Suppression of Ischemia-Induced Hippocampal Pyramidal Neuron Death by Hyaluronan Tetrasaccharide through Inhibition of Toll-Like Receptor 2 Signaling Pathway.
Toll-like receptors (TLRs) are one of the main contributors that induce inflammation under tissue injury and infection. Because excessive inflammation can aggravate disease states, it is important to control inflammation at a moderate level. Herein, we show that hyaluronan (HA) oligomer, HA tetrasaccharide (HA4), could suppress the expression of proinflammatory cytokine IL-1β when stimulated with both TLR2- and TLR4-specific agonists in primary hippocampal neurons. To understand the effect of HA4 against ischemic insult, we performed hypoxic-ischemic (H/I) brain injury against neonatal mice. HA4 treatment significantly prevented hippocampal pyramidal cell death even 7 days after H/I injury, compared with the control mice. Although TLR2 and TLR4 are known as receptors for HA and also act as a receptor for inducing inflammation, only TLR2-deficient mice showed tolerance against H/I injury. Moreover, HA4 administration suppressed gliosis by inhibiting the activation of NF-κB, the downstream target of TLR2, which led to the suppression of IL-1β expression. Taken together, our data suggest that the neuroprotective effect of HA4 relies on antagonizing the TLR2/NF-κB pathway to reduce inflammation through suppressing the expression of proinflammatory cytokines after neonatal H/I brain injury.
Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, Bunkyo-Ku, Tokyo, Japan; Department of Cellular and Molecular Neuropathology, Juntendo University Graduate School of Medicine, Bunkyo-Ku, Tokyo, Japan.
Takehiko
T
Sunabori
Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, Bunkyo-Ku, Tokyo, Japan.
Masato
M
Koike
Department of Biomedical Engineering (ND20), Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio.
Akira
A
Asari
Glycoscience Laboratories Inc., Tokyo, Japan.
Yoji
Y
Oonuki
Department of Cellular and Molecular Neuropathology, Juntendo University Graduate School of Medicine, Bunkyo-Ku, Tokyo, Japan. Electronic address: y-uchi@juntendo.ac.jp.
Yasuo
Y
Uchiyama
D000818:Animals; D016923:Cell Death; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006820:Hyaluronic Acid / Q000737:chemistry / Q000494:pharmacology*; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000473:pathology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D018696:Neuroprotective Agents; D016133:Polymerase Chain Reaction; D017966:Pyramidal Cells / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D051195:Toll-Like Receptor 2 / Q000378:metabolism*
D018696:Neuroprotective Agents; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D006820:Hyaluronic Acid