Crystal-induced neutrophil activation. VII. Involvement of Syk in the responses to monosodium urate crystals

Abstract

The inflammatory response in acute gouty arthritis is in large part a result of the interaction between neutrophils and monosodium urate (MSU) crystals. The tyrosine kinase Syk, which has been largely associated with the phagocytic response by Fc receptors and with spreading mediated by integrins, has been identified as one of the major proteins tyrosine-phosphorylated in human neutrophils upon stimulation by MSU crystals and is known to be mediated in part by the Fc receptor, CD16. This has led to the present examination of the implication of Syk in the activation pathways used by MSU crystals. The tyrosine-phosphorylation patterns induced by MSU crystals and by the ligation of CD16 were inhibited by piceatannol, which, conversely, only slightly delayed but did not diminish the peak of tyrosine phosphorylation induced by cross-linking CD32 or by the addition of fMet-Leu-Phe. Moreover, piceatannol inhibited the activity of Syk as monitored by in vitro kinase assays, by its in situ tyrosine phosphorylation, and by its activity toward exogenous substrates after stimulation by MSU crystals. We also measured the impact of piceatannol on the mobilization of calcium, the production of superoxide anions, and the activity of PLD stimulated by MSU crystals. We noted a distinct inhibition of all these responses by piceatannol. Finally, the morphological changes observed in neutrophils as characteristic of MSU crystal internalization were diminished significantly by piceatannol. The results obtained show that Syk plays a critical and central role in the signal-transduction pathways called upon by MSU crystals subsequent to their interaction with human neutrophils.

Tanshinone IIA Improves Acute Gouty Arthritis in Rats through Regulating Neutrophil Activation and the NLRP3 Inflammasome

“…In AGA, after MSU induces neutrophil autophagy, the ingested MSU promotes the release of lysosomal content by destroying the lysosomal membrane. The excessive release of neutrophil lysosomal content and the abnormal production and secretion of cytokines and inflammatory chemokines are the main causes of tissue damage [ 39 ]. Therefore, inhibiting neutrophil autophagy is essential to resolving inflammation.…”

A role of IgM antibodies in monosodium urate crystal formation and associated adjuvanticity (135.71)

“…Most recently, the NLRP3 inflammasome, a multi-protein complex capable of activating caspase-1, was found to be involved in producing IL-1β in response to MSU crystal stimulation (134). PLA2, PLD, PKC, Syk and PI3K have also been implicated in signal transduction when neutrophils interact with MSU crystals (100,101,105,111,185,187). Ng et al had obtained similar results using dendritic cells where Syk dependent activation signals were measured during DC MSU crystal activation (179).…”

“…The main idea derived from this study, is the Syk tyrosine kinase plays a central role in MSU crystals induced activation of neutrophils, and the described downstream events, including the activation of phosphotidylinositol tyrosine kinase, (PI3K) (108,109). Earlier, PI3K was found to be activated upon MSU crystal stimulation, but now it is apparent that Syk can be found a step above PI3K in the signal transduction pathway (105,110).…”

“…They showed that upon stimulation, Syk phosphorylation increased significantly, but was inhibited in cells pre-incubated with antibodies against CD16, prior to MSU crystal stimulation (104). Upon further investigation of the Syk involvement in MSU crystal neutrophil interactions, Desaulniers et al showed that with the use of a Syk specific inhibitor (piceatannol), the phosphorylation pattern seen before, was inhibited in a concentration dependent manner (101,105). They were also able to decrease the downstream events of MSU crystal neutrophil interactions, such as intracellular calcium mobilization, the activation of PLD, and production of superoxides (100,106,107).…”

“…The next step was to investigate whether the presence of the UBAs in vivo would affect other cell types involved in the inflammatory response. Past research suggests that neutrophils are involved in the induction of the inflammation in gout and could potentially be affected by the presence of micro MSU crystals in vivo (65,66,72,100,101,104,105,111,(185)(186)(187)(188). After three days of injections of uric acid and UBA solutions, blood from the injected mice was isolated, hemolysed and fluorescently labelled with CD11b and CD62L antibodies.…”