Intracellular trafficking and secretion of inflammatory cytokines

Stow, Jennifer L.; Murray, Rachael Z.

doi:10.1016/j.cytogfr.2013.04.001

Cited by 113 publications

(110 citation statements)

References 145 publications

(283 reference statements)

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“…We have previously demonstrated that PI3Kd regulates postGolgi trafficking and secretion of TNF in macrophages stimulated by LPS 18 . Interestingly, PI3Kd inhibition does not fully abolish TNF secretion under GD conditions in microglia or after tMCAO in mice, supporting the existence of two parallel pathways for TNF secretion: a constitutive low capacity one, independent of PI3Kd and an inflammation-elicited pathway as previously described 18,42 . Difference in cellular sources of TNF might also be important for controlling TNF levels and effects in the brain.…”

Section: Discussionsupporting

confidence: 77%

“…Such leukocytic recruitment following experimental stroke has been documented in several species 45,46 . Leukocytes are involved in the secondary progression of brain damage, with a dramatic accumulation of frontline neutrophils occurring in the infarcted tissue during reperfusion 12,42,47 , an observation replicated in our mouse I/R model. Our results reveal a key role of the PI3Kd-TNF axis in mediating leukocyte recruitment into the ischaemic brain post reperfusion.…”

Section: Discussionsupporting

confidence: 64%

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PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model

et al. 2014

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Stroke is a major cause of death worldwide and the leading cause of permanent disability. Although reperfusion is currently used as treatment, the restoration of blood flow following ischaemia elicits a profound inflammatory response mediated by proinflammatory cytokines such as tumour necrosis factor (TNF), exacerbating tissue damage and worsening the outcomes for stroke patients. Phosphoinositide 3-kinase delta (PI3Kd) controls intracellular TNF trafficking in macrophages and therefore represents a prospective target to limit neuroinflammation. Here we show that PI3Kd inhibition confers protection in ischaemia/ reperfusion models of stroke. In vitro, restoration of glucose supply following an episode of glucose deprivation potentiates TNF secretion from primary microglia-an effect that is sensitive to PI3Kd inhibition. In vivo, transient middle cerebral artery occlusion and reperfusion in kinase-dead PI3Kd (p110d D910A/D910A ) or wild-type mice pre-or post-treated with the PI3Kd inhibitor CAL-101, leads to reduced TNF levels, decreased leukocyte infiltration, reduced infarct size and improved functional outcome. These data identify PI3Kd as a potential therapeutic target in ischaemic stroke.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionsupporting

confidence: 64%

PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model

et al. 2014

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“…Accordingly, the macrophage cell surface is armed with various membrane protrusions, is serviced by multiple endocytic and exocytic pathways and has a high rate of plasma membrane turnover to accommodate environmental sampling and pathogen sensing 1 . Members of the Rab family of small GTPases regulate multiple steps of membrane trafficking 2 and, in macrophages, Rabs associated with the cell surface and endocytic pathways are uniquely poised to influence pathogen recognition and internalization [3][4][5] .…”

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confidence: 99%

“…Members of the Rab family of small GTPases regulate multiple steps of membrane trafficking 2 and, in macrophages, Rabs associated with the cell surface and endocytic pathways are uniquely poised to influence pathogen recognition and internalization [3][4][5] . Multiple Rabs are involved in the phagocytosis of pathogens 6,7 and in the trafficking and secretion of cytokines in pathogen-activated cells 1 . Several Rabs [3][4][5] have also been implicated in regulating the trafficking of Toll-like receptor 4 (TLR4), a member of the TLR family of pattern recognition receptors that initiate cellular responses to pathogens and danger signals 8 .…”

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confidence: 99%

Rab8a interacts directly with PI3Kγ to modulate TLR4-driven PI3K and mTOR signalling

et al. 2014

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Toll-like receptor 4 (TLR4) is activated by bacterial lipopolysaccharide (LPS) to mount innate immune responses. The TLR4-induced release of pro-and anti-inflammatory cytokines generates robust inflammatory responses, which must then be restrained to avoid disease. New mechanisms for the critical regulation of TLR-induced cytokine responses are still emerging. Here we find TLR4 complexes localized in LPS-induced dorsal ruffles on the surface of macrophages. We discover that the small GTPase Rab8a is enriched in these ruffles and recruits phosphatidylinositol 3-kinase (PI3Kg) as an effector by interacting directly through its Ras-binding domain. Rab8a and PI3Kg function to regulate Akt signalling generated by surface TLR4. Rab8a and PI3Kg do not affect TLR4 endocytosis, but instead regulate mammalian target of rapamycin signalling as a mechanism for biasing the cytokine profile to constrain inflammation in innate immunity.

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“…Macrophages also secrete IL-6 and IL-10 by the classical pathway by recycling endosomes [7]. Cytokines such as IL-1, lacking the N-terminal signal sequence required for ER entry, are synthesized in the cytoplasm, and thereafter released from cells by non-classical pathways [8]. Our group [4] found that TNF- was released through exosomes from hypoxic cardiomyocytes.…”

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confidence: 99%

New insights into autocrine cytokines produced by ischemic cardiomyocytes and ventricular remodeling

Lei

Liao

2015

Sci. China Life Sci.

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Intracellular trafficking and secretion of inflammatory cytokines

Cited by 113 publications

References 145 publications

PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model

PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model

Rab8a interacts directly with PI3Kγ to modulate TLR4-driven PI3K and mTOR signalling

New insights into autocrine cytokines produced by ischemic cardiomyocytes and ventricular remodeling

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