Introduction Monosodium urate crystals (MSU), the etiological agent of gout, are

Introduction Monosodium urate crystals (MSU), the etiological agent of gout, are one of the most potent proinflammatory stimuli for neutrophils. and IL-8 by enzyme-linked immunosorbent assay. Adjustments in the concentration of cytoplasmic free calcium were monitored with the Fura-2-acetoxymethyl ester calcium indicator. MICL manifestation was modulated with an anti-MICL antibody in neutrophils and siRNA in the PLB-985 neutrophil-like cell collection. Results MSU induced the downregulation of MICL manifestation in neutrophils. A diminution in the manifestation of MICL induced SB 216763 by antibody cross-linking or siRNA enhanced the MSU-dependent SB 216763 increase in cytoplasmic calcium levels, protein tyrosine phosphorylation and IL-8 but not IL-1 production. Pretreatment of neutrophils with colchicine inhibited the MSU-induced downregulation of MICL manifestation. Conclusions Our findings strongly suggest that MICL functions as an inhibitory receptor in human being neutrophils since the downregulation of MICL manifestation enhances MSU-induced neutrophil activation. Since MSU downregulates the manifestation of MICL, MICL may play a pathogenic part in gout by enhancing neutrophil effector functions. In support of this notion, colchicine counteracts the MSU-induced loss of MICL manifestation. Our findings therefore also provide further insight into the potential molecular mechanisms behind the anti-inflammatory properties of this drug. Keywords: Cytokine production, out, Immunoreceptor tyrosine-based inhibitory motif, Monosodium urate crystals, Neutrophil, Signaling Intro Gout is one of the most painful types of arthritis, and its prevalence is on the rise worldwide [1,2]. The inflammatory reaction typical of an acute gout attack is initiated from the crystallized form of a by-product of purine metabolism, monosodium urate crystals (MSU). A gout attack can be viewed in three phases: the initiation phase, the effector phase and the subsequent resolution phase. According to the current understanding of the pathogenesis of acute gout, MSU activate resident articular cells (for example, macrophages) during the initiation phase, most commonly in the metatarsophalangeal joint [3]. The activation of resident cells by MSU induces the synthesis of several inflammatory mediators, including active interleukin 1 (IL-1), a cytokine that plays a pivotal role in the pathogenesis of gout, implicating nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome in this inflammatory disorder. IL-1 contributes to the initiation and perpetuation of the effector phase by virtue of its ability to stimulate endothelial cells of the vasculature to express potent chemokines (for example, IL-8) and adhesion molecules responsible for the massive recruitment of neutrophils to the joint. The recruitment of a large number of neutrophils to the affected joint during the effector phase is the pathological hallmark of gouty arthritis [4]. The presence of activated phagocytes in the joint is one of the main causes of tissue destruction and pain in gout. When activated by MSU, neutrophils release a panoply of inflammatory molecules, including cytokines (for example, IL-1, IL-8, S100) and degradative enzymes, that perpetuate the inflammatory reaction as well as oxygen radicals that cause damage to the surrounding tissues (recently reviewed by Popa-Nita and Naccache [4]). At the molecular level, the signaling molecules driving MSU-induced neutrophil responses are just beginning to be identified. They include activated Src family kinases (for example, Lyn), Syk, protein kinase C (PKC), phosphoinositide 3-kinase (PI3K) and Tec [4]. Since the activation of Src kinases is an early signaling event, the majority of MSU-induced effector functions depend on these kinases. Animal studies and clinical observations underscore the pivotal role of the neutrophil in gout. A significant decrease in MSU-induced inflammation was reported in neutropenic mice. Moreover, medications used to treat gout, such as colchicine, downregulate MSU-induced neutrophil effector functions [4]. It is thus of interest to characterize molecular mechanisms that Kit regulate MSU-induced neutrophil activation. Leukocyte activation is regulated in part by phosphatases that block early signaling events of activating receptors when recruited to the plasma membrane. Phosphatase recruitment occurs via immunoreceptor tyrosine-based inhibitory motifs (ITIMs) located in the cytoplasmic portion of inhibitory SB 216763 receptors expressed on the surface of leukocytes [5]. Inhibitory receptors can be classified into two main groups on the basis of their structure, namely, the immunoglobulin or the C-type lectin superfamily. Proteins of the latter contain at least one C-type lectin-like domain (CTLD). Myeloid inhibitory C-type lectin receptors are poorly characterized in comparison to their counterparts in natural killer cells (recently reviewed by Pyz et al. [6]). Findings from the few myeloid inhibitory receptors studied suggest, however, that these.

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