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Neuregulin1‐β decreases interleukin‐1β‐induced RhoA activation, myosin light chain phosphorylation, and endothelial hyperpermeability
Author(s) -
Wu Limin,
Ramirez Servio H.,
Andrews Allison M.,
Leung Wendy,
Itoh Kanako,
Wu Jiang,
Arai Ken,
Lo Eng H.,
Lok Josephine
Publication year - 2016
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13374
Subject(s) - rhoa , microbiology and biotechnology , myosin light chain kinase , phosphorylation , tyrosine phosphorylation , biology , neuregulin 1 , signal transduction , endothelial stem cell , biochemistry , in vitro
Neuregulin‐1 ( NRG 1) is an endogenous growth factor with multiple functions in the embryonic and postnatal brain. The NRG 1 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, NRG 1 functions have been studied most extensively in neurons and glia, as well as in the peripheral vasculature. Recently, NRG 1 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 NRG 1‐β isoform acts on IL ‐1β‐induced endothelial permeability. Our data show that NRG 1‐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 NRG 1‐β on endothelial permeability is mediated through RhoA activation and myosin light chain phosphorylation, events which affect filamentous actin morphology. In addition, AG 825, an inhibitor of the erbB2‐associated tyrosine kinase, reduces the effect of NRG 1‐β on IL ‐1β‐induced RhoA activation and myosin light chain phosphorylation. These data add to the evidence that NRG 1‐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.