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Articles de revues sur le sujet "Dendritic cells, LPS, CD14, Edema"
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Marongiu, Laura, Francesca Mingozzi, Clara Cigni, Roberta Marzi, Marco Di Gioia, Massimiliano Garrè, Dario Parazzoli et al. « Inositol 1,4,5-trisphosphate 3-kinase B promotes Ca2+ mobilization and the inflammatory activity of dendritic cells ». Science Signaling 14, no 676 (30 mars 2021) : eaaz2120. http://dx.doi.org/10.1126/scisignal.aaz2120.
Texte intégralRésumé :
Innate immune responses to Gram-negative bacteria depend on the recognition of lipopolysaccharide (LPS) by a receptor complex that includes CD14 and TLR4. In dendritic cells (DCs), CD14 enhances the activation not only of TLR4 but also that of the NFAT family of transcription factors, which suppresses cell survival and promotes the production of inflammatory mediators. NFAT activation requires Ca2+ mobilization. In DCs, Ca2+ mobilization in response to LPS depends on phospholipase C γ2 (PLCγ2), which produces inositol 1,4,5-trisphosphate (IP3). Here, we showed that the IP3 receptor 3 (IP3R3) and ITPKB, a kinase that converts IP3 to inositol 1,3,4,5-tetrakisphosphate (IP4), were both necessary for Ca2+ mobilization and NFAT activation in mouse and human DCs. A pool of IP3R3 was located on the plasma membrane of DCs, where it colocalized with CD14 and ITPKB. Upon LPS binding to CD14, ITPKB was required for Ca2+ mobilization through plasma membrane–localized IP3R3 and for NFAT nuclear translocation. Pharmacological inhibition of ITPKB in mice reduced both LPS-induced tissue swelling and the severity of inflammatory arthritis to a similar extent as that induced by the inhibition of NFAT using nanoparticles that delivered an NFAT-inhibiting peptide specifically to phagocytic cells. Our results suggest that ITPKB may represent a promising target for anti-inflammatory therapies that aim to inhibit specific DC functions.
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Palucka, Karolina A., Nicolas Taquet, Francoise Sanchez-Chapuis et Jean Claude Gluckman. « Dendritic Cells as the Terminal Stage of Monocyte Differentiation ». Journal of Immunology 160, no 9 (1 mai 1998) : 4587–95. http://dx.doi.org/10.4049/jimmunol.160.9.4587.
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Abstract Monocytes (MO) cultured for ≥5 days with either macrophage-CSF (M-CSF) or granulocyte macrophage (GM)-CSF and IL-4 differentiated without concomitant proliferation into CD14+ macrophages (Mφ) or CD1a+ dendritic cells (DC), respectively. When adherent and nonadherent CD14high Mφ from M-CSF cultures were separated and cultured further in cytokine-free medium or with GM-CSF/IL-4, most cells from both fractions that were exposed to GM-CSF/IL-4 acquired CD1a expression and DC morphology and function. Conversely, GM-CSF/IL-4 withdrawal at day 5 and additional culture of sorted CD1a+ DC for 2 to 7 days in cytokine-free medium led to cells rapidly becoming adherent CD1a−CD14+ Mφ. Replacing GM-CSF/IL-4 with M-CSF hastened the conversion of DC to Mφ without increasing cell numbers. CD1a+CD14−CD83+ mature DC were induced by a ≥2-day exposure to MO-conditioned medium, LPS, or TNF-α/IL-1β. Upon cytokine removal or culture with M-CSF, DC that had been pushed to maturation by conditioned medium or LPS remained stable or died in the new environment. TNF-α/IL-1β-driven DC displayed heterogeneous CD83 expression and could thus be sorted into CD83high and CD83low/− cells; in cytokine-free medium or in M-CSF, most CD83low/− cells converted to Mφ, whereas most CD83high cells remained nonadherent CD1a+CD14− or died and thus appeared truly terminally differentiated. Hence, MO are precursors of Mφ as well as of DC, with each cell type having the capability to convert into the other until late in the differentiation/maturation process. Accordingly, the cytokine environment and the presence of differentiation and/or other stimulatory signals may be the “final decision-making factors” determining whether these cells will acquire DC or Mφ characteristics and function.
