title: Activation of microglial Toll-like receptor 3 promotes neuronal survival against cerebral ischemia.
abstract: Emerging experimental evidence suggests that activation of Toll-like receptor 3 (TLR3) by its agonist polyinosinic polycytidylic acid (poly-ICLC) protects neurons against cerebral ischemia, but the underlying mechanisms remain largely unknown. In the brain, TLR3 is mostly expressed in glial cells. Therefore, we assess the hypothesis that TLR3 activation in microglia is required for neuroprotection against ischemia. After transient focal cerebral ischemia, microglia/macrophages (MMs) demonstrate a significant reduction in TLR3 and its downstream cytokine interleukin 6 (IL-6). Subsequently, activation of TLR3 by poly-ICLC restored TLR3 expression and decreased infarction. To further investigate these mechanisms, we turned to a primary cell culture system. Consistent with the in vivo findings, oxygen-glucose deprivation (OGD) significantly reduced TLR3 and IL-6 mRNA expression in microglia, but poly-ICLC significantly rescued TLR3 and IL-6 expression. Importantly, conditioned media from OGD-treated microglia increased neuronal death after OGD. In contrast, the conditioned media from microglia treated with poly-ICLC after OGD significantly protected against OGD-induced neuron death. Taken together, our findings provide proof-of-concept that activation of TLR3 in microglia may promote neuron survival after ischemia. We assessed the hypothesis that Toll-like receptor 3 (TLR3) activation in microglia is required for neuroprotection against ischemia. After transient focal cerebral ischemia, microglia/macrophage demonstrates a reduction in TLR3 and Interleukin 6 (IL-6). Also, oxygen-glucose deprivation (OGD) reduces TLR3 and IL-6 expression in microglia, but polyinosinic polycytidylic acid (poly-ICLC) rescues TLR3 and IL-6. Importantly, conditioned media from microglia treated with poly-ICLC protects against OGD-induced neuron death. We propose that activation of TLR3 in microglia may promote neuron survival after ischemia.
authors.affiliation: College of Pharmacy, Sookmyung Women's University, Seoul, Korea.
authors.forename: Si-Yeon
authors.initials: SY
authors.lastname: Jeong
authors.affiliation: College of Pharmacy, Sookmyung Women's University, Seoul, Korea.
authors.forename: Raok
authors.initials: R
authors.lastname: Jeon
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Yoon Kyung
authors.initials: YK
authors.lastname: Choi
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Joo Eun
authors.initials: JE
authors.lastname: Jung
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Liang
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Changhong
authors.initials: C
authors.lastname: Xing
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Wang
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
authors.affiliation: College of Pharmacy, Sookmyung Women's University, Seoul, Korea.|Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Yun Seon
authors.initials: YS
authors.lastname: Song
keywords: Toll-like receptor 3; cerebral ischemia; interleukin-6; microglia; neuroprotection; oxygen glucose deprivation