Differential regulation of proinflammatory mediators following LPS- and ATP-induced activation of monocytes from patients with antiphospholipid syndrome.
15 Feb 2015-BioMed Research International (Hindawi Publishing Corporation)-Vol. 2015, pp 292851-292851
TL;DR: Increased sensitivity of APS cells to LPS that may contribute to thrombus formation and enhance development or progression of autoimmune processes is indicated.
Abstract: Antiphospholipid syndrome (APS) is an acquired autoimmune disorder characterized by recurrent thrombosis and pregnancy morbidity in association with the presence of antiphospholipid antibodies. Growing evidence supports the involvement of monocytes in APS pathogenesis. Inflammatory activation of monocytes promotes thrombus formation and other APS complications. However, mechanisms underlying their activation are poorly investigated. We aimed to determine transcriptional activity of monocytes after exposing them to low concentrations of lipopolysaccharide (LPS) and LPS + adenosine triphosphate (ATP) using comparative qRT-PCR. The results showed that LPS significantly increased transcriptional levels of TLR2, IL-23, CCL2, CXCL10, IL-1β, and IL-6 in APS cells, while, in cells from healthy donors, LPS resulted in IL-6 and STAT3 elevated mRNAs. Double stimulation of the cells resulted in decreased mRNA levels of NLRP3 in monocytes isolated from healthy donors and CCL2, IL-1β in APS cells. By contrast, TLR2 mRNAs were elevated in both investigated groups after culture of the cells with LPS + ATP. Thus, the findings indicate increased sensitivity of APS cells to LPS that may contribute to thrombus formation and enhance development or progression of autoimmune processes. Low concentrations of ATP diminish LPS-induced inflammatory state of APS monocytes which might be a potential mechanism which regulates inflammatory state of the cells.
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TL;DR: A plea is made for future extensive immune cell profiling by a systems medicine approach in order to better unravel the pathogenesis of APS to gain more insight in the role of the immune system in APS as well as having the potential to reveal biomarkers or novel therapeutic targets.
53 citations
TL;DR: This review summarizes and critically assess the pathogenic and non-pathogenic formation of aPLs and its contribution to the development of APS.
Abstract: Antiphospholipid antibodies (aPLs) comprise a diverse family of autoantibodies targeted against proteins with the affinity toward negatively charged phospholipids or protein-phospholipid complexes. Their clinical significance, including prothrombotic potential of anti-cardiolipin antibodies (aCLs), anti-β2-glycoprotein I antibodies (aβ2-GPIs), and lupus anti-coagulant (LA), is well-established. However, the ontogeny of these pathogenic aPLs remains less clear. While transient appearance of aPLs could be induced by various environmental factors, in genetically predisposed individuals these factors may eventually lead to the development of the antiphospholipid syndrome (APS). Since the first description of APS, it has been found that a wide variety of microbial and viral agents influence aPLs production and contribute to clinical manifestations of APS. Many theories attempted to explain the pathogenic potential of different environmental factors as well as a phenomenon termed molecular mimicry between β2-GPI molecule and infection-relevant structures. In this review, we summarize and critically assess the pathogenic and non-pathogenic formation of aPLs and its contribution to the development of APS.
38 citations
Cites background from "Differential regulation of proinfla..."
...It is a widely accepted view that pathogenesis of many autoimmune diseases is largely driven by inappropriate or inadequate immune responses toward bacterial agents (50, 51)....
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TL;DR: LDL(−) promotes release of biologically active IL-1β in monocytes and MDM by induction of the two steps involved: priming and NLRP3 inflammasome activation.
37 citations
TL;DR: The results suggest that arterial hypertension and monocyte counts may be independent factors for thrombosis recurrence in APS, and may support the evaluation of therapeutic measures to a rigid control of blood pressures and modulation of inflammatory response in APs, as additional prophylaxis against the recurrence of vascular events.
25 citations
Cites background from "Differential regulation of proinfla..."
...Monocytes have been recognized as key cells for the pathogenesis of APS [11] and previous “in vitro” and clinical studies have demonstrated an increased activation of monocytes in patients with APS [27,28]....
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...For the pathogenesis of thrombotic APS, the immune-complex formed by aCL or aβ2GP1 and their antigens, in particular LDL oxidized, would activatemonocytes to express tissue factor, to secrete inflammatory cytokines [11,27] and possibly contribute to the formation of atherosclerotic plaques on the vascular wall [30]....
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TL;DR: Levels of sTREM-1 might serve as a biomarker for thrombosis in patients with primary antiphospholipid syndrome as well as other predictors (thrombotic PAPS-ever, age, and sex).