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Verhasselt, V., C. Buelens, F. Willems, D. De Groote, N. Haeffner-Cavaillon et M. Goldman. « Bacterial lipopolysaccharide stimulates the production of cytokines and the expression of costimulatory molecules by human peripheral blood dendritic cells : evidence for a soluble CD14-dependent pathway. » Journal of Immunology 158, no 6 (15 mars 1997) : 2919–25. http://dx.doi.org/10.4049/jimmunol.158.6.2919.
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Abstract To investigate the responses of dendritic cells (DC) during Gram-negative infections, we analyzed the effects of graded doses of LPS on the cytokine profile, phenotype, and allostimulatory potential of human DC generated by culturing plastic-adherent PBMC in presence of IL-4 and granulocyte-macrophage-CSF. First, we found that LPS stimulates the production of high levels of TNF-alpha, IL-6, IL-8, IL-12 by DC and up-regulates their expression of HLA-DR, B7-1, B7-2, and CD40. The effects of LPS were dose dependent, with a significant stimulatory effect already observed at a concentration of 0.1 ng/ml and a plateau being reached at 10 ng/ml. These phenotypic changes correlated with increased allostimulatory properties of LPS-activated DC because DC treated with LPS were significantly more efficient than untreated DC in eliciting IL-2 and IFN-gamma synthesis by alloreactive T cells and stimulating their proliferation. Experiments using neutralizing anti-IL-12 mAb indicated that LPS-induced IL-12 is responsible for the increased production of IFN-gamma but not for the increased proliferation during MLR. Finally, we observed that the DC responses to low levels of LPS (1 ng/ml) were dramatically inhibited by a blocking anti-CD14 mAb, although DC do not express CD14 molecules on their membrane. Experiments using serum depleted of soluble CD14 (sCD14) and sCD14 either purified from human serum or in recombinant form further established that DC respond to LPS via a soluble CD14-dependent pathway.
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Ziros, Panos, Ilina Micheva, Ioannis Habeos, Athanasios Papavasiliou et Nicholas Zoumbos. « Expression and Activation of the Farnsesoid X Receptor in Human Dendritic Cells. » Blood 106, no 11 (16 novembre 2005) : 2220. http://dx.doi.org/10.1182/blood.v106.11.2220.2220.
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Abstract Baground: The farnesoid X receptor/bile acid receptor (FXR, NR1H4) is a member of the nuclear hormone superfamily that regulates bile acid as well as lipoprotein and glucose metabolism after heterodimerization with retinoid X receptor. Dendritic cells (DCs) are potent antigen presenting cells capable of regulating immune responses. It has previously been reported that spleen, a tissue rich in DCs, expresses FXR. Taking this into account, we wanted to investigate the possible involvement of FXR in DCs biology. Material and Methods: Immature DCs were generated from peripheral human blood monocytes (CD14+ cells) by culturing them with GM-CSF and IL4 for 7 days. For maturation, immature DCs were cultured with the addition of TNFα, and LPS for another 24 hours. The expression and activity of FXR in DCs was assessed with RT-PCR, western immunoblotting, immunofluoresence and EMSA analysis. Results and Discusion:We have shown with RT-PCR that FXR is marginally expressed in human monocytes (CD14+ cells) and its expression is elevated during the differentiation process of these to dendritic cells. Moreover, using specific primers we have found that only FXR -alpha and not FXR-beta is expressed in DCs. Western blot analysis with a specific anti-FXR antibody confirmed the FXR expression in DCs. Immunofluoresence microscopy with a specific anti-FXR antibody showed that FXR, in contrast with the classical FXR-expressing tissues (liver, kidney), has strong cytoplasmic and perinuclear localization and weak nuclear localization in DCs. The nuclear localization is potentiated upon treatment of the immature dendritic cells with LPS or TNFα. Finally, using a DNA probe that contains consensus FXR binding sites, we have shown with EMSA analysis that FXR is transcriptional active in immature DCs but not in CD14 monocytes, and is strongly activated upon LPS or TNFα treatment for 48 h of immature DCs. Overall our study reveals, for the first time, that FXR, a nuclear hormone receptor with a limited tissue expression, might have a new role in DCs biology, since it is not only expressed in human dendritic cells but moreover its transcriptional activity is affected by signals (TNFα, LPS) that influence the function of DCs.
