Altered Macrophage Function Contributes to Colitis in Mice Defective in the Phosphoinositide-3 Kinase Subunit p110δ

Uno, Jennifer K.; Rao, Kavitha N.; Matsuoka, Katsuyoshi; Sheikh, Shehzad Z.; Kobayashi, Taku; Li, Fengling; Steinbach, Erin C.; Sepulveda, Antonia R.; Vanhaesebroeck, Bart; Sartor, R. Balfour; Plevy, Scott E.

doi:10.1053/j.gastro.2010.07.008

Cited by 80 publications

(94 citation statements)

References 34 publications

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confidence: 62%

“…In p110δ D910A/ D910A mice, macrophages are hyperresponsive to TLR singaling and the augmented TLR signaling pathways elicits an exuberant inflammatory response. 25 Besides, the direct inhibition of Akt in monocytes resulted in a proinflammtory phenotype similar to that observed with PI3K inhibition.26 Therefore, we hypothesized that inactivation of PI3Kδ/Akt signaling in macrophages play a crucial role in AAA development.To test this hypothesis, we investigated the effect of PI3Kδ inactivation on artery architecture and AAA development in 2 distinct murine models in p110δ D910A/D910A mice and in vitro experiments with macrophage migration and MMPs expression. Our results suggested that MMP-12 is the most important molecules influenced by p110δ inactivation in arteries and in vascular injury models.…”

mentioning

confidence: 79%

“…24,46 Our results showed that genetic inactivation of p110δ or pharmacological inhibitor IC87114 has by guest on May 12, 2018 http://atvb.ahajournals.org/ Downloaded from similar effect on significantly increasing macrophages migration. Other studies 25 has showed that PI3K signaling is significantly diminished in PI3K p110δ D910A/D910A bone marrow monocytes (BMMs) as demonstrated by decreased phosphorylation of the PI3K downstream target Akt in LPS-activated PI3K p110δ D910A/D910A BMMs compared with WT BMMs. In addition, LPS-activated p110δ D910A/D910A BMMs displayed that earlier activation and enhanced phosphorylation p38 mitogenactivated protein kinase but there were no significant differences in extracellular-signal-regulated kinases activation and nuclear factor-κB p65 phosphorylation in comparison with WT BMMs.…”

Section: Discussionmentioning

confidence: 99%

“…Taken together, a genetic defect in specific intracellular signaling molecule contributes to global defects in adaptive homeostatic pathways in the intestine 25 and in vessels. Pathogenesis of AAA was closely associated with innate immune disorder.…”

Section: Discussionmentioning

confidence: 99%

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Inactivation of PI3Kδ Induces Vascular Injury and Promotes Aneurysm Development by Upregulating the AP-1/MMP-12 Pathway in Macrophages

Zheng

Xing

Zeng

et al. 2015

ATVB

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A neurysms frequently lead to high morbidity and mortality as a result of rupture or dissection without symptoms. 1 Aortic aneurysms, including abdominal aortic aneurysm (AAA), thoracic aneurysms, and carotid aneurysms, are highly common conditions, with AAA being 3 times more prevalent than thoracic aneurysm.2 Although they are typically regarded as being distinct entities, vascular inflammation is a common pathogenic factor in them. 3,4 Pathological features of aneurismal diseases include transmural inflammatory cell infiltration, noticeable breakdown of elastic lamellae, smooth muscle cell loss, endothelial cell death and detachment, neovascularization, calcium deposition, and focal aneurysmal dilation of the vessel wall. 5,6 However, the specific cellular mechanisms that underlie aneurysm formation and progression are poorly understood.Increasing evidence 7,8 points to an important role for innate immune cells in the pathobiology of aneurysms. Monocytes/ macrophages infiltrate the vessel wall and release proteases, including elastase (matrix metalloproteinase-12 ) and metalloproteinases that compromise the integrity of the vascular wall through degradation of the extracellular matrix (ECM). Monocytes/macrophages also secrete inflammatory cytokines in the media and adventitia of aneurysmatic vessels, such as tumor necrosis factor (TNF)-α, interferon-γ, © 2014 American Heart Association, Inc. Objective-An aneurysm is an inflammatory vascular condition. Phosphatidylinositol 3-kinases δ is highly expressed in leukocytes, and play a key role in innate immunity. However, the link between phosphatidylinositol 3-kinases δ and aneurysm development has not yet been elucidated. Approach and Results-Carotid ligation unexpectedly induced characteristic aneurysm formation beneath the ligation point in p110δ D910A/D910A mice (n=25; P<0.001 versus wild-type). Besides, p110δ inactivation exacerbated CaCl 2 -induced abdominal aortic aneurysms development. A reverse transcription polymerase chain reaction microarray revealed significant extracellular matrix components degradation and matrix metalloproteinases (MMPs) upregulation in the abdominal aorta of p110δ D910A/D910A mice. Similarly, the expression of both collagen I and IV was significantly decreased (n=10; P<0.05 versus wild-type) in carotid artery. Western blot assay confirmed that MMP-12 was significantly upregulated in arteries of p110δ D910A/D910A mice (n=10; P<0.01 versus wild-type). In vitro, p110δ inactivation marked increase peritoneal macrophages recruitment and synergistically enhance tumor necrosis factor-α-induced recruitment. A specific phosphatidylinositol 3-kinases δ inhibitor (IC87114) or genetic p110δ inactivation upregulated MMP-12 expression and c-Jun phosphorylation (n=6; P<0.05 versus wild-type macrophages). IC87114 also increased activator protein-1 DNA-binding activity (n=6; P<0.001 versus control) and enhanced the effect of tumor necrosis factor-α on activator protein-1-binding activity (n=5; P<0.01 versus tumor necrosis factor-α treatment ...

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confidence: 62%

mentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Inactivation of PI3Kδ Induces Vascular Injury and Promotes Aneurysm Development by Upregulating the AP-1/MMP-12 Pathway in Macrophages

Zheng

Xing

Zeng

et al. 2015

ATVB

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“…It it is considered an excellent potential therapeutic target for reducing inflammation both in the acute allergic context but also in the context of chronic inflammatory disorders Rommel et al, 2007). The importance of p110delta in the regulation of inflammatory responses is highlighted by the development of spontaneous chronic colonic inflammation in the p110delta D910A/D910A mice, which has been attributed to a failure to repress inflammatory responses to commensal bacteria in the gut (Uno et al, 2010). Thus p110delta-selective drugs are currently under investigation as a treatment for rheumatoid arthritis, asthma and other inflammatory conditions.…”

Section: Chronic Inflammatory Conditionsmentioning

confidence: 99%