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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.

AbstractAntiphospholipid 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.

Topics: CCL2 (55%), CXCL10 (55%), Lipopolysaccharide (53%), Inflammation (53%), Proinflammatory cytokine (52%)

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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.
Abstract: The antiphospholipid syndrome (APS) is a systemic autoimmune disease that is characterized serologically by the presence of antiphospholipid antibodies (aPL) and clinically by vascular thrombosis and obstetric complications. The protein β2 glycoprotein I (β2GPI) is identified as the most important autoantigen in this syndrome. Activation of endothelial cells, thrombocytes and placental tissue by anti-β2GPI antibodies relates to the clinical manifestations of APS. This review describes genetic and environmental factors in relation to APS and summarizes the current knowledge on abnormalities in components of both the innate and adaptive immune system in APS. The role of dendritic cells, T-cells, B-cells, monocytes, neutrophils and NK-cells as well as the complement system in APS are discussed. Several gaps in our knowledge on the pathophysiology of APS are identified and 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.

47 citations


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.
Abstract: Background: Electronegative LDL (LDL(−)), a modified LDL fraction found in blood, induces the release of inflammatory mediators in endothelial cells and leukocytes However, the inflammatory pathways activated by LDL(−) have not been fully defined We aim to study whether LDL(−) induced release of the first-wave proinflammatory IL-1β in monocytes and monocyte-derived macrophages (MDM) and the mechanisms involved Methods: LDL(−) was isolated from total LDL by anion exchange chromatography Monocytes and MDM were isolated from healthy donors and stimulated with LDL(+) and LDL(−) (100 mg apoB/L) Results: In monocytes, LDL(−) promoted IL-1β release in a time-dependent manner, obtaining at 20 h-incubation the double of IL-1β release induced by LDL(−) than by native LDL LDL(−)-induced IL-1β release involved activation of the CD14-TLR4 receptor complex LDL(−) induced priming, the first step of IL-1β release, since it increased the transcription of pro-IL-1β (8-fold) and NLRP3 (3-fold) compared to native LDL Several findings show that LDL(−) induced inflammasome activation, the second step necessary for IL-1β release Preincubation of monocytes with K+ channel inhibitors decreased LDL(−)-induced IL-1β release LDL(−) induced formation of the NLRP3-ASC complex LDL(−) triggered 2-fold caspase-1 activation compared to native LDL and IL-1β release was strongly diminished in the presence of the caspase-1 inhibitor Z-YVAD In MDM, LDL(−) promoted IL-1β release, which was also associated with caspase-1 activation Conclusions: LDL(−) promotes release of biologically active IL-1β in monocytes and MDM by induction of the two steps involved: priming and NLRP3 inflammasome activation Significance: By IL-1β release, LDL(−) could regulate inflammation in atherosclerosis

32 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.

23 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: 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.
Abstract: Introduction Antiphospholipid syndrome (APS) is a pro-thrombotic autoimmune disease that affects different vascular beds, with potential risk for recurrence. Systemic lupus erythematosus (SLE), specific autoantibodies profile and atherogenic disorders have been described as risk factors for the occurrence of first thrombosis in patients with antiphospholipid antibodies (aPL). However, factors associated with recurrent thrombosis have not yet been completely elucidated in APS. The aim of this study was to evaluate the association of recurrent thrombosis with markers of inflammation, autoimmunity and the presence of atherogenic disorders in APS patients. Materials and methods We performed a retrospective evaluation of a cohort of APS patients in order to determine if markers of inflammation, autoimmunity and cardiovascular risk were associated with recurrence of thrombosis. Results One hundred fifteen patients with APS were included, 60% had primary APS. History of recurrent thrombosis was positive in 38.3% of patients, and 40% of them were on oral anticoagulants at the time of recurrence. Independent risk factors associated with recurrent thrombosis were arterial hypertension (OR = 3.7, 95% CI = 1.6–8.5, P = 0.002) and monocytosis above 500 u/mm 3 (OR = 2.4, 95% CI = 1.2–5.3, P = 0.02). These factors were particularly relevant in cases of venous index event. Conclusion The results suggest that arterial hypertension and monocyte counts may be independent factors for thrombosis recurrence in APS. Given the morbidity of recurrent cases, the results 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.

15 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: Circulating TF is associated with thrombotic complications related to APS, but not with the risk of unprovoked VTE, as compared with controls.
Abstract: The mechanisms behind the severe hypercoagulable state in antiphospholipid syndrome (APS) have not yet been fully elucidated. Knowledge on the etiology of thrombosis in APS is needed to improve treatment. We performed a case control study to evaluate the association of the levels of circulating tissue factor (TF) with thrombotic APS and unprovoked venous thromboembolism (VTE), as compared with controls without a history of thrombosis. Study participants were selected in the same geographic area. Linear regression was used to evaluate possible determinants of TF levels among controls and logistic regression was used to evaluate the association between TF, unprovoked VTE and t-APS. TF levels were grouped into three categories based on: below 50th percentile [reference], between 50-75th percentiles [second category] and 75th percentile [third category]. Two hundred and eighty participants were included in the study; 51 patients with unprovoked VTE, 111 patients with t-APS and 118 control individuals. The levels of TF were not associated with an increased risk of unprovoked VTE, as compared with controls. The adjusted odds ratio for t-APS was 2.62 (95%CI 1.03 to 6.62) with TF levels between 50-75th percentiles and 8.62 (95%CI 3.76 to 19.80) with TF levels above the 75th percentile, as compared with the reference category (below the 50th percentile). In the subgroup analysis, higher levels of TF were associated with both arterial and venous thrombosis in APS and with both primary and secondary APS. Circulating TF is associated with thrombotic complications related to APS, but not with the risk of unprovoked VTE.

8 citations


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

  • ...Toll-like receptors (TLRs) are membrane receptors responsible for the self- and nonself-recognition of evolutionarily conserved structures on pathogens, termed pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) [16, 17]....

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Journal ArticleDOI
09 Mar 2006-Nature
TL;DR: It is shown that cryopyrin-deficient macrophages cannot activate caspase-1 in response to Toll-like receptor agonists plus ATP, the latter activating the P2X7 receptor to decrease intracellular K+ levels.
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Journal ArticleDOI
TL;DR: The CD8+ effector cells raised in the CD4 subset- deficient host were able of clear vital tissues from productive infection and to restrict asymptomatic, persistent infection to acinar glandular epithelial cells in salivary gland tissue.
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2,165 citations


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