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Borriello, Francesco, Raffaella Iannone, Sarah Di Somma, Viviana Vastolo, Giuseppe Petrosino, Feliciano Visconte, Maddalena Raia et al. « LPS-elicited TSLPR expression enriches a functionally discrete subset of human CD14+ CD1c+ monocytes ». Journal of Immunology 198, no 1_Supplement (1 mai 2017) : 75.1. http://dx.doi.org/10.4049/jimmunol.198.supp.75.1.
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Abstract Thymic stromal lymphopoietin (TSLP) is a cytokine produced mainly by epithelial cells in response to inflammatory or microbial stimuli and binds to the TSLP receptor complex, a heterodimer composed of TSLP receptor (TSLPR) and IL-7 receptor α (CD127). TSLP activates multiple immune cell subsets expressing the TSLP receptor complex and plays a role in several models of disease. Although human monocytes express TSLPR and CD127 mRNAs in response to the TLR4 agonist LPS, their responsiveness to TSLP is ill-defined. We demonstrate that TSLP enhances human CD14+ monocyte CCL17 production in response to LPS and IL-4. Surprisingly, only a subset of CD14+ CD16− monocytes (TSLPR+ mono) expresses TSLP receptor complex upon LPS stimulation in an NF-κB- and p38-dependent manner. Phenotypic, functional and transcriptomic analysis revealed specific features of TSLPR+ mono, including higher CCL17 and IL-10 production and increased expression of genes with important immune functions (i.e. GAS6, ALOX15B, FCGR2B, LAIR1). Strikingly, TSLPR+ mono express higher levels of the dendritic cell marker CD1c. This evidence led us to identify a subset of peripheral blood CD14+ CD1c+ cells that expresses the highest levels of TSLPR upon LPS stimulation. The translational relevance of these findings is highlighted by the higher expression of TSLPR and CD127 mRNAs in monocytes isolated from patients with Gram-negative sepsis compared to healthy controls. Our results emphasize a phenotypic and functional heterogeneity in an apparently homogeneous population of human CD14+ CD16− monocytes and prompt further ontogenetic and functional analysis of CD14+ CD1c+ and LPS-activated CD14+ CD1c+ TSLPR+ monocytes.
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Kurochkina, Y., A. Sizikov, E. Chernykh et T. Tyrinova. « AB0072 GLUCOCORTICOIDS MODIFY NOT ONLY THE PROPERTIES OF DENDRITIC CELLS, BUT ALSO PROGENITOR CELLS ». Annals of the Rheumatic Diseases 81, Suppl 1 (23 mai 2022) : 1168.2–1168. http://dx.doi.org/10.1136/annrheumdis-2022-eular.2571.
