Toll-like receptors modulate adult hippocampal neurogenesis

Abstract

Neurogenesis - the formation of new neurons in the adult brain - is considered to be one of the mechanisms by which the brain maintains its lifelong plasticity in response to extrinsic and intrinsic changes. The mechanisms underlying the regulation of neurogenesis are largely unknown. Here, we show that Toll-like receptors (TLRs), a family of highly conserved pattern-recognizing receptors involved in neural system development in Drosophila and innate immune activity in mammals, regulate adult hippocampal neurogenesis. We show that TLR2 and TLR4 are found on adult neural stem/progenitor cells (NPCs) and have distinct and opposing functions in NPC proliferation and differentiation both in vitro and in vivo. TLR2 deficiency in mice impaired hippocampal neurogenesis, whereas the absence of TLR4 resulted in enhanced proliferation and neuronal differentiation. In vitro studies further indicated that TLR2 and TLR4 directly modulated self-renewal and the cell-fate decision of NPCs. The activation of TLRs on the NPCs was mediated via MyD88 and induced PKCalpha/beta-dependent activation of the NF-kappaB signalling pathway. Thus, our study identified TLRs as players in adult neurogenesis and emphasizes their specified and diverse role in cell renewal.

Inflammation, plasticity and real-time imaging after cerebral ischemia

“…Another interesting detail is that, in addition to activated glial cells the TLR2 immunoreactivity was also detected in the subset of doublecortin (DCX) positive cells in OB as well as in the small subset of stressed neurons situated with the center of ischemic lesion. These Wndings are in agreement with earlier reports by Rolls et al [117] where TLR2 expression was detected in the cells expressing early neuronal markers such as DCX. Moreover, TLR2 deWciency in mice was associated with signiWcantly impaired neurogenesis [117], thus suggesting that TLR2 signaling may represent an important link for cross dialog between injury-induced innate immune response and brain neurogenesis/recovery.…”

“…These Wndings are in agreement with earlier reports by Rolls et al [117] where TLR2 expression was detected in the cells expressing early neuronal markers such as DCX. Moreover, TLR2 deWciency in mice was associated with signiWcantly impaired neurogenesis [117], thus suggesting that TLR2 signaling may represent an important link for cross dialog between injury-induced innate immune response and brain neurogenesis/recovery.…”

“…In the recent work, Lehnardt et al [83] and Ziegler et al [147] reported smaller infarction size in the mice lacking TLR2 receptors, yet, on the other hand, the same signaling pathway has been reported instrumental for brain neurogenesis [117]. From the experimental results, it is conceivable that in acute response to injuries activated microglial cells may play an early detrimental role that can be converted into supportive role in the later, chronic phase of the brain response to ischemic injury.…”

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

“…Nonetheless, not all TLRs are localized exclusively on microglia. TLR4, for example, has been observed on microglia, neurons, astrocytes, neural progenitor cells, and endothelial cells (AlfonsoLoeches et al, 2010;Grace et al, 2014b;Jack et al, 2005;June et al, 2015;Liu et al, 2011;Rolls et al, 2007). Advanced transcriptome analysis of purified cell populations in rodent cortex confirms that these other cells have transcript copies for TLR4 .…”

Evaluating the role of Toll-like receptors in diseases of the central nervous system

“…In addition to this much work will be required to 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 32 understand how new neurons survive and integrate in order to be properly functional, therefore the processes following neuronal generation may be manipulated therapeutically in diseases of the CNS [21]. The finding that TLRs modulate adult neurogenesis [108] suggests that TLR manipulation may, in the future, be beneficial in therapies aimed at enhancing neurogenesis.…”