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

ABSTRACT: Phosphoinositide-3 kinases (PI3Ks) are central signaling enzymes that are involved in many aspects of immune cell function. PI3K? and PI3K? are the major isoforms expressed in leukocytes. The role of PI3K isoforms in the resolution of inflammation is still poorly understood. Here, we investigated the contribution of PI3K? and PI3K? to the resolution of inflammation in a model of gout in mice. Methods and Results: Experiments were performed in wild-type male C57/Bl6 mice. Selective inhibitors of PI3K-? (AS605240) or PI3K? (GSK045) were injected in the joint 12 h after injection of MSU crystals, hence at the peak of inflammation. Inhibition of either PI3K isoform decreased number of neutrophils that migrated in response to the injection of MSU crystals. This was associated with reduction of myeloperoxidase activity and IL-1? levels in periarticular tissues and reduction of histological score. Joint dysfunction, as seen by reduced mechanical hypernociception, was improved by treatment with either inhibitor. The decrease in neutrophil numbers was associated with enhanced apoptosis and efferocytosis of these cells. There was shortening of resolution intervals, suggesting inhibition of either isoform induced the resolution of neutrophilic inflammation. Blockade of PI3K? or PI3K? reduced Nuclear Factor kappa B (NF-?B) activation. A pan-PI3K inhibitor (CL27c) reduced inflammation induced by MSU crystals by a magnitude that was similar to that attained by the PI3K? or PI3K? selective inhibitors alone. Conclusion: Taken together, these results suggest that neutrophils can use PI3K? or PI3K? to remain in the cavity and blockade of either isoenzyme is sufficient to induce their apoptosis and resolve inflammation in a murine model of gout.

SUBMITTER: Galvao I

PROVIDER: S-EPMC6330337 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Galvão Izabela I Queiroz-Junior Celso Martins CM de Oliveira Vivian Louise Soares VLS Pinho Vanessa V Hirsch Emilio E Teixeira Mauro Martins MM

Frontiers in pharmacology 20190107

Phosphoinositide-3 kinases (PI3Ks) are central signaling enzymes that are involved in many aspects of immune cell function. PI3Kγ and PI3Kδ are the major isoforms expressed in leukocytes. The role of PI3K isoforms in the resolution of inflammation is still poorly understood. Here, we investigated the contribution of PI3Kγ and PI3Kδ to the resolution of inflammation in a model of gout in mice. <b>Methods and Results:</b> Experiments were performed in wild-type male C57/Bl6 mice. Selective inhibit ...[more]

PMID: 30666201

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Project description:Sarcoidosis is a multisystem inflammatory disease characterized by the development of Th1/Th17/regulatory T cells (Tregs)-related non-caseating granulomas. Phosphoinositide-3 kinases δ/γ (PI3Kδ/γ) play an important role in the maintenance of effective immunity, especially for Tregs homeostasis and stability. In the present study, superoxide dismutase A (SodA) stimulation was used to establish the sarcoidosis mouse model. The second immune stimulus was accompanied by CAL-101 (PI3Kδ inhibitor) or AS-605240 (PI3Kδ/γ inhibitor) treatment. To detect the effect of the PI3Kδ/γ inhibitor on the morphology of pulmonary granuloma and the activation of the PI3K signaling pathway, hematoxylin and eosin staining and immunofluorescence and western blotting was used, respectively. Fluorescence-activated cell sorting analysis and reverse transcription-quantitative PCR were adopted to detect the effect of the PI3Kδ/γ inhibitor on the SodA-induced sarcoidosis mouse model in respect to immune cell disorder and the function of Treg cells, with CD4+CD25- T cells and CD4+CD25+ T cells sorted by magnetic cell sorting. The results demonstrated that the inhibition of PI3Kδ/γ by transtracheal CAL-101/AS-605240 administration facilitated pulmonary granuloma formation. These therapeutic effects were associated with certain mechanisms, including suppressing the aberrantly activated PI3K/Akt signaling in both pulmonary granuloma and Tregs, particularly rescuing the suppressive function of Tregs. Notably, CAL-101 was more effective in immune modulation compared with AS-605240 and could overcome the aberrantly activated Akt in the lung and Tregs. These results suggest that PI3K/Akt signaling, especially the PI3Kδ subunit, can play a key role in optimal Tregs-mediated protection against pulmonary sarcoidosis. Therefore, transtracheal usage of PI3Kδ/γ inhibitors is an attractive therapy that may be developed into a new immune-therapeutic principle for sarcoidosis in the future.

Project description:ObjectivesGout is the most prevalent inflammatory arthritis. To study the effects of regular physical activity and exercise intensity on inflammation and clinical outcome, we examined inflammatory pathogenesis in an acute model of murine gout and analyzed human gout patient clinical data as a function of physical activity.MethodsNF-κB-luciferase reporter mice were organized into four groups and exercised at 0 m/min (non-exercise), 8 m/min (low-intensity), 11 m/min (moderate-intensity), and 15 m/min (high-intensity) for two weeks. Mice subsequently received intra-articular monosodium urate (MSU) crystal injections (0.5mg) and the inflammatory response was analyzed 15 hours later. Ankle swelling, NF-κB activity, histopathology, and tissue infiltration by macrophages and neutrophils were measured. Toll-like receptor (TLR)2 was quantified on peripheral monocytes/neutrophils by flow cytometry and both cytokines and chemokines were measured in serum or synovial aspirates. Clinical data and questionnaires accessing overall physical activity levels were collected from gout patients.ResultsInjection of MSU crystals produced a robust inflammatory response with increased ankle swelling, NF-κB activity, and synovial infiltration by macrophages and neutrophils. These effects were partially mitigated by low and moderate-intensity exercise. Furthermore, IL-1β was decreased at the site of MSU crystal injection, TLR2 expression on peripheral neutrophils was downregulated, and expression of CXCL1 in serum was suppressed with low and moderate-intensity exercise. Conversely, the high-intensity exercise group closely resembled the non-exercised control group by nearly all metrics of inflammation measured in this study. Physically active gout patients had significantly less flares/yr, decreased C-reactive protein (CRP) levels, and lower pain scores relative to physically inactive patients.ConclusionsRegular, moderate physical activity can produce a quantifiable anti-inflammatory effect capable of partially mitigating the pathologic response induced by intra-articular MSU crystals by downregulating TLR2 expression on circulating neutrophils and suppressing systemic CXCL1. Low and moderate-intensity exercise produces this anti-inflammatory effect to varying degrees, while high-intensity exercise provides no significant difference in inflammation compared to non-exercising controls. Consistent with the animal model, gout patients with higher levels of physical activity have more favorable prognostic data. Collectively, these data suggest the need for further research and may be the foundation to a future paradigm-shift in conventional exercise recommendations provided by Rheumatologists to gout patients.

Dataset Information

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

Publications

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

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