in CNS neoplasms and in fact, early studies reported the absence of CD15 expression. Recent published reports, however, have identified CD15 as a potential marker for cancer stem-like cells in glioblastomas (GBM). To obtain a better understanding, CD15 and CD15s expression were re-examined in glioma cell lines. METHOD: Extracellular expression of CD15 and CD15s were determined by Immunocytochemistry, Western blotting and flow cytometry in GBM cells (UP-007 and SNB-19). Non-neoplastic astrocytes (SC-1800) served as controls. Cells were synchronised at G1, S or G2/M phases via serum starvation, Hydroxyurea and Colcemid, respectively followed by validation using the fluorescence ubiqutination cell cycle indicator (FUCCI) system. RESULTS: In non-synchronised cultures, only 5-12% of GBM cells expressed CD15 and CD15s where respective cell cycle distributions averaged 55-59% for G1, 6-13% for S and 15-25% for G2/M. When GBM cells were synchronised in G1, a higher percentage of cells expressed CD15 (18-20%) and CD15s (35-50%) compared to SC-1800 cells CD15 (1.5%), CD15s (1.0%). Of GBM cells synchronised in S phase (G1, 25-34%; S, 56-64%; G2/M, 1-5%), 7-10% of GBM cells were CD15 positive. Of GBM cells synchronised to G1/M phase (G1, 20%; S, 6-18%; G2/M, 71-76%) 4.5-14% of cells were CD15 positive. CONCLUSION: CD15 and CD15s expression is cell cycle dependent in glioma cells and may account for the discrepancy of previous experimental data.