TLR Activation Induces TNF-α Production from Adult Neural Stem/Progenitor Cells

Abstract

Adult neural stem cells (NSCs) are believed to facilitate CNS repair and tissue regeneration. However, it is not yet clear how these cells are influenced when the cellular environment is modified during neurotrauma or neuroinflammatory conditions. In this study, we determine how different proinflammatory cytokines modulate the expression of TLR2 and TLR4 in NSCs and how these cells respond to TLR2 and TLR4 agonists. Primary cultures of neural stem/progenitor cells isolated from the subventricular zone of brains from adult Dark Agouti rats were exposed to 1) supernatants from activated macrophages; 2) proinflammatory cytokines IFN-gamma, TNF-alpha, or both; and 3) agonists for TLR2 and TLR4. Both TLR2 and TLR4 were expressed during basal conditions and their mRNA levels were further increased following cytokine exposure. TLR4 was up-regulated by IFN-gamma and this effect was reversed by TNF-alpha. TLR2 expression was increased by supernatants from activated macrophages and by TNF-alpha, which synergized with IFN-gamma. TLR agonists induced the expression of TNF-alpha mRNA. Importantly, TNF-alpha could be translated into protein and released into the supernatants where it was quantified by cytokine ELISA. In conclusion, we demonstrate that NSCs constitutively express TLR2 and TLR4 and that their expression is increased as a consequence of exposure to proinflammatory mediators. Additionally, activation of these receptors can induce production of proinflammatory cytokines. These findings suggest that NSCs may be primed to participate in cytokine production during neuroinflammatory or traumatic conditions.

How stem cells speak with host immune cells in inflammatory brain diseases

“…While TLR 2 ligation stimulates neurogenesis (Rolls et al, 2007), TLR 3 and 4 downstream signaling has inhibitory effects on both stem cell proliferation and self-renewal (Rolls et al, 2007;Yaddanapudi et al, 2011), partly by inhibiting Sonic Hedgehog (Shh) signaling. Remarkably, the exposure to TLR 2 and 4 ligands induces the secretion of TNF-α by NPCs (Covacu et al, 2009) (Tables 1 and 2). …”

Controversial Role of Toll-like Receptor 4 in Adult Stem Cells

“…A more recent study by Covaku et al revealed no significant changes of proliferation and differentiation in rat-derived NSCs and NPS after stimulation with TLR4-agonists [82]. Notably, treatment with LPS resulted in production of TNF-α [82], which itself seems to have different effects of NSCs/NPCs depending on the species, developmental stage and concentration.…”

“…A more recent study by Covaku et al revealed no significant changes of proliferation and differentiation in rat-derived NSCs and NPS after stimulation with TLR4-agonists [82]. Notably, treatment with LPS resulted in production of TNF-α [82], which itself seems to have different effects of NSCs/NPCs depending on the species, developmental stage and concentration. We and others showed that TNF-α and subsequent NF-κB activation lead to increased proliferation of SVZ NSCs [85][86][87][88] without affecting their neuronal and glial differentiation.…”

“…Notably, its expression is not limited to microglia, but has also been reported in astrocytes, oligodendrocytes, neurons, neuronal progenitors as well as in adult neural stem cells [22,82]. In adult brain, tripotent NSCs and unipotent NPCs are responsible for adult neurogenesis taking place in at least two distinct brain regions -the subventricular zone (SVZ) and the Dentate gyrus (DG) of the hippocampus.…”

Neuroimmunomodulation in the Pathogenesis of Alzheimer’s Disease

“…This protein has been crystallized, providing clues on its mechanism of action. These exciting discoveries have highlighted the new functional aspects on TLR4 signaling [9] , thus facilitating potential transfer of this knowledge into drug developments for AD and other brain disorders.…”