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BackgroundDendritic cells (DCs) are universal antigen-presenting cells that can have both tolerant and immunosuppressive properties. Tolerogenic properties of DCs are mediated by activation T-regulatory cells, production of anti-inflammatory cytokines and activation T cell apoptosis. Currently, DC is an attractive object of study as a new treatment for rheumatoid arthritis. It is known that glucocorticoids make it possible to control properties of DCs to the tolerogenic side.ObjectivesThe aim of the study is to investigate the effect of pulse therapy by glucocorticodes on the properties of DCs and peripheral blood monocytes from which DCs were generated.MethodsTwenty five patients with rheumatoid arthritis were recruited in this study. All patients follow ACR/EULAR criteria (2010). All studies were performed after receiving informed consent. All patients received conventional synthetic DMARDs. DCs were generated from blood monocytes culturing for 5 days with GM-CSF and IFN-α, LPS as maturation stimuli was added on fourth day. The functions of DCs were evaluated by allostimulatory activity in mixed lymphocyte culture. The properties of DC were studied before pulse therapy (methylprednisolone 500mg №3) and 4 days after pulse therapy.The relative number of monocytes (classical CD14++CD16+, intermediate CD14+CD16+ and nonclassical CD14+CD16++) before and after pulse therapy was also studied in comparison with healthy donors.ResultsPrior to pulse therapy, the DCs from RA patients were characterized by a high ability to stimulate the proliferation of allogenic T-lymphocytes about 20000 cpm. After pulse therapy, the stimulating ability of DCs significantly decreased (9800 vs. 2000 cpm, p=0.04). Evaluation of the relative content of classical (CD14++CD16-), intermediate (CD14++CD16+) and nonclassical (CD14+CD16++) monocytes of healthy donors (n=18) and RA patients (n=25) revealed a decrease in the relative content of CD14++CD16- cells in patients (Me 78 vs. 90%; p=0.02) and an increase in the proportion of CD14++CD16+ (Me 4.0 vs. 2.0%; p=0.034) and CD14+ CD16++ monocytes (Me 5.0 vs. 1.5%; p=0.02). After the end of pulse therapy in RA patients, the relative content of CD14++CD16-cells increased (89 vs. 78%), and the proportion of CD14+CD16++ monocytes decreased (1 vs. 5%), and RA patients no longer significantly differed in these indicators from healthy donors. Thus, a decrease in the content of CD14+CD16++ cells in the monocytes population after pulse therapy was associated with a decrease in the effectiveness of DCs generated to stimulate the proliferation of allogenic T cells.ConclusionThe effect of pulse therapy of glucocorticoids is associated not only with the ability of glucocorticoids to inhibit the maturation of IFN-DC and induce their tolerant phenotype at the stage of differentiation of monocytes into DCs, but also with the effect on the subpopulation of circulating monocytes that are precursors of DC.Disclosure of InterestsNone declared
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Brosbøl-Ravnborg, Anne, Bettina Bundgaard et Per Höllsberg. « Synergy between Vitamin D3and Toll-Like Receptor Agonists Regulates Human Dendritic Cell Response during Maturation ». Clinical and Developmental Immunology 2013 (2013) : 1–8. http://dx.doi.org/10.1155/2013/807971.
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Human dendritic cells (DC) can be differentiated from blood monocytes in the presence of GM-CSF and IL-4 and matured by lipopolysaccharide (LPS). Vitamin D3inhibits the maturation of human DC measured by changes in surface expression of HLA-DR, CD14, CD40, CD80, CD83, and CD86. We here examine the function of vitamin D3during DC maturation. One of the earliest changes to LPS-induced maturation was an increase in CD83 expression. Vitamin D3inhibited the increase in expression of HLA-DR, CD40, CD80, CD83, and CD86 and the decrease in expression of CD14, which was paralleled morphologically by vitamin D3-induced inhibition of dendritic cell differentiation. Vitamin D3acted in synergy with the TLR agonists LPS and peptidoglycan (PGN) in inducing IL-6, IL-8, and IL-10, whereas vitamin D3completely inhibited LPS-induced secretion of IL-12. The synergy occurred at concentrations where neither vitamin D3nor the TLR agonists alone induced measurable cytokine secretion. Both LPS and PGN enhanced the level of the vitamin D3receptor (VDR). Taken together, these data demonstrated that vitamin D3and TLR agonists acted in synergy to alter secretion of cytokines from human DC in a direction that may provide an anti-inflammatory environment.