Abstract: Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is an innate-immune receptor found in blood. Its presence reflects innate immune cell activation. We sought to investigate plasma sTREM-1 levels in patients with primary antiphospholipid syndrome (PAPS). A cross-sectional, case-control design was used. Plasma sTREM-1 levels were analyzed by enzyme-linked immunosorbent assay (ELISA) in consecutive patients diagnosed with PAPS or asymptomatic antiphospholipid antibody (APLA) carriers and controls. The study cohort included 33 patients with PAPS, 10 asymptomatic APLA carriers, and 73 controls. Mean plasma sTREM-1 levels were significantly higher in patients with PAPS (299.2 ± 146.7 pg/ml) and thrombotic PAPS-ever (current and past thrombotic event) (327.2 ± 151.3 pg/ml) compared with controls (230.2 ± 85.5 pg/ml; p = 0.006 and p = 0.003, respectively), patients with thrombotic PAPS compared with patients with past obstetric APS (195.12 ± 58.52 pg/ml, p = 0.01) and APLA carriers (215.8 ± 51.6 pg/ml, p = 0.02), patients with current thrombotic PAPS (429.5 ± 227.5 pg/ml) compared with patients with past thrombotic PAPS (289.5 ± 94.65 pg/ml, p = 0.01), and patients with PAPS who had ever had a stroke or venous thromboembolic event compared with patients who had not (p = 0.007 and p = 0.02, respectively). On receiver operator characteristic curve analysis, plasma sTREM-1 levels differentiated patients with current thrombotic PAPS from asymptomatic APLA carriers and controls, with an area under the curve of 0.7292 (p = 0.0014) and 0.88 (p < 0.0001), respectively. Multivariate regression analysis to identify sTREM-1 predictors (thrombotic PAPS-ever, age, and sex) yielded an independent association of sTREM-1 levels with thrombotic PAPS (p < 0.0001). Plasma sTREM-1 levels are significantly elevated in patients with thrombotic PAPS. Levels of sTREM-1 might serve as a biomarker for thrombosis in patients with PAPS.
10 citations
References
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TL;DR: Evidence for the presence of myeloid-derived suppressor cells in murine and human autoimmune disease and the mechanisms by which such cells inhibit T cell proliferation are discussed.
Abstract: In chronic inflammation, across a number of quite different pathological conditions, monocytes accumulate. In autoimmune disease, these cells are widely recognised to play an inflammatory and tissue destructive role. But these cells also inhibit T cell proliferation by a range of different mechanisms that are accompanied by the depletion of specific amino acids in the local microenvironment and the downregulation of the T cell receptor ζ chain. This occurs within the pro-inflammatory environment and in the presence of Th1 (IFNγ) and Th17 (IL-17) cytokines. In tumours, related cells are part of a population called myeloid-derived suppressor cells (MDSC) and they are associated with immunosuppression. Their depletion can lead to clinical improvement. In organ specific autoimmune disease, where such cells can be found in the spleen and in target organs, recent evidence indicates that they may play a role in limiting the T cell response to autoantigens in the target tissue. This occurs by a targeted disruption of T cell division. In this review we discuss evidence for the presence on MDSC in murine and human autoimmune disease and the mechanisms by which such cells inhibit T cell proliferation.
57 citations
"Differential regulation of proinfla..." refers background in this paper
...Accumulation of activated monocytes in the inflamed sites is widely recognized to play an inflammatory and tissue destructive role [32]....
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TL;DR: Low-grade inflammation and immune activation occur in primary thrombotic PAPS and relate to clinical features and aPL levels.
Abstract: Objective. To test the inflammation and immune activation hypothesis in primary thrombotic APS (PAPS) and to identify clinical and laboratory factors related to inflammation and immune activation. Methods. PAPS (n ¼ 41) patients were compared with patients with inherited thrombophilia (IT, n ¼ 44) and controls (CTR, n ¼ 39). IgG aCL, IgG anti-� 2-glycoprotein I (� 2GPI), high-sensitivity CRP (hs-CRP), serum amyloid A (SAA), CRP bound to oxidized low-density lipoprotein– � 2GPI complex (CRP–oxLDL–� 2GPI) (as inflammatory markers) neopterin (NPT), soluble CD14 (sCD14) (as immune activation markers) were measured by ELISA. Results. After correction for confounders, PAPS showed higher plasma levels of hs-CRP (P ¼ 0.0004), SAA (P < 0.01), CRP–oxLDL–� 2GPI (P ¼ 0.0004), NPT (P < 0.0001) and sCD14 (P ¼ 0.007) than IT and CTR. Two regression models were applied to the PAPS group: in the first, IgG aCL and IgG � 2GPI were included amongst the independent variables and in the second they were excluded. In the first model, SAA (as the dependent variable) independently related to thrombosis number (P ¼ 0.003); NPT (as the dependent variable) independently related to thrombosis type (arterial, P ¼ 0.03) and number (P ¼ 0.04); sCD14 (as the dependent variable) independently related to IgG � 2GPI (P ¼ 0.0001), age (0.001) and arterial thrombosis (P ¼ 0.01); CRP–oxLDL–� 2GPI (as the dependent variable) independently related to IgG � 2GPI (P ¼ 0.0001). In the second model, sCD14 and NPT independently related to each other (P ¼ 0.002) (this was noted also in the IT group, P < 0.0001) and CRP–oxLDL–� 2GPI independently predicted SAA (P ¼ 0.002). Conclusion. Low-grade inflammation and immune activation occur in thrombotic PAPS and relate to clinical features and aPL levels.
