Mechanism of neutrophil activation by an unopsonized inflammatory particulate: Monosodium urate crystals induce pertussis toxin-insensitive hydrolysis of phosphatidylinositol 4,5-bisphosphate

E. Onello, A. Traynor-Kaplan, L. Sklar, R. Terkeltaub

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Monosodium urate crystals are believed to trigger acute inflammation via the direct stimulation of leukocytes. Unopsonized urate crystals activate neutrophil (PMN) membrane G proteins in a pertussis toxin (PT)-sensitive manner, but induce PT-insensitive cytosolic [Ca2+](i) elevation. Thus, we have further defined the mechanism of PMN responsiveness to urate crystals in this study. Though urate crystals can increase membrane permeability by lytic effects, we observed elevation of PMN cytosolic [Ca2+](i) in the absence of extracellular [Ca2+](i). In addition, the early, crystal-induced cytosolic [Ca2+](i) transient was buffered in cells loaded with a [Ca2+](i)-chelator. This suggested mobilization of internal [Ca2+](i) stores, which was supported by demonstrating rapid phosphatidylinositol bisphosphate (PIP2) hydrolysis, and the formation of inositol (1,4,5) trisphosphate (as well as phosphatidic acid) in a PT-insensitive manner. Importantly, PMN activation by urate crystals was discriminatory, as evidenced by the absence of phosphatidylinositol trisphosphate formation, a PT-sensitive event triggered by chemotactic factors. Urate crystal-induced PIP2 hydrolysis was not a nonspecific consequence of the early cytosolic [Ca2+](i) transient itself, and it did not require phagocytosis. However, crystal-induced O-/2 release was markedly inhibited by buffering of the early cytosolic [Ca2+](i) transient under conditions where crystal phagocytosis and PMA-induced O-/2 release were unaffected. We conclude that urate crystals activate PT-insensitive PIP2 hydrolysis, resulting in IP3 generation, and early urate crystal-induced mobilization of cytosolic [Ca2+](i). This pathway appears to modulate crystal-induced O-/2 release.

Original languageEnglish (US)
Pages (from-to)4289-4294
Number of pages6
JournalJournal of Immunology
Volume146
Issue number12
StatePublished - 1991

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