Lipid Raft-Associated GTPase Signaling Controls Morphology and CD8+ T Cell Stimulatory Capacity of Human Dendritic Cells

Jaksits, Silvia; Bauer, Wolfgang; Kriehuber, Ernst; Zeyda, Maximilian; Stulnig, Thomas M.; Stingl, Georg; Fiebiger, Edda; Maurer, Dieter

doi:10.4049/jimmunol.173.3.1628

Cited by 40 publications

(43 citation statements)

References 50 publications

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“…PUFAs were incorporated into DC membrane lipids in our studies and probably also in raft lipids since raft lipid alterations by exogenous fatty acids generally reflect those in cellular membranes (21). We did not detect any functional differences in early LPS-induced signaling events in PUFA-treated DCs though rafts could be involved in DC activation and LPS signal transduction as suggested by other studies (63,64). However, lipid raft-dependent LPS signaling in DCs has not yet been characterized in enough detail in order to completely understand a possible interference of PUFA with DC lipid raft signaling and its contribution to the inhibitory effects of PUFAs on DC activation.…”

Section: Discussionmentioning

confidence: 55%

Polyunsaturated Fatty Acids Block Dendritic Cell Activation and Function Independently of NF-κB Activation

Zeyda

Säemann

Stuhlmeier³

et al. 2005

Journal of Biological Chemistry

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126

110

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Polyunsaturated fatty acids (PUFAs) modulate immune responses leading to clinically significant beneficial effects in a variety of inflammatory disorders. PUFA effects on T cells have been extensively studied, but their influence on human dendritic cells (DCs), which are the most potent antigen-presenting cells and play a key role in initiating immune responses, has not been elucidated so far. Here we show that PUFAs of the n-3 and n-6 series (arachidonic and eicosapentaenoic acid) affect human monocyte-derived DC differentiation and inhibit their activation by LPS, resulting in altered DC surface molecule expression and diminished cytokine secretion. Furthermore, the potency to stimulate T cells was markedly inhibited in PUFA-treated DCs. The PUFA-mediated block in LPS-induced DC activation is reflected by diminished TNF-␣, IL-12p40, CD40, and COX-2 mRNA levels. Strikingly, typical LPS-induced signaling events such as degradation of IB and activation of NF-B were not affected by PUFAs, even though DC membrane lipid composition was markedly altered. Arachidonic and eicosapentaenoic acid both altered DC prostaglandin production, but inhibitors of cyclooxygenases and lipoxygenases did not abolish PUFA effects, indicating that the observed PUFA actions on DCs were independent of autoregulation via eicosanoids. These data demonstrate a unique interference with DC activation and function that could significantly contribute to the well known anti-inflammatory effects of PUFAs.

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Section: Discussionmentioning

confidence: 55%

Polyunsaturated Fatty Acids Block Dendritic Cell Activation and Function Independently of NF-κB Activation

Zeyda

Säemann

Stuhlmeier³

et al. 2005

Journal of Biological Chemistry

Self Cite

126

110

View full text Add to dashboard Cite

show abstract

“…We have also demonstrated a high basal activity of 5-HT 7 R towards Cdc42 signaling in neuronal cells (Kvachnina et al, 2005), suggesting that both basal activity and agonist-mediated stimulation of the 5-HT 7 R-Cdc42 signaling pathway might contribute to morphological rearrangements of cells. Referring to dendritic cell morphology, Cdc42 has previously been shown to modulate cell shape changes by inducing alterations in the length and number of membrane protrusions, and it is required for the induction and maintenance of the typical stellate cytoskeletal architecture of mature dendritic cells (Jaksits et al, 2004;Nikolic et al, 2011;Swetman et al, 2002). Furthermore, it has been shown that Cdc42 deficiency induces a more rounded morphology in cultured cells (Chen et al, 2000;Wu et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Serotonin receptor 5-HT7 regulates morphology and migratory properties of dendritic cells

