title: Neuregulin1-β decreases interleukin-1β-induced RhoA activation, myosin light chain phosphorylation, and endothelial hyperpermeability.
abstract: Neuregulin-1 (NRG1) is an endogenous growth factor with multiple functions in the embryonic and postnatal brain. The NRG1 gene is large and complex, transcribing more than twenty transmembrane proteins and generating a large number of isoforms in tissue and cell type-specific patterns. Within the brain, NRG1 functions have been studied most extensively in neurons and glia, as well as in the peripheral vasculature. Recently, NRG1 signaling has been found to be important in the function of brain microvascular endothelial cells, decreasing IL-1β-induced increases in endothelial permeability. In the current experiments, we have investigated the pathways through which the NRG1-β isoform acts on IL-1β-induced endothelial permeability. Our data show that NRG1-β increases barrier function, measured by transendothelial electrical resistance, and decreases IL-1β-induced hyperpermeability, measured by dextran-40 extravasation through a monolayer of brain microvascular endothelial cells plated on transwells. An investigation of key signaling proteins suggests that the effect of NRG1-β on endothelial permeability is mediated through RhoA activation and myosin light chain phosphorylation, events which affect filamentous actin morphology. In addition, AG825, an inhibitor of the erbB2-associated tyrosine kinase, reduces the effect of NRG1-β on IL-1β-induced RhoA activation and myosin light chain phosphorylation. These data add to the evidence that NRG1-β signaling affects changes in the brain microvasculature in the setting of neuroinflammation. We propose the following events for neuregulin-1-mediated effects on Interleukin-1 β (IL-1β)-induced endothelial hyperpermeability: IL-1β leads to RhoA activation, resulting in an increase in phosphorylation of myosin light chain (MLC). Phosphorylation of MLC is known to result in actin contraction and alterations in the f-actin cytoskeletal structure. These changes are associated with increased endothelial permeability. Neuregulin-1β acts through its transmembrane receptors to activate intracellular signaling pathways which inhibit IL-1β-induced RhoA activation and MLC phosphorylation, thereby preserving the f-actin cytoskeletal structure and endothelial barrier function.
authors.affiliation: Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.|Department of Neurology, the First Bethune Hospital of Jilin University, Changchun, Jilin, China.
authors.forename: Limin
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Pathology & Laboratory Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.|The Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Servio H
authors.initials: SH
authors.lastname: Ramirez
authors.affiliation: Department of Pathology & Laboratory Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Allison M
authors.identifier: http://orcid.org/0000-0003-1752-7450
authors.initials: AM
authors.lastname: Andrews
authors.affiliation: Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Leung
authors.affiliation: Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Kanako
authors.initials: K
authors.lastname: Itoh
authors.affiliation: Department of Neurology, the First Bethune Hospital of Jilin University, Changchun, Jilin, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Wu
authors.affiliation: Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Arai
authors.affiliation: Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.|Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
authors.affiliation: Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.|Department of Pediatrics, Pediatric Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Josephine
authors.initials: J
authors.lastname: Lok
mesh_terms: D000293:Adolescent; D052160:Benzothiazoles / Q000494:pharmacology; D001921:Brain; D002478:Cells, Cultured; D017097:Electric Impedance; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D018994:Myosin Light Chains / Q000378:metabolism*; D020890:Neuregulin-1 / Q000378:metabolism / Q000494:pharmacology*; D010539:Permeability / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020032:Tyrphostins / Q000494:pharmacology; D055815:Young Adult; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D018994:Myosin Light Chains; C094131:NRG1 protein, human; D020890:Neuregulin-1; D020032:Tyrphostins; C098214:tyrphostin AG825; D054460:rho-Associated Kinases
keywords: IL-1β; RhoA; endothelial; myosin light chain; neuregulin-1; permeability