| First Author | Tavares LD | Year | 2019 |
| Journal | J Leukoc Biol | Volume | 106 |
| Issue | 3 | Pages | 619-629 |
| PubMed ID | 31392775 | Mgi Jnum | J:280807 |
| Mgi Id | MGI:6364704 | Doi | 10.1002/JLB.MA1118-470RR |
| Citation | Tavares LD, et al. (2019) Phosphoinositide-3 kinase gamma regulates caspase-1 activation and leukocyte recruitment in acute murine gout. J Leukoc Biol 106(3):619-629 |
| abstractText | This study investigates the participation of PI3Kgamma in the development of joint inflammation and dysfunction in an experimental model of acute gout in mice. Acute gout was induced by injection of monosodium urate (MSU) crystals into the tibiofemoral joint of mice. The involvement of PI3Kgamma was evaluated using a selective inhibitor and mice deficient for PI3Kgamma (PI3Kgamma(-/-) ) or with loss of kinase activity. Neutrophils recovered from the inflamed joint were quantified and stained for phosphorylated Akt (pAkt) and production of reactive oxygen species (ROS). The adherence of leukocytes to the joint microvasculature was assessed by intravital microscopy and cleaved caspase-1 by Western blot. Injection of MSU crystals induced massive accumulation of neutrophils expressing phosphorylated Akt. In the absence of PI3Kgamma, there was reduction of pAkt expression, chemokine production, and neutrophil recruitment. Genetic or pharmacological inhibition of PI3Kgamma reduced the adherence of leukocytes to the joint microvasculature, even in joints with established inflammation. Neutrophils from PI3Kgamma(-/-) mice produced less ROS than wild-type neutrophils. There was decreased joint damage and dysfunction in the absence of PI3Kgamma. In addition, in the absence of PI3Kgamma activity, there was reduction of cleaved caspase-1 and IL-1beta production in synovial tissue after injection of MSU crystals and leukotriene B4 . Our studies suggest that PI3Kgamma is crucial for MSU crystal-induced acute joint inflammation. It is necessary for regulating caspase-1 activation and for mediating neutrophil migration and activation. Drugs that impair PI3Kgamma function may be useful to control acute gout inflammation. |
