TLR2 activation inhibits embryonic neural progenitor cell proliferation

Abstract

J. Neurochem. (2010) 114, 462–474. Abstract 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 Pam3CSK4 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.

The functional expression of TLR3 in EPCs impairs cell proliferation by induction of cell apoptosis and cell cycle progress inhibition

“…The activation of TLR3 and TLR4 with ligands inhibited the ability of these cells to suppress the proliferation of T cells by impairing Notch signaling [27]. TLR2 is expressed and functional in the developing telencephalon from early embryonic stages, and the infectious agent-related activation of TLR2 inhibits neuronal progenitor cell proliferation [28]. TLR2-agonist stimulation increases the amount of IL-6 and IL-8 cytokines secreted by adult renal progenitor/stem cells, and induced proliferation of these cells [29].…”

Human Neural Progenitor Cells Show Functional Neuronal Differentiation and Regional Preference After Engraftment onto Hippocampal Slice Cultures

“…The failure of the hNPCs to differentiate into astrocytes or oligodendrocytes while showing some degree of neuronal differentiation hints that the hNPCs remain neurogenic, as neurogenesis and gliogenesis are temporally segregated in the developing brain [47,48]. Therefore, given the appropriate cues, a much greater proportion of neurons might be obtained from this and similar immortalized hNPC lines.…”

TLR2 Hypersensitivity of Astrocytes as Functional Consequence of Previous Inflammatory Episodes

“…As TLR2 activation triggers a further release of inflammatory factors, a self-sustaining inflammatory loop may be generated in the brain and may explain glial long-term activation (10,11,19,27). In brain, TLR2 upregulation has indeed been observed in several CNS disease states (6,26,(28)(29)(30) and may be functionally involved in the damage generation (22)(23)(24)(31)(32)(33)(34)(35).…”

“…Such situations arise under conditions of damage, aging, or neurodegeneration, when astrocytes are pre-exposed to TNF-a or IL-1b, and then faced with a respective microbial stimulus, virus, or components of damaged tissue (e.g., low m.w. hyaluronan [35]) that stimulates TLR2.…”