TLR2 activation inhibits embryonic neural progenitor cell proliferation.
Toll-like receptors (TLRs) play essential roles in innate immunity, and increasing evidence indicates that these receptors are expressed in neurons, astrocytes, and microglia in the brain, where they mediate responses to infection, stress, and injury. To address the possibility that TLR2 heterodimer activation could affect progenitor cells in the developing brain, we analyzed the expression of TLR2 throughout mouse cortical development, and assessed the role of TLR2 heterodimer activation in neuronal progenitor cell (NPC) proliferation. TLR2 mRNA and protein was expressed in the cortex in embryonic and early postnatal stages of development, and in cultured cortical NPC. While NPC from TLR2-deficient and wild type embryos had the same proliferative capacity, TLR2 activation by the synthetic bacterial lipopeptides Pam(3)CSK(4) and FSL1, or low molecular weight hyaluronan, an endogenous ligand for TLR2, inhibited neurosphere formation in vitro. Intracerebral in utero administration of TLR2 ligands resulted in ventricular dysgenesis characterized by increased ventricle size, reduced proliferative area around the ventricles, increased cell density, an increase in phospho-histone 3 cells, and a decrease in BrdU(+) cells in the sub-ventricular zone. Our findings indicate that loss of TLR2 does not result in defects in cerebral development. However, TLR2 is expressed and functional in the developing telencephalon from early embryonic stages and infectious agent-related activation of TLR2 inhibits NPC proliferation. TLR2-mediated inhibition of NPC proliferation may therefore be a mechanism by which infection, ischemia, and inflammation adversely affect brain development.
Okun
Eitan
E
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland 21224, USA.
Griffioen
Kathleen J
KJ
Son
Tae Gen
TG
Lee
Jong-Hwan
JH
Roberts
Nicholas J
NJ
Mughal
Mohamed R
MR
Hutchison
Emmette
E
Cheng
Aiwu
A
Arumugam
Thiruma V
TV
Lathia
Justin D
JD
van Praag
Henriette
H
Mattson
Mark P
MP
D000818:Animals; D000831:Animals, Newborn; D002452:Cell Count; D049109:Cell Proliferation; D002478:Cells, Cultured; D002552:Cerebral Ventricles / Q000002:abnormalities / Q000166:cytology; D004075:Diglycerides / Q000494:pharmacology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006820:Hyaluronic Acid / Q000494:pharmacology; D055666:Lipopeptides / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis; D013687:Telencephalon / Q000166:cytology / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics
D004075:Diglycerides; C460864:FSL-1 lipoprotein, synthetic; D006657:Histones; D055666:Lipopeptides; D009842:Oligopeptides; C508075:Pam(3)CSK(4) peptide; D012333:RNA, Messenger; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D006820:Hyaluronic Acid
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