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Ruiz-Jiménez, Caleb, Daiana Celias, Leonardo Silvane, Laura Cervi et Ana M. Espino. « Fasciola hepatica Fatty Acid Binding Protein (Fh12) inhibits the activation of murine dendritic cells. » Journal of Immunology 198, no 1_Supplement (1 mai 2017) : 68.15. http://dx.doi.org/10.4049/jimmunol.198.supp.68.15.
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Abstract Fasciola hepatica, is a helminth that excretes-secretes different proteins that modulate cells of the immune system, generating anti-inflammatory responses. It has been demonstrated that Fh12 achieves this anti-inflammatory effect by inhibiting the expression of TLR4 induced by LPS in macrophages. Fh12 target the CD14 co-receptor, thus blocking the LPS-CD14 binding, which stop the entire TLR4 activation cascade from the beginning of the LPS-stimuli. Concurrently, Fh12 suppress the phosphorylation of various kinases (p38, JNK and ERK) downstream the TLR4 signaling cascade and induce the activation of macrophages by an alternative pathway. Dendritic cells (DCs) are antigen-presenting cells that play a key role at early phase of innate immunity and that are essential in the development of adaptive immune response. The main objective of the current study was to investigate the effect of Fh12 on the activation of murine DCs matured in the presence of LPS. DCs were isolated from bone marrow of naïve C57BL/6 mice, cultured, differentiated and stimulated in vitro with Fh12 1h prior to stimulation with LPS for 18 hrs. ELISA was used to quantify the amount of a panel of secreted cytokines in culture supernatant. FACS was used to determine the activation of MHCII and co-stimulatory molecules. Results demonstrated that Fh12 significantly inhibits the production of IL-12 and IL-6 and reduced the expression of MHCII and co-stimulatory molecules like CD80 on DCs surface. All assays have a significant P value < 0.05. These results suggest that Fh12 exerts a strong suppressive effect on activation of DC cells, which could have relevant implications in the subsequent development of adaptive immune response to microbial pathogens.
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Stec, Malgorzata, Bozena Mytar, Kazimierz Weglarczyk, Irena Ruggiero et Marek Zembala. « Characterization of Monocyte Subpopulations (CD14+CD16− and CD14++CD16+) generated from Cord Blood Haematopoietic Progenitor CD34+ ». Blood 112, no 11 (16 novembre 2008) : 3551. http://dx.doi.org/10.1182/blood.v112.11.3551.3551.
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Abstract Introduction. In the past decade significant advances in ex vivo expansion of haematopoietic stem cells were made. Protocols of differentiating CD34+ cells into cells from hematopoietic linages, especially dendritic cells, were described. However, little is known about in vitro differentiation of CD34+ cells to monocytes. In peripheral blood there are two main populations of monocytes CD14++CD16− and CD14+CD16+. They represent about 10 percent of total blood monocytes. Recently we have showed that expansion and differentiation of cord blood CD34+ cells to monocytes/macrophages leads to generation of CD14+CD16− and CD14++CD16+ monocyte subpopulations (Stec et al, J Leukoc Biol. 2007). Aim of study. To compare two monocyte subpopulation: CD14+CD16− and CD14++CD16+ obtained from our expansion and differentiation protocol of CD34+ cord blood cells. Materials and methods. After 3–10 days expansion in X-VIVO10 medium with FBS, SCF, IL-3, FLT-3L, TPO and then 7–10 days differentiation in IMDM medium with FBS, M-CSF, FLT-3L, IL-3, SCF, CD14+CD16− and CD14++CD16+ subpopulations were isolated by FACS sorting (FACSVantage). Release of IL-6, IL8, IL-12, IP-10, MIP1 α, MIP-1 β, RANTES, VEGF and FGF after LPS/INFγ or cancer cells stimulation were analysed using CBA (Cytometric Bead Array) method. Cytotoxic