The Inhibition of Phosphoinositide-3 Kinases Induce Resolution of Inflammation in a Gout Model

Galvão, Izabela; Queiroz-Junior, Celso Martins; Oliveira, Vívian Louise Soares de; Pinho, Vanessa; Hirsch, Emilio; Teixeira, Mauro Martins

doi:10.3389/fphar.2018.01505

Cited by 16 publications

(13 citation statements)

References 39 publications

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“…In those studies, crystals promoted the phosphorylation of the regulatory subunit p85 (class 1A PI3K) and phosphorylation of AKT in a mechanism dependent on protein kinase C activation . Interestingly, a recent study demonstrated that PI3Kγ and PI3Kδ isoforms were important to keep neutrophil viability in synovial cavity after MSU crystal injection and the blockade of those PI3K activities caused neutrophil apoptosis, stimulating the resolution of acute gout inflammation in mouse . However, the contribution of PI3Kγ isoform for the trigger events in gout arthritis was still unknown.…”

Section: Discussionmentioning

confidence: 99%

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

Tavares

Galvão

Costa

et al. 2019

Journal of Leukocyte Biology

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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.

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Section: Discussionmentioning

confidence: 99%

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

Tavares

Galvão

Costa

et al. 2019

Journal of Leukocyte Biology

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“…[3] Many natural-product PI3K inhibitors, such as wortmannin, have side effects and poor metabolic stability. [5][6][7] In this work, we focused on a PI3K inhibitor, Pi103, that causes reductions in tumor volume in models of acute myeloid leukemia (AML), [8] lung cancer, [9] and skin cancer but has serious side effects. [5][6][7] In this work, we focused on a PI3K inhibitor, Pi103, that causes reductions in tumor volume in models of acute myeloid leukemia (AML), [8] lung cancer, [9] and skin cancer but has serious side effects.…”

Section: Introductionmentioning

confidence: 99%

Oxidative Cyclization‐Induced Activation of a Phosphoinositide 3‐Kinase Inhibitor for Enhanced Selectivity of Cancer Chemotherapeutics

et al. 2019

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In this work, we designed a prodrug that reacts with cellular oxidative equivalents leading to ether cleavage and cyclization to release an active phosphatidylinositol 3-kinase (PI3K) inhibitor. We show that the compound reduces affinity for PI3KA relative to the PI3K inhibitor, is slow to intercellularly oxidize, and is resistant to liver microsomes. We observed modest activity in untreated acute myeloid leukemia cells and 14-fold selectivity relative to non-cancerous cells. The cellular activity of the compound can be modulated by the addition of antiox-idants or oxidants, indicating the compound activity is sensitive to cellular reactive oxygen species (ROS) state. Co-treatment with cytosine arabinoside or doxorubicin was used to activate the compound inside cells. We observed strong synergistic activity specifically in acute myeloid leukemia (AML) cancer cells with an increase in selective anticancer activity of up to 90-fold. Thus, these new self-cyclizing compounds can be used to increase the selectivity of anticancer agents.

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“…Rho kinase inhibition prevents nuclear factor kappa B activation and I-kappa B phosphorylation and degradation [31]. Prevention of NFκB activation and reduced levels of IκBα phosphorylation was associated with resolution of inflammation [35,59,79,80]. We used different mouse backgrounds because the models of pleurisy induced by LPS and gout were established in the Balb/C and C57Bl/6, respectively, hence their use.…”

Section: Discussionmentioning

confidence: 99%

“…We used different mouse backgrounds because the models of pleurisy induced by LPS and gout were established in the Balb/C and C57Bl/6, respectively, hence their use. In both systems, there are much data suggesting that both systems share the same pathway for neutrophil recruitment and survival [35,59,79,80]. Thus, the requirement of same pathway in different systems to neutrophil survival highlights the importance of this pathway to inflammation resolution.…”

Section: Discussionmentioning

confidence: 99%

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ROCK Inhibition Drives Resolution of Acute Inflammation by Enhancing Neutrophil Apoptosis

Galvão

Athayde

Perez

et al. 2019

Cells

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Uncontrolled inflammation leads to tissue damage and it is central for the development of chronic inflammatory diseases and autoimmunity. An acute inflammatory response is finely regulated by the action of anti-inflammatory and pro-resolutive mediators, culminating in the resolution of inflammation and restoration of homeostasis. There are few studies investigating intracellular signaling pathways associated with the resolution of inflammation. Here, we investigate the role of Rho-associated kinase (ROCK), a serine/threonine kinase, in a model of self-resolving neutrophilic inflammatory. We show that ROCK activity, evaluated by P-MYPT-1 kinetics, was higher during the peak of lipopolysaccharide-induced neutrophil influx in the pleural cavity of mice. ROCK inhibition by treatment with Y-27632 decreased the accumulation of neutrophils in the pleural cavity and was associated with an increase in apoptotic events and efferocytosis, as evaluated by an in vivo assay. In a model of gout, treatment with Y-27632 reduced neutrophil accumulation, IL-1β levels and hypernociception in the joint. These were associated with reduced MYPT and IκBα phosphorylation levels and increased apoptosis. Finally, inhibition of ROCK activity also induced apoptosis in human neutrophils and destabilized cytoskeleton, extending the observed effects to human cells. Taken together, these data show that inhibition of the ROCK pathway might represent a potential therapeutic target for neutrophilic inflammatory diseases.

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The Inhibition of Phosphoinositide-3 Kinases Induce Resolution of Inflammation in a Gout Model

Cited by 16 publications

References 39 publications

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

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

Oxidative Cyclization‐Induced Activation of a Phosphoinositide 3‐Kinase Inhibitor for Enhanced Selectivity of Cancer Chemotherapeutics

ROCK Inhibition Drives Resolution of Acute Inflammation by Enhancing Neutrophil Apoptosis

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