Holst

Guseva

Schindler

et al. 2015

Journal of Cell Science

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Dendritic cells are potent antigen-presenting cells endowed with the unique ability to initiate adaptive immune responses upon inflammation. Inflammatory processes are often associated with an increased production of serotonin, which operates by activating specific receptors. However, the functional role of serotonin receptors in regulation of dendritic cell functions is poorly understood. Here, we demonstrate that expression of serotonin receptor 5-HT7 (5-HT 7 R) as well as its downstream effector Cdc42 is upregulated in dendritic cells upon maturation. Although dendritic cell maturation was independent of 5-HT 7 R, receptor stimulation affected dendritic cell morphology through Cdc42-mediated signaling. In addition, basal activity of 5-HT 7 R was required for the proper expression of the chemokine receptor CCR7, which is a key factor that controls dendritic cell migration. Consistent with this, we observed that 5-HT 7 R enhances chemotactic motility of dendritic cells in vitro by modulating their directionality and migration velocity. Accordingly, migration of dendritic cells in murine colon explants was abolished after pharmacological receptor inhibition. Our results indicate that there is a crucial role for 5-HT 7 R-Cdc42-mediated signaling in the regulation of dendritic cell morphology and motility, suggesting that 5-HT 7 R could be a new target for treatment of a variety of inflammatory and immune disorders.

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“…The functional role of Rac1 and Cdc42 for the morphology and Ag-presenting capacity of DCs was described for DCs grown from hemopoietic stem cells (23) and PBMC-derived DC (24,25). Selective Rac1 inhibition in DCs was shown to diminish apoptotic cell uptake and cross-presentation in transgenic mice (26).…”

Section: Endritic Cells (Dc)mentioning

confidence: 99%

Small Rho GTPases Mediate Tumor-Induced Inhibition of Endocytic Activity of Dendritic Cells

Tourkova¹,

Shurin²,

Wei

et al. 2007

The Journal of Immunology

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The generation, maturation, and function of dendritic cells (DC) have been shown to be markedly compromised in the tumor microenvironment in animals and humans. However, the molecular mechanisms and intracellular pathways involved in the regulation of the DC system in cancer are not yet fully understood. Recently, we have reported on the role of the small Rho GTPase family members Cdc42, Rac1, and RhoA in regulating DC adherence, motility, and Ag presentation. To investigate involvement of small Rho GTPases in dysregulation of DC function by tumors, we next evaluated how Cdc42, Rac1, and RhoA regulated endocytic activity of DC in the tumor microenvironment. We revealed a decreased uptake of dextran 40 and polystyrene beads by DC generated in the presence of different tumor cell lines, including RM1 prostate, MC38 colon, 3LL lung, and B7E3 oral squamous cell carcinomas in vitro and by DC prepared from tumor-bearing mice ex vivo. Impaired endocytic activity of DC cocultured with tumor cells was associated with decreased levels of active Cdc42 and Rac1. Transduction of DC with the dominant negative Cdc42 and Rac1 genes also led to reduced phagocytosis and receptor-mediated endocytosis. Furthermore, transduction of DC with the constitutively active Cdc42 and Rac1 genes restored endocytic activity of DC that was inhibited by the tumors. Thus, our results suggest that tumor-induced dysregulation of endocytic activity of DC is mediated by reduced activity of several members of the small Rho GTPase family, which might serve as new targets for improving the efficacy of DC vaccines.

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Lipid Raft-Associated GTPase Signaling Controls Morphology and CD8+ T Cell Stimulatory Capacity of Human Dendritic Cells

Cited by 40 publications

References 50 publications

Polyunsaturated Fatty Acids Block Dendritic Cell Activation and Function Independently of NF-κB Activation

Polyunsaturated Fatty Acids Block Dendritic Cell Activation and Function Independently of NF-κB Activation

Serotonin receptor 5-HT7 regulates morphology and migratory properties of dendritic cells

Small Rho GTPases Mediate Tumor-Induced Inhibition of Endocytic Activity of Dendritic Cells

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