Role of PI3Kδ and PI3Kγ in inflammatory arthritis and tissue localization of neutrophils

Randis, Tara M.; Puri, Kamal D.; Zhou, Hairu; Diacovo, Thomas G.

doi:10.1002/eji.200838266

Cited by 115 publications

(105 citation statements)

References 32 publications

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“…Conversely, both Fc␥R (8,14) and PI3K␦ are critical for local C5 and C5a production. Our observations also indicate that the two class IA and IB PI3K molecules might be essential components of the immune response to pathogenic IC and, as recently discussed for rheumatoid arthritis (41,51), may represent potential molecular targets for pharmacological intervention in inflammatory and rheumatic autoimmune diseases.…”

Section: Discussionsupporting

confidence: 79%

Phosphoinositide 3-Kinases γ and δ, Linkers of Coordinate C5a Receptor-Fcγ Receptor Activation and Immune Complex-induced Inflammation

Konrad¹,

Ali²,

Wiege³

et al. 2008

Journal of Biological Chemistry

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Fc␥ receptors (Fc␥R) and the C5a receptor (C5aR) are key effectors of the acute inflammatory response to IgG immune complexes (IC). Their coordinated activation is critical in ICinduced diseases, although the significance of combined signaling by these two different receptor classes in tissue injury is unclear. Here we used the mouse model of the passive reverse lung Arthus reaction to define their requirements for distinct phosphoinositide 3-kinase (PI3K) activities in vivo. We show that genetic deletion of class IB PI3K␥ abrogates C5aR signaling that is crucial for Fc␥R-mediated activation of lung macrophages. Thus, in PI3K␥ ؊/؊ mice, IgG IC-induced Fc␥R regulation, cytokine release, and neutrophil recruitment were blunted. Notably, however, C5a production occurred normally in PI3K␥ ؊/؊ mice but was impaired in PI3K␦ ؊/؊ mice. Consequently, class IA PI3K␦ deficiency caused resistance to acute IC lung injury. These results demonstrate that PI3K␥ and PI3K␦ coordinate the inflammatory effects of C5aR and Fc␥R and define PI3K␦ as a novel and essential element of Fc␥R signaling in the generation of C5a in IC disease.

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Section: Discussionsupporting

confidence: 79%

Phosphoinositide 3-Kinases γ and δ, Linkers of Coordinate C5a Receptor-Fcγ Receptor Activation and Immune Complex-induced Inflammation

Konrad¹,

Ali²,

Wiege³

et al. 2008

Journal of Biological Chemistry

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“…Among them, class I PI3K isoforms (PI3Ka, PI3Kb, PI3Kϒ, and PI3Kd) are the best studied and are emerging drug targets in the treatment of arthritis (23297340). Mice lacking PI3Kd were shown to be resistant to the development of experimental arthritis (47,81), and PI3Kϒ blockade by both genetic and pharmacological approaches suppressed joint inflammation and cartilage damage in various mice models of RA (47,81,82). It was therefore of interest to know which isoforms contributed to invadosome formation.…”

Section: Discussionmentioning

confidence: 99%

Platelet-Derived Growth Factor Receptor Activation Promotes the Prodestructive Invadosome-Forming Phenotype of Synoviocytes from Patients with Rheumatoid Arthritis

