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Journal ArticleDOI

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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Citations
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Journal ArticleDOI
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

Journal ArticleDOI
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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Journal ArticleDOI
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

Journal ArticleDOI
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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Journal ArticleDOI
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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Journal ArticleDOI
TL;DR: Th17/IL‐17 and Treg biology is reviewed and it is proposed that skewing of responses towards Th17 or Th1 and away from Treg may be responsible for the development and/or progression of AD or acute transplant rejection in humans.
Abstract: Uncommitted (naive) murine CD4+ T helper cells (Thp) can be induced to differentiate towards T helper 1 (Th1), Th2, Th17 and regulatory (Treg) phenotypes according to the local cytokine milieu. This can be demonstrated most readily both in vitro and in vivo in murine CD4+ T cells. The presence of interleukin (IL)-12 [signalling through signal transduction and activator of transcription (STAT)-4] skews towards Th1, IL-4 (signalling through STAT-6) towards Th2, transforming growth factor (TGF)-beta towards Treg and IL-6 and TGF-beta towards Th17. The committed cells are characterized by expression of specific transcription factors, T-bet for Th1, GATA-3 for Th2, forkhead box P3 (FoxP3) for Tregs and RORgammat for Th17 cells. Recently, it has been demonstrated that the skewing of murine Thp towards Th17 and Treg is mutually exclusive. Although human Thp can also be skewed towards Th1 and Th2 phenotypes there is as yet no direct evidence for the existence of discrete Th17 cells in humans nor of mutually antagonistic development of Th17 cells and Tregs. There is considerable evidence, however, both in humans and in mice for the importance of interferon (IFN)-gamma and IL-17 in the development and progression of inflammatory and autoimmune diseases (AD). Unexpectedly, some models of autoimmunity thought traditionally to be solely Th1-dependent have been demonstrated subsequently to have a non-redundant requirement for Th17 cells, notably experimental allergic encephalomyelitis and collagen-induced arthritis. In contrast, Tregs have anti-inflammatory properties and can cause quiescence of autoimmune diseases and prolongation of transplant function. As a result, it can be proposed that skewing of responses towards Th17 or Th1 and away from Treg may be responsible for the development and/or progression of AD or acute transplant rejection in humans. Blocking critical cytokines in vivo, notably IL-6, may result in a shift from a Th17 towards a regulatory phenotype and induce quiescence of AD or prevent transplant rejection. In this paper we review Th17/IL-17 and Treg biology and expand on this hypothesis.

733 citations


"Differential regulation of proinfla..." refers background in this paper

  • ...InappropriateTh17 activation was shown to play a crucial role in the induction/maintenance of multiple types of diseases, including autoimmune tissue injury [38]....

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Journal ArticleDOI
TL;DR: It is suggested that ATP and nigericin induce a net decrease in intracellular levels of K+ which is necessary for activation of the post-translational maturation of IL-1 beta.

716 citations

Journal ArticleDOI
TL;DR: Neither secretory lysosome exocytosis nor microvesicle shedding models constitute the major pathways for nonclassical IL-1β secretion from ATP-stimulated murine macrophages, and the findings suggest an alternative model of IL- 1β release that may involve the P2X7R-induced formation of multivesicular bodies that contain exosomes with entrapped IL-2β, caspase-1, and other inflammasome components.
Abstract: Several mechanistically distinct models of nonclassical secretion, including exocytosis of secretory lysosomes, shedding of plasma membrane microvesicles, and direct efflux through plasma membrane transporters, have been proposed to explain the rapid export of caspase-1-processed IL-1 beta from monocytes/macrophages in response to activation of P2X7 receptors (P2X7R) by extracellular ATP. We compared the contribution of these mechanisms to P2X7R-stimulated IL-1 beta secretion in primary bone marrow-derived macrophages isolated from wild-type, P2X7R knockout, or apoptosis-associated speck-like protein containing a C-terminal CARD knockout mice. Our experiments revealed the following: 1) a novel correlation between IL-1 beta secretion and the release of the MHC-II membrane protein, which is a marker of plasma membranes, recycling endosomes, multivesicular bodies, and released exosomes; 2) a common and absolute requirement for inflammasome assembly and active caspase-1 in triggering the cotemporal export of IL-1 beta and MHC-II; and 3) mechanistic dissociation of IL-1 beta export from either secretory lysosome exocytosis or plasma membrane microvesicle shedding on the basis of different requirements for extracellular Ca(2+) and differential sensitivity to pharmacological agents that block activation of caspase-1 inflammasomes. Thus, neither secretory lysosome exocytosis nor microvesicle shedding models constitute the major pathways for nonclassical IL-1 beta secretion from ATP-stimulated murine macrophages. Our findings suggest an alternative model of IL-1 beta release that may involve the P2X7R-induced formation of multivesicular bodies that contain exosomes with entrapped IL-1 beta, caspase-1, and other inflammasome components.

543 citations


"Differential regulation of proinfla..." refers background in this paper

  • ...In particular, the P2X7 receptor has attracted considerable interest since its activation triggers maturation and release of proinflammatory IL-1β in monocytes and macrophages [46]....

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Journal ArticleDOI
TL;DR: The ways in which an infectious agent can initiate or exacerbate autoimmunity are described and the evidence linking certain infectious agents to autoimmune diseases in humans and animal models are discussed.
Abstract: Autoimmunity occurs when the immune system recognizes and attacks host tissue. In addition to genetic factors, environmental triggers (in particular viruses, bacteria and other infectious pathogens) are thought to play a major role in the development of autoimmune diseases. In this review, we (i) describe the ways in which an infectious agent can initiate or exacerbate autoimmunity; (ii) discuss the evidence linking certain infectious agents to autoimmune diseases in humans; and (iii) describe the animal models used to study the link between infection and autoimmunity.

336 citations


"Differential regulation of proinfla..." refers background in this paper

  • ...Currently, mechanisms by which microbial agents trigger autoimmune reaction include induction of pathogenic autoantibody production as a result of molecular mimicry and cross reactivity [29] and polyclonal activation of distinct T cell subclasses [27]....

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  • ...Autoimmune diseases have a multifactorial etiology depending on both genetic and environmental factors [27]....

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Journal ArticleDOI
01 May 2003-Blood
TL;DR: It is demonstrated that anti-beta(2)-GPI antibodies react with their antigen likely associated to a member of the TLR/IL-1 receptor family on the EC surface and directly induce activation, suggesting an involvement of the toll-like receptor (TLR) family.

309 citations


"Differential regulation of proinfla..." refers background in this paper

  • ...Several mechanisms have been proposed for how autoantibodies cause the disease, including interaction with cell surface receptors, such as TLR/IL-1 receptor family members [3], annexin A2 [4], and activation of the complement complex in vessels [5]....

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