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

Luo, Lin; Wall, Adam A.; Yeo, Jeremy C.; Condon, