Synovial fluid from patients with rheumatoid arthritis inhibits neutrophil apoptosis: role of adenosine and proinflammatory cytokines

Ottonello, Luciano; Cutolo, Maurizio; Frumento, Guido; Arduino, Nicoletta; Bertolotto, Maria; Mancini, Marina; Sottofattori, Enzo; Dallegri, Franco

doi:10.1093/rheumatology/41.11.1249

Cited by 75 publications

(107 citation statements)

References 58 publications

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“…For instance, in rheumatoid arthritis (RA), the most common form of autoimmune joint inflammation, neutrophils are represented preponderantly in the diseased joint fluid and display a prolonged lifespan and reduced migratory activity, suggesting the accumulation of factor(s) in RA that promote neutrophil plasticity (23)(24)(25).…”

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confidence: 99%

Platelet microparticles are internalized in neutrophils via the concerted activity of 12-lipoxygenase and secreted phospholipase A ₂ -IIA

Duchez

Boudreau

Naika

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

200

174

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Platelets are anucleated blood elements highly potent at generating extracellular vesicles (EVs) called microparticles (MPs). Whereas EVs are accepted as an important means of intercellular communication, the mechanisms underlying platelet MP internalization in recipient cells are poorly understood. Our lipidomic analyses identified 12(S)-hydroxyeicosatetranoic acid [12(S)-HETE] as the predominant eicosanoid generated by MPs. Mechanistically, 12(S)-HETE is produced through the concerted activity of secreted phospholipase A2 IIA (sPLA2-IIA), present in inflammatory fluids, and platelet-type 12-lipoxygenase (12-LO), expressed by platelet MPs. Platelet MPs convey an elaborate set of transcription factors and nucleic acids, and contain mitochondria. We observed that MPs and their cargo are internalized by activated neutrophils in the endomembrane system via 12(S)-HETE. Platelet MPs are found inside neutrophils isolated from the joints of arthritic patients, and are found in neutrophils only in the presence of sPLA2-IIA and 12-LO in an in vivo model of autoimmune inflammatory arthritis. Using a combination of genetically modified mice, we show that the coordinated action of sPLA2-IIA and 12-LO promotes inflammatory arthritis. These findings identify 12(S)-HETE as a trigger of platelet MP internalization by neutrophils, a mechanism highly relevant to inflammatory processes. Because sPLA2-IIA is induced during inflammation, and 12-LO expression is restricted mainly to platelets, these observations demonstrate that platelet MPs promote their internalization in recipient cells through highly regulated mechanisms.

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confidence: 99%

Platelet microparticles are internalized in neutrophils via the concerted activity of 12-lipoxygenase and secreted phospholipase A ₂ -IIA

Duchez

Boudreau

Naika

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

200

174

View full text Add to dashboard Cite

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“…There is evidence of B-cell anergy for soluble antigens at serum concentration of >0.1 nM (34). Even in inflammatory conditions like rheumatoid arthritis, GM-CSF is present in synovial fluid at <35 pM (31,35). One group has reported that the frequency of autoantibodies in normal subjects reaches 100% if cytokine-autoantibody complexes are dissociated at low pH before autoantibodies are measured against IL-2, granulocyte colony-stimulating factor (G-CSF), VEGF, TNF, IL-8 (32), and GM-CSF (33).…”

Section: Discussionmentioning

confidence: 99%

Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

Wang

Thomson

Allan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The origin of pathogenic autoantibodies remains unknown. Idiopathic pulmonary alveolar proteinosis is caused by autoantibodies against granulocyte–macrophage colony-stimulating factor (GM-CSF). We generated 19 monoclonal autoantibodies against GM-CSF from six patients with idiopathic pulmonary alveolar proteinosis. The autoantibodies used multiple V genes, excluding preferred V-gene use as an etiology, and targeted at least four nonoverlapping epitopes on GM-CSF, suggesting that GM-CSF is driving the autoantibodies and not a B-cell epitope on a pathogen cross-reacting with GM-CSF. The number of somatic mutations in the autoantibodies suggests that the memory B cells have been helped by T cells and re-entered germinal centers. All autoantibodies neutralized GM-CSF bioactivity, with general correlations to affinity and off-rate. The binding of certain autoantibodies was changed by point mutations in GM-CSF that reduced binding to the GM-CSF receptor. Those monoclonal autoantibodies that potently neutralize GM-CSF may be useful in treating inflammatory disease, such as rheumatoid arthritis and multiple sclerosis, cancer, and pain.

