Nerve Growth Factor Promotes TLR4 Signaling-Induced Maturation of Human Dendritic Cells In Vitro through Inducible p75NTR 1

Abstract

Nerve growth factor (NGF) has been shown to play important roles in the differentiation, function, and survival of immune cells, contributing to immune responses and pathogenesis of autoimmune diseases. Dendritic cells (DCs) are a potent initiator for immune and inflammatory responses upon recognition of pathogens via Toll-like receptors (TLR). However, expression of NGF and its receptors on human monocyte-derived DCs (MoDCs) and the role of NGF in the response of DCs to TLR ligands remain to be investigated. In the present study, we demonstrate that there were weak expressions of NGF and no expression of NGF receptors p140TrkA and p75NTR on human immature MoDCs, however, the expression of NGF and p75NTR on MoDCs could be significantly up-regulated by LPS in a dose- and time-dependent manner. NGF could markedly promote LPS-induced expression of HLA-DR, CD40, CD80, CD83, CD86, CCR7, secretion of IL-12p40 and proinflammatory cytokines IL-1, IL-6, TNF-α, and the T cell-stimulating capacity of MoDCs, indicating that NGF can promote LPS-induced DC maturation. The promoting effect of NGF on LPS-induced MoDCs maturation could be completely abolished by pretreatment of MoDCs with p75NTR antagonist, suggesting that LPS-induced p75NTR mediates the effect. Furthermore, increased activation of the p38MAPK and NF-κB pathways has been shown to be responsible for the NGF-promoted DC maturation. Therefore, NGF facilitates TLR4 signaling-induced maturation of human DCs through LPS-up-regulated p75NTR via activation of p38 MAPK and NF-κB pathways, providing another mechanism for the involvement of NGF in the immune responses and pathogenesis of autoimmune diseases.

Nerve Growth Factor-Induced Cell Cycle Reentry in Newborn Neurons Is Triggered by p38MAPK-Dependent E2F4 Phosphorylation

“…Instead, our work confirms and extends previous findings showing that p75 NTR is able to activate p38 MAPK (12,33). This effect cannot be induced by the NGF neurotrophic receptor TrkA since we have previously demonstrated that blocking antibodies against p75…”

“…Neurotrophin binding to p75 NTR has been shown to activate different members of the MAPK family of Ser/Thr kinases, including p38 MAPK (12,33), ERK (70), and c-Jun N-terminal kinase (JNK) (10). In accordance with these latter reports, sustained activation of p38 MAPK in response to NGF was observed to rapidly occur in the nuclear compartment of DCRNs (Fig.…”

“…Thus far, several signaling pathways have been shown to be induced by p75 NTR (58), including those regulated by mitogen-ac-tivated protein kinases (MAPKs) (10,12,33,70). Activation of p75 NTR can also result in ␥-secretase-dependent release of its intracellular domain (p75 ICD ) (18,38,65), thus inducing apoptosis (38,47,65).…”

MicroRNAs in the regulation of TLR and RIG-I pathways

“…), endosome/lysosome-localized molecules (Rab7b, 22,23 CLM-3 24 ), gene transcription coactivators (beta-catenin 25 ), antigen-presenting molecules (MHC I and MHC II 26,27 ), and even HSP70, 28 HSP70L1 29 and NGF. 30 Recently, RIG-I signal pathway regulation was extensively investigated; [31][32][33][34] however, the full anti-inflammatory response mechanisms and the precise finetuning of this process still remain incompletely elucidated.…”

Regulation of innate receptor pathways by microRNAs

“…There is growing evidence to indicate that many molecules have been identified as positive or negative regulators of signaling for these innate receptors. For TLRs, these include membrane molecules (CD11b [8] and PECAM1 [9]), antigen presenting molecules (MHCI [10] and MHCII [11]), ubiquitin related proteins (Nrdp1 [12] and CHIP [13]), phosphatases (SHP-1 [14], SHP-2 [15], SHIP-1 [16] and PTP1B [17]), protein kinases (CaMKII [18]), endosome/lysosome-localized molecules (Rab7b [19,20], CLM [21]), a co-activator of gene transcription (-catenin [22]), HSP70 [23], HSP70L1 [24], and NGF [25]. The regulation of RLR and NLR signal pathways has been extensively investigated recently [26,27]; however, the precise mechanisms of regulation remain to be fully elucidated.…”