Histamine Regulates Actin Cytoskeleton in Human Toll-like Receptor 4-activated Monocyte-derived Dendritic Cells Tuning CD4+ T Lymphocyte Response

Abstract

Histamine, a major mediator in allergic diseases, differentially regulates the polarizing ability of dendritic cells after Tolllike receptor (TLR) stimulation, by not completely explained mechanisms. In this study we investigated the effects of histamine on innate immune reaction during the response of human monocyte-derived DCs (mDCs) to different TLR stimuli: LPS, specific for TLR4, and Pam3Cys, specific for heterodimer molecule TLR1/TLR2. We investigated actin remodeling induced by histamine together with mDCs phenotype, cytokine production, and the stimulatory and polarizing ability of Th0. By confocal microscopy and RT-PCR expression of Rac1/CdC42 Rho GTPases, responsible for actin remodeling, we show that histamine selectively modifies actin cytoskeleton organization induced by TLR4, but not TLR2 and this correlates with increased IL4 production and decreased IFN␥ by primed T cells. We also demonstrate that histamine-induced cytoskeleton organization is at least in part mediated by down-regulation of small Rho GTPase CdC42 and the protein target PAK1, but not by down-regulation of Rac1. The presence and relative expression of histamine receptors HR1-4 and TLRs were determined as well. Independently of actin remodeling, histamine downregulates IL12p70 and CXCL10 production in mDCs after TLR2 and TLR4 stimulation. We also observed a trend of IL10 up-regulation that, despite previous reports, did not reach statistical significance.

Histamine modulates hippocampal inflammation and neurogenesis in adult mice

“…Considering the previously mentioned studies and our results, the superior anti-inflammatory and pro-neurogenic response induced by histamine when 2 mg/Kg LPS was given might be due to a weaker inflammatory response due to low availability of LPS in the DG when 1 mg/Kg is used and/or the acquisition of immune tolerance when 2 mg/Kg of LPS is administered. Nevertheless, the anti-inflammatory role induced by histamine reported by us is in agreement with other reports showing that histamine is able to suppress LPS-induced inflammation in human monocytes 34,35 , human monocyte-derived dendritic cells 36 , in microglia 1,9 , in the liver, and in the substantia nigra 1,37,38 . In these situations, histamine reduced the expression of pro-inflammatory cytokines (e.g.…”

“…In these situations, histamine reduced the expression of pro-inflammatory cytokines (e.g. TNF-α, INF-γ, IL-18), led to cytoskeleton rearrangements and inhibited microglial activation, namely in terms of the phagocytic activity and ROS production 1,9,36–38 . Since LPS induces an upregulation of histamine receptors, a higher concentration of LPS (2 mg/kg) may be needed to boost its anti-inflammatory and protective effects in the DG.…”

Modulation of Mast Cell Toll-Like Receptor 3 Expression and Cytokines Release by Histamine

“…Since TLRs are known as receptors for micro-organism pathogens that are highly expressed in mast cells, histamine has been reported to regulate TLR expression and cytokine production in inflammatory cells [16-19]; to enhance the secretion of Th2 cytokines such as IL-4, IL-5, IL-10 and IL-13; and to inhibit the production of Th1 cytokines such as IL-2 and IFN-γ [20], we anticipated that histamine ought to regulate TLR expression and cytokine production in mast cells, and thus participate in the pathogenies of allergic diseases. In the present study, we found that histamine was able to upregulate expressions of TLR3, and IL-13 and MCP-1 released from human and mouse mast cells lines.…”

Myelin-specific T cells carry and release magnetite PGLA–PEG COOH nanoparticles in the mouse central nervous system

“…Electron microscopy imaging suggests that NBR locate in vesicle-like structures, and confocal microscopy shows that NBR are in close contact with actin, which resulted in a different distribution in loaded cells compared to controls. In previous work, we have demonstrated that actin cytoskeleton modications regulate proinammatory effector functions in myeloid dendritic cells; 19,20 here, we may speculate that a similar mechanism, driven by actin organization aer NBR loading, is acting on T cells and is partially responsible of IL17 and IFNg down-regulation. In contrast with other reports concerning bare magnetite nanoparticles (5-30 nm), 21 NBR in part enters the nucleus, suggesting that this PGLA-covered nanomaterial is able to passively diffuse through all the membranes.…”