Phosphoinositide-3 kinase gamma regulates caspase-1 activation and leukocyte recruitment in acute murine gout.

Abstract

This study investigates the participation of PI3Kγ 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 PI3Kγ was evaluated using a selective inhibitor and mice deficient for PI3Kγ (PI3Kγ-/- ) 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 PI3Kγ, there was reduction of pAkt expression, chemokine production, and neutrophil recruitment. Genetic or pharmacological inhibition of PI3Kγ reduced the adherence of leukocytes to the joint microvasculature, even in joints with established inflammation. Neutrophils from PI3Kγ-/- mice produced less ROS than wild-type neutrophils. There was decreased joint damage and dysfunction in the absence of PI3Kγ. In addition, in the absence of PI3Kγ activity, there was reduction of cleaved caspase-1 and IL-1β production in synovial tissue after injection of MSU crystals and leukotriene B4 . Our studies suggest that PI3Kγ 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 PI3Kγ function may be useful to control acute gout inflammation.

• Authors: Lívia D Tavares, Izabela Galvão, Vivian V Costa, Nathalia V Batista, Lívia C R Rossi, Camila B Brito, Alesandra C Reis, Celso M Queiroz-Junior, Amanda D Braga, Fernanda M Coelho, Ana C Dias, Dario S Zamboni, Vanessa Pinho, Mauro M Teixeira, Flávio A Amaral, Daniele G Souza
• Journal: Journal of leukocyte biology (J Leukoc Biol) Vol. 106 Issue 3 Pg. 619-629 (09 2019) ISSN: 1938-3673 [Electronic] United States
• PMID: 31392775 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 Society for Leukocyte Biology.

Chemical References

• Inflammasomes
• Interleukin-1beta
• Leukotriene B4
• Uric Acid
• Class Ib Phosphatidylinositol 3-Kinase
• Pik3cg protein, mouse
• Proto-Oncogene Proteins c-akt
• Caspase 1

Topics

• Acute Disease
• Animals
• Arthritis, Gouty (enzymology, immunology)
• Caspase 1 (metabolism)
• Cell Adhesion
• Cell Movement
• Class Ib Phosphatidylinositol 3-Kinase (deficiency, metabolism)
• Cytoplasm (metabolism)
• Enzyme Activation
• Inflammasomes (metabolism)
• Inflammation (pathology)
• Interleukin-1beta (metabolism)
• Joints (pathology)
• Leukotriene B4 (metabolism)
• Male
• Mice, Inbred C57BL
• Microvessels (pathology)
• Neutrophil Infiltration
• Neutrophils (metabolism)
• Nociception
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• Synovial Membrane (blood supply)
• Uric Acid