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“…[8][9][10][11][12] Indeed, a percentage of neutrophils obtained from lungs in inflammatory lung injury and from synovial fluids of patients with rheumatoid arthritis have been seen to persist for days. [13][14][15][16] The dogma that neutrophils are all alike is countered by a growing number of studies showing the functional heterogeneity of neutrophils. Neutrophil subsets have been demarcated with identifiable characteristics in terms, for example, of their expression of formyl-methionyl-leucylphenylalanine (fMLP) receptors.…”

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confidence: 99%

Reprogramming of a subpopulation of human blood neutrophils by prolonged exposure to cytokines

Chakravarti

Rusu

Flamand

et al. 2009

Laboratory Investigation

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Essential cells of innate immunity, neutrophils are often considered to be a homogenous population of terminally differentiated cells. During inflammation, neutrophils are extravasated cells exposed to local factors that prolong their survival and activate their production of mediators implicated in disease progression. In this study, a phenotypically distinct subset of human neutrophils that appear after prolonged exposure to cytokines was characterized. Freshly isolated neutrophils from healthy donors were incubated with granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-a and interleukin (IL)-4, three cytokines that are locally present in various inflammatory conditions. Eight to 17% of neutrophils survived beyond 72 h. This subset of non-apoptotic neutrophils, as evaluated by three different markers, was enriched by discontinuous Percoll gradient centrifugation before studying their phenotype. These viable neutrophils showed neoexpression of HLA-DR, CD80 and CD49d. Compared with freshly isolated neutrophils, they responded differentially to second signals similar to formyl-methionyl-leucyl-phenylalanine with three-to four-fold increases in production of superoxide anions and leukotrienes. These cells augmented their phagocytic index by 141%, increased their adhesion to human primary fibroblasts, but reduced their migration in response to chemotactic stimuli and decreased exocytosis of primary and secondary granules. In addition, they produced substantial amounts of IL-8, IL-1Ra and IL-1b. This neutrophil subset had a unique profile of phosphorylation of intracellular signaling molecules. In conclusion, the present identification of a novel neutrophil phenotype highlights the reprogammable character of the neutrophil. This aspect is crucial for our understanding of its contribution to disease pathogenesis and host defense.

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Synovial fluid from patients with rheumatoid arthritis inhibits neutrophil apoptosis: role of adenosine and proinflammatory cytokines

Abstract: The microenvironment of rheumatoid SF is a proinflammatory milieu responsible for the in loco persistence of activated and long-surviving neutrophils. Adenosine plays a crucial role in this phenomenon, which is related to anti-apoptotic activity.

Cited by 75 publications

References 58 publications

Platelet microparticles are internalized in neutrophils via the concerted activity of 12-lipoxygenase and secreted phospholipase A ₂ -IIA

Platelet microparticles are internalized in neutrophils via the concerted activity of 12-lipoxygenase and secreted phospholipase A ₂ -IIA

Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

Reprogramming of a subpopulation of human blood neutrophils by prolonged exposure to cytokines

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Synovial fluid from patients with rheumatoid arthritis inhibits neutrophil apoptosis: role of adenosine and proinflammatory cytokines

Abstract: The microenvironment of rheumatoid SF is a proinflammatory milieu responsible for the in loco persistence of activated and long-surviving neutrophils. Adenosine plays a crucial role in this phenomenon, which is related to anti-apoptotic activity.

Cited by 75 publications

References 58 publications

Platelet microparticles are internalized in neutrophils via the concerted activity of 12-lipoxygenase and secreted phospholipase A 2 -IIA

Platelet microparticles are internalized in neutrophils via the concerted activity of 12-lipoxygenase and secreted phospholipase A 2 -IIA

Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

Reprogramming of a subpopulation of human blood neutrophils by prolonged exposure to cytokines

Contact Info

Product

Resources

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Platelet microparticles are internalized in neutrophils via the concerted activity of 12-lipoxygenase and secreted phospholipase A ₂ -IIA

Platelet microparticles are internalized in neutrophils via the concerted activity of 12-lipoxygenase and secreted phospholipase A ₂ -IIA