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1.
Cell Rep ; 18(5): 1256-1269, 2017 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-28147279

RESUMO

Endothelial basement membranes constitute barriers to extravasating leukocytes during inflammation, a process where laminin isoforms define sites of leukocyte exit; however, how this occurs is poorly understood. In addition to a direct effect on leukocyte transmigration, we show that laminin 511 affects endothelial barrier function by stabilizing VE-cadherin at junctions and downregulating expression of CD99L2, correlating with reduced neutrophil extravasation. Binding of endothelial cells to laminin 511, but not laminin 411 or non-endothelial laminin 111, enhanced transendothelial cell electrical resistance (TEER) and inhibited neutrophil transmigration. Data suggest that endothelial adhesion to laminin 511 via ß1 and ß3 integrins mediates RhoA-induced VE-cadherin localization to cell-cell borders, and while CD99L2 downregulation requires integrin ß1, it is RhoA-independent. Our data demonstrate that molecular information provided by basement membrane laminin 511 affects leukocyte extravasation both directly and indirectly by modulating endothelial barrier properties.


Assuntos
Membrana Basal/metabolismo , Movimento Celular/fisiologia , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Laminina/metabolismo , Leucócitos/metabolismo , Animais , Antígenos CD/metabolismo , Caderinas/metabolismo , Adesão Celular/fisiologia , Células Cultivadas , Masculino , Camundongos , Camundongos Knockout , Neutrófilos/metabolismo , Neutrófilos/fisiologia
2.
Nat Commun ; 7: 10828, 2016 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-26940548

RESUMO

Acute peritonitis is a frequent medical condition that can trigger severe sepsis as a life-threatening complication. Neutrophils are first-responders in infection but recruitment mechanisms to the abdominal cavity remain poorly defined. Here, we demonstrate that high endothelial venules (HEVs) of the greater omentum constitute a main entry pathway in TNFα-, Escherichia coli (E. coli)- and caecal ligation and puncture-induced models of inflammation. Neutrophil transmigration across HEVs is faster than across conventional postcapillary venules and requires a unique set of adhesion receptors including peripheral node addressin, E-, L-selectin and Mac-1 but not P-selectin or LFA-1. Omental milky spots readily concentrate intra-abdominal E. coli where macrophages and recruited neutrophils collaborate in phagocytosis and killing. Inhibition of the omental neutrophil response exacerbates septic progression of peritonitis. This data identifies HEVs as a clinically relevant vascular recruitment site for neutrophils in acute peritonitis that is indispensable for host defence against early systemic bacterial spread and sepsis.


Assuntos
Neutrófilos/fisiologia , Omento/irrigação sanguínea , Peritonite/imunologia , Sepse/imunologia , Vênulas/fisiologia , Animais , Antígenos Ly/genética , Antígenos Ly/metabolismo , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Escherichia coli , Infecções por Escherichia coli/imunologia , Feminino , Regulação da Expressão Gênica , Genes Transgênicos Suicidas , Masculino , Camundongos , Camundongos Knockout , Fator de Necrose Tumoral alfa/metabolismo
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