46 citations
"Differential regulation of proinfla..." refers background in this paper
...Altered sensing of the innate immune cells to bacterial products and/or “danger” signals may contribute to the ongoing inflammation in APS [25]....
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TL;DR: It is shown that extracellular ATP impairs in an IL-10-dependent fashion the expression of the tolerogenic soluble and membrane-bound HLA-G Ag in human monocytes, pointing to a specific role of the P2X7 receptor.
Abstract: Bacterial LPS induces the release of ATP from immune cells. Accruing evidence suggests that extracellular ATP participates in the inflammatory response as a proinflammatory mediator by activating the inflammasome complex, inducing secretion of cytokines (IL-1, IL-18) and cell damaging agents such as oxygen radicals, cationic proteins, and metalloproteases. It is not known whether ATP can also act as a proinflammatory mediator by inhibiting production of molecules down-modulating the immune response. Here, we show that extracellular ATP impairs in an IL-10-dependent fashion the expression of the tolerogenic soluble and membrane-bound HLA-G Ag in human monocytes. The effect of ATP was mimicked by BzATP (3'-O-(4-benzoyl)benzoyl-ATP) and greatly reduced by pretreatment with oATP (periodate-oxidized ATP), KN-62 (1-[N,O-bis(5-isoquinoline-sulfonyl)-N-methyl-l-tyrosyl]-4-phenylpiperazine), and an anti-P2X(7) mAb, thus pointing to a specific role of the P2X(7) receptor. The effect of ATP was time- and dose-dependent and was not due to a decrease in expression of IL-10 receptor. Inhibition by ATP was reverted by supplementation of culture medium with exogenous IL-10. Due to the well-known immunosuppressive activity of IL-10 and soluble HLA-G, this novel effect of ATP might be relevant for the pathophysiology and therapy of inflammatory disorders.
34 citations
"Differential regulation of proinfla..." refers background in this paper
...Once outside of the cell, ATP functions as a potent regulatory molecule and modulates a broad range of cell functions in a dose-dependent manner [42, 43]....
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TL;DR: The ability of monocytes to produce radiolabeled pro‐IL‐1β in response to LPS and to posttranslationally process the procytokine after ATP stimulation was affected both by time in culture and by the presence of specific media components.
Abstract: Despite a large production capacity, freshly isolated lipopolysaccharide (LPS)-activated human monocytes release only a small percentage of their newly synthesized interleukin (IL)-1 beta into the medium. Extracellular ATP, acting via surface P2z-type purino-receptors, increases cytokine posttranslational processing. To explore whether this ATP response was affected by culture conditions, monocytes were maintained for different time periods in the absence and presence of various media components including fetal bovine and human sera and recombinant human cytokines. The ability of monocytes to produce radiolabeled pro-IL-1 beta in response to LPS and to posttranslationally process the procytokine after ATP stimulation was affected both by time in culture and by the presence of specific media components. These observations indicate that ATP's ability to promote human monocyte IL-1 beta posttranslational processing is a dynamic process that is subject to regulation by cytokines and/or growth factors. Changes in monocyte/macrophage ATP responsiveness may provide an important regulatory mechanism for the control of IL-1 biological activity in vivo.
26 citations
"Differential regulation of proinfla..." refers background in this paper
...IL-1β lacks a secretory signal peptide and is secreted through a nonclassical pathway [19], and there is a need for a secondary stimulus, such as endogenous adenosine triphosphate (ATP), to promote posttranslational processing of IL-1β [20, 21]....
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TL;DR: Findings indicate activation of beta2GPI-specific T cells and subsequent production of pathogenic anti-beta2G PI antibodies can be induced by the exposure of such T cells to cryptic peptides of beta1GPI efficiently presented by functional antigen-presenting cells (APC).
23 citations