Phosphoinositide-3 Kinase γ Activity Contributes to Sepsis and Organ Damage by Altering Neutrophil Recruitment

Martin, Erica L.; Souza, Danielle G.; Fagundes, Caio T.; Amaral, Flávio A.; Assenzio, Barbara; Puntorieri, Valeria; Sorbo, Lorenzo Del; Fanelli, Vito; Bosco, Martino; Delsedime, Luisa; Pinho, José Felipe; Lemos, Virgı́nia S.; Souto, Fabrício Oliveira; Alves-Filho, José C.; Cunha, Fernando; Slutsky, Arthur S.; Rückle, Thomas; Hirsch, Emilio; Teixeira, Mauro Martins; Ranieri, V. Marco

doi:10.1164/rccm.201001-0088oc

Cited by 54 publications

(50 citation statements)

References 60 publications

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“…For example, atherosclerotic lesions are attenuated in apoEdeficient mice by inhibitors of PI3K␥, or by replacing the macrophages of the apoE mice with ones originated from PI3K␥-deficient animals (231, 456). Sepsis-induced multiorgan damage was also significantly reduced in mice with genetic or pharmacological inactivation of PI3K␥ (1002), and PI3K␥ deleted mice were largely protected in mouse models of rheumatoid arthritis (208). PI3K␥ inhibition also alleviated the severity of glomerulonephritis in a mouse model of systemic lupus (104).…”

Section: Pi3k␥/pi3kcgmentioning

confidence: 96%

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

Balla

2013

Physiological Reviews

1,300

1,569

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Phosphoinositides (PIs) make up only a small fraction of cellular phospholipids, yet they control almost all aspects of a cell's life and death. These lipids gained tremendous research interest as plasma membrane signaling molecules when discovered in the 1970s and 1980s. Research in the last 15 years has added a wide range of biological processes regulated by PIs, turning these lipids into one of the most universal signaling entities in eukaryotic cells. PIs control organelle biology by regulating vesicular trafficking, but they also modulate lipid distribution and metabolism via their close relationship with lipid transfer proteins. PIs regulate ion channels, pumps, and transporters and control both endocytic and exocytic processes. The nuclear phosphoinositides have grown from being an epiphenomenon to a research area of its own. As expected from such pleiotropic regulators, derangements of phosphoinositide metabolism are responsible for a number of human diseases ranging from rare genetic disorders to the most common ones such as cancer, obesity, and diabetes. Moreover, it is increasingly evident that a number of infectious agents hijack the PI regulatory systems of host cells for their intracellular movements, replication, and assembly. As a result, PI converting enzymes began to be noticed by pharmaceutical companies as potential therapeutic targets. This review is an attempt to give an overview of this enormous research field focusing on major developments in diverse areas of basic science linked to cellular physiology and disease.

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Section: Pi3k␥/pi3kcgmentioning

confidence: 96%

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

Balla

2013

Physiological Reviews

1,300

1,569

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“…PI3Kγ plays a critical role in inflammation, with mice lacking the Pik3cg gene for p110γ having reduced inflammatory responses (1-3), increased protection from anaphylaxis (4), and protection from sepsis (5). Aberrant activation of the PI3K pathway is one of the most common events in cancer (6).…”

mentioning

confidence: 99%

Molecular determinants of PI3Kγ-mediated activation downstream of G-protein–coupled receptors (GPCRs)

Vadas

Dbouk²,

Shymanets

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

116

177

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Phosphoinositide 3-kinase gamma (PI3Kγ) has profound roles downstream of G-protein-coupled receptors in inflammation, cardiac function, and tumor progression. To gain insight into how the enzyme's activity is shaped by association with its p101 adaptor subunit, lipid membranes, and Gβγ heterodimers, we mapped these regulatory interactions using hydrogen-deuterium exchange mass spectrometry. We identify residues in both the p110γ and p101 subunits that contribute critical interactions with Gβγ heterodimers, leading to PI3Kγ activation. Mutating Gβγ-interaction sites of either p110γ or p101 ablates G-protein-coupled receptor-mediated signaling to p110γ/p101 in cells and severely affects chemotaxis and cell transformation induced by PI3Kγ overexpression. Hydrogen-deuterium exchange mass spectrometry shows that association with the p101 regulatory subunit causes substantial protection of the RBD-C2 linker as well as the helical domain of p110γ. Lipid interaction massively exposes that same helical site, which is then stabilized by Gβγ. Membrane-elicited conformational change of the helical domain could help prepare the enzyme for Gβγ binding. Our studies and others identify the helical domain of the class I PI3Ks as a hub for diverse regulatory interactions that include the p101, p87 (also known as p84), and p85 adaptor subunits; Rab5 and Gβγ heterodimers; and the β-adrenergic receptor kinase.

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“…Another report provided evidence that phosphoinositide-3 kinase (PI3K)-g, a key regulator of leukocyte recruitment, plays an important role in the pathogenesis of sepsis. Genetic inhibition of PI3K-g improved survival, reduced multiorgan damage, and limited bacterial decompartmentalization in cecal ligation and perforation-induced sepsis (41). In the same sepsis model, hydrogen sulfide restored impaired neutrophil migration and reduced bacteremia and lung injury via a K ATP 1 channel-dependent mechanism, thereby increasing survival (42).…”

Section: Mediators Biomarkers and Experimental Therapies Of Sepsis mentioning

confidence: 96%

Update in Acute Lung Injury and Critical Care 2010

Vadász

Sznajder

2011

Am J Respir Crit Care Med

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Phosphoinositide-3 Kinase γ Activity Contributes to Sepsis and Organ Damage by Altering Neutrophil Recruitment

Abstract: This study establishes PI3Kγ as a key molecule in the pathogenesis of septic infection and the transition from SIRS to organ damage and identifies it as a novel possible therapeutic target.

Cited by 54 publications

References 60 publications

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

Molecular determinants of PI3Kγ-mediated activation downstream of G-protein–coupled receptors (GPCRs)

Update in Acute Lung Injury and Critical Care 2010

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