Charbonneau

Lavoie

Lauzier

et al. 2016

The Journal of Immunology

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Fibroblast-like synoviocytes (FLS) play a major role in invasive joint destruction in rheumatoid arthritis (RA). This prodestructive phenotype has been shown to involve autocrine TGF-β that triggers formation of matrix-degrading invadosomes through molecular mechanisms that are not fully elucidated. The platelet-derived growth factor (PDGF) receptor (PDGFR) family of receptor tyrosine kinases (RTK) has been shown to cooperate with TGF-β in various pathological conditions. We therefore sought to determine whether RTK activity played a role in invadosome biogenesis. We demonstrated that, among the common RTKs, PDGFR-αβ was specifically phosphorylated in FLS from RA patients. Phosphorylation of PDGFR-αβ was also elevated in RA synovial tissues. Interference with PDGFR activation or PDGF neutralization inhibited invadosome formation in RA synoviocytes, indicating the presence of an autocrine PDGFR activation loop that involved endogenous PDGF. Among the PDGF-A–D isoforms, only PDGF-B was found both significantly elevated in FLS lines from RA patients, and related to high-invadosome forming cells. Addition of TGF-β upregulated invadosome formation, PDGF-B mRNA expression, and phosphorylation of PDGFR. All of these functions were efficiently suppressed by TGF-β neutralization or interference with the Smad/TβR1or PI3K/Akt pathway. Among the class 1 PI3K family proteins known to be expressed in RA synoviocytes, PI3Kα was selectively involved in PDGF-B expression, whereas both PI3Kα and PI3Kδ participated in invadosome formation. Our findings demonstrate that PDGFR is a critical RTK required for the prodestructive phenotype of RA synovial cells. They also provide evidence for an association between autocrine TGF-β and PDGFR-mediated invadosome formation in RA synoviocytes that involves the production of PDGF-B induced by TGF-β.

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“…Previous animal studies with PI3Kg and PI3Kd inhibition show that they independently regulate the development and progression of arthritis Hayer et al, 2009;Gruen et al, 2010). Combined deficiency or inhibition of PI3Kg and PI3Kd has striking therapeutic impact with near complete suppression of arthritis (Randis et al, 2008).…”

Section: Discussionmentioning

confidence: 97%

“…Notably, combined p110d and p110g deficiency more effectively reduces disease severity than lack of either individual isoform (Randis et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Novel Phosphoinositide 3-Kinaseδ,γInhibitor: Potent Anti-Inflammatory Effects and Joint Protection in Models of Rheumatoid Arthritis

Boyle

Kim

Topolewski

et al. 2013

J Pharmacol Exp Ther

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Phosphoinositide 3-kinases g and d (PI3Kg and PI3Kd) are expressed in rheumatoid arthritis (RA) synovium and regulate innate and adaptive immune responses. We determined the effect of a potent PI3Kd,g inhibitor, IPI-145, in two preclinical models of RA. IPI-145 was administered orally in rat adjuvantinduced arthritis (AA) and intraperitoneally in mouse collageninduced arthritis (CIA). Efficacy was assessed by paw swelling, clinical scores, histopathology and radiography, and microcomputed tomography scanning. Gene expression and Akt phosphorylation in joint tissues were determined by quantitative real-time polymerase chain reaction and Western blot analysis. Serum concentrations of anti-type II collagen (CII) IgG and IgE were measured by immunoassay. T-cell responses to CII were assayed using thymidine incorporation and immunoassay. IPI-145 significantly reduced arthritis severity in both RA models using dosing regimens initiated before onset of clinical disease. Treatment of established arthritis with IPI-145 in AA, but not CIA, significantly decreased arthritis progression. In AA, histology scores, radiographic joint damage, and matrix metalloproteinase (MMP)-13 expression were reduced in IPI-145-treated rats. In CIA, joint histology scores and expression of MMP-3 and MMP-13 mRNA were lower in the IPI-145 early treatment group than in the vehicle group. The ratio of anti-CII IgG2a to total IgG in CIA was modestly reduced. Interleukin-17 production in response to CII was decreased in the IPI-145-treated group, suggesting an inhibitory effect on T-helper cell 17 differentiation. These data show that PI3Kd,g inhibition suppresses inflammatory arthritis, as well as bone and cartilage damage, through effects on innate and adaptive immunity and that IPI-145 is a potential therapy for RA.

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Role of PI3Kδ and PI3Kγ in inflammatory arthritis and tissue localization of neutrophils

Cited by 115 publications

References 32 publications

Phosphoinositide 3-Kinases γ and δ, Linkers of Coordinate C5a Receptor-Fcγ Receptor Activation and Immune Complex-induced Inflammation

Phosphoinositide 3-Kinases γ and δ, Linkers of Coordinate C5a Receptor-Fcγ Receptor Activation and Immune Complex-induced Inflammation

Platelet-Derived Growth Factor Receptor Activation Promotes the Prodestructive Invadosome-Forming Phenotype of Synoviocytes from Patients with Rheumatoid Arthritis

Novel Phosphoinositide 3-Kinaseδ,γInhibitor: Potent Anti-Inflammatory Effects and Joint Protection in Models of Rheumatoid Arthritis

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