activity against cancer cells were assessed by MTT test and migration capacity was assesed with uncoated porous filters (8 μm) in a 24-well Boyden chamber. The adhesion capacity of subpopulations on human umbilical vein endothelial cells (HUVEC) were assessed with 5(6)-CFDA, SE (Molecular Probes) application and fluorescent microscope. NOD-SCID mice were used to evaluate the influence of subpopulations on angiogenesis and tumour growth. Results. CD14++CD16+ monocytes released more IL-8, IL-12, IP-10, MIP1-α, MIP1-β, and RANTES than CD14+CD16− monocytes after LPS/INFγ or cancer cells stimulation. After 24 hours culture in medium without cytokines and than stimulation with LPS/INFγ or cancer cells, CD14++CD16+ subpopulation released more RANTES, TNF, MIP1-α, IL10 than CD14+CD16−cells. CD14+CD16− subpopulation exhibited greater chemotaxis to SDF-1 and MIP1-α than CD14++CD16+ (12,2%±5,5% versus 2,2%±1%). At the same time CD14++CD16+ monocytes showed significantly higher cytotoxic activity against tumour cells in vitro than CD14+CD16− (34,04±17,45% versus 15,56±13,66%). CD14++16+ population showed increased adhesion to HUVEC than CD14+16− population (79±20 cells versus 30±13 cells). In in vivo tests in NODSCID mice both subpopulations together inhibited angiogenesis, but CD14+CD16− subpopulation inhibited stronger tumour growth than CD14++CD16+ subpopulation. Conclusions. Using our expansion protocol it was possible to obtain two subpopulations of monocytes: CD14+CD16− and CD14++CD16+ which showed the differences in the release of cytokines/chemokines following stimulation with LPS/INFγ or tumour cells, chemotactic and antiangiogenic activity and cytotoxicity and are clearly distinct from known main subpopulations of blood monocytes CD14+CD16+ and CD14++. Additional tests, which are still in progress in our lab will provide evidence if both populations are functional monocytes.
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Tsan, Min-Fu, et Baochong Gao. « Cytokine function of heat shock proteins ». American Journal of Physiology-Cell Physiology 286, no 4 (avril 2004) : C739—C744. http://dx.doi.org/10.1152/ajpcell.00364.2003.
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Extensive work in the last 10 years has suggested that heat shock proteins (HSPs) may be potent activators of the innate immune system. It has been reported that Hsp60, Hsp70, Hsp90, and gp96 are capable of inducing the production of proinflammatory cytokines by the monocyte-macrophage system and the activation and maturation of dendritic cells (antigen-presenting cells) in a manner similar to the effects of lipopolysaccharide (LPS) and bacterial lipoprotein, e.g., via CD14/Toll-like receptor2 (TLR2) and CD14/TLR4 receptor complex-mediated signal transduction pathways. However, recent evidence suggests that the reported cytokine effects of HSPs may be due to the contaminating LPS and LPS-associated molecules. The reasons for previous failure to recognize the contaminant(s) as being responsible for the reported HSP cytokine effects include failure to use highly purified, low-LPS preparations of HSPs; failure to recognize the heat sensitivity of LPS; and failure to consider contaminant(s) other than LPS. Thus it is essential that efforts should be directed to conclusively determine whether the reported HSP cytokine effects are due to HSPs or to contaminant(s) present in the HSP preparations before further exploring the implication and therapeutic potential of the putative cytokine function of HSPs.
Thèses sur le sujet "Dendritic cells, LPS, CD14, Edema"
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DI, GIOIA MARCO. « Defining the consequences of CD14 engagement and NFAT activation in innate immune cells : from molecular mechanisms to a preclinical model ». Doctoral thesis, Università degli Studi di Milano-Bicocca, 2013. http://hdl.handle.net/10281/43580.
