The exposure of autoantigens by microparticles underlies the formation of potent inflammatory components: the microparticle-associated immune complexes.
Bottom Line: Rather, mpICs display autoantigens vimentin and fibrinogen, and recognition of these targets by anti-citrullinated peptide antibodies contributes to the production of mpICs.Functionally, platelet mpICs are highly pro-inflammatory, eliciting leukotriene production by neutrophils.Taken together, our data suggest a unique role for platelet MPs as autoantigen-expressing elements capable of perpetuating formation of inflammatory ICs.
Affiliation: Faculté de Médecine de l'Université Laval, Centre de Recherche en Rhumatologie et Immunologie, Centre de Recherche du Centre Hospitalier Universitaire de Québec, Québec, Québec, Canada.Show MeSH
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Mentions: The inflammatory lipid mediators leukotrienes are present in RA synovial fluid (Klickstein et al, 1980) and its production by neutrophils, a cellular lineage dominant in the synovial fluid from RA patients (Edwards & Hallett, 1997), contribute to the pathophysiology of inflammatory arthritis in in vivo mechanistic models (Chen et al, 2006). Similarly to MPs, the mpICs can be centrifuged and used as cellular stimulus. We thus centrifuged SF from RA patients and used the resulting pellet to determine its potency on human neutrophils. We demonstrate that this fraction, which contains both MPs and mpICs, can stimulate neutrophils to produce leukotrienes (Fig 7A). We next used in vitro generated mpICs to examine whether they could elicit the release of leukotrienes from neutrophils. We find that mpICs, which spontaneously form after the co-incubation of platelet MPs with anti-fibrinogen (Fig 7B), induce robust leukotriene production by neutrophils (Fig 7C). For comparison, platelet MPs and anti-fibrinogen are only modestly active when added to neutrophils separately (Fig 7C). To assess the relative pro-inflammatory activity of mpICs, we fractionated mpICs, MPs and anti-fibrinogen ICs via size exclusion filtration (800 nm pores). Interestingly, we show that the mpIC depletion abrogates much of the leukotriene stimulation in this assay (Fig 7C), establishing that the platelet mpICs are active and highly pro-inflammatory.
Affiliation: Faculté de Médecine de l'Université Laval, Centre de Recherche en Rhumatologie et Immunologie, Centre de Recherche du Centre Hospitalier Universitaire de Québec, Québec, Québec, Canada.