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DCs sense the presence of pathogens through germline-encoded PRRs, which recognize molecular patterns expressed by various microorganisms and endogenous stimuli. Following activation with LPS, DCs sequentially acquire the ability to produce soluble and cell surface molecules critical for the initiation and control of innate and then adaptive immune responses. The production of most of these factors is regulated by the activation of TLR4-MD2 pathway. Nevertheless, we have recently described that following LPS exposure different NFAT isoforms are also activated. The initiation of the pathway that leads to nuclear NFAT translocation is totally dependent on CD14 that, through the activation of src family kinases and PLCγ2, leads to Ca2+ mobilization and calcineurin activation. Nuclear NFAT translocation is required for IL-2 production and apoptotic cell death of terminally differentiated DCs.
In the present work, we analyzed the role of CD14-NFAT pathway in a preclinical model of skin edema formation and its implications in antigen delivery. In addition, we investigated the Ca2+ entry process in LPS-stimulated DCs, defining the molecular mechanism downstream CD14 activation that leads to Ca2+ mobilization.
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OSTUNI, RENATO. « "The role of CD14-NFAT pathway in the regulation of innate immune functions" ». Doctoral thesis, Università degli Studi di Milano-Bicocca, 2010. http://hdl.handle.net/10281/19946.
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Innate and adaptive defense mechanisms participate to immunological protection. Innate immune cells like macrophages, neutrophils and dendritic cells (DCs) regulate the first part of the response, which is rapidly activated at the site of infection. At this stage, phagocytic cells eliminate pathogens from the infected tissue and additionally establish a local inflammatory state by releasing proinflammatory cytokines (e.g. TNF-alpha, IL-1beta) and lipid mediators (PGE2). Subsequently, activated tissue-resident DCs acquire a migratory phenotype and reach the draining lymph node to prime antigen-specific T cells for the initiation of adaptive immunity.
Innate immune cells detect invading pathogens through a set of receptors recognizing conserved patterns that are unique to microbes. Specifically, Gram-negative bacteria are perceived by means of TLR4 and CD14, which act as a receptor complex for lipopolysaccharide (LPS), the main constituent of the bacterial cell wall. Upon LPS recognition, TLR4 and CD14 cooperate to trigger signal transduction cascades leading to activation of the transcription factors NF-kappaB, AP-1 and IRF3, which in turn promote expression of proinflammatory genes. Despite the signaling pathways induced by LPS have been mainly described in macrophages, it is widely believed that they do not differ significantly across innate immune cell types, including DCs. However, DCs do show very specific biological responses to LPS stimulation such as the ability to release IL-2, a key factor for Natural Killer (NK) cell activation. We found that CD14 triggers a pathway involving Ca++ influx, Src family kinases (SFKs) and PLC-gamma2 that leads to NFAT activation in LPS-stimulated DCs. Notably, activation of this pathway was DC-specific and TLR4-independent. We also showed that CD14-NFAT pathway promotes the expression of pro-apoptotic genes that induce apoptosis of activated DCs as a strategy to prevent excessive immune responses. Our work revealed several novel aspects as: (i) the unexpected capability of CD14 to function independently of TLR4 as a transducing receptor; (ii) the previously unrecognized biological role of NFAT in DCs; (iii) a molecular explanation for the differential life cycle of DCs and macrophages after activation, consistent with their specific physiological role in innate immunity.
Additional work revealed that LPS-induced NFAT activation in DCs is also necessary for the efficient synthesis of PGE2, a crucial lipid mediator regulating many proinflammatory processes such as swelling and pain. We also showed that tissue edema formation induced by subcutaneous administration of LPS is CD14-NFAT-dependent, and that DCs play a major role in this process. Not only these results highlight another crucial biological function of this signal transduction pathway in DCs, but they also point to a key direct role of this cell type in the proinflammatory response to LPS. These data suggest that CD14 signaling in DCs may constitute a valuable target for the development of a novel class of anti-inflammatory compounds devoid of the secondary effects observed with COX-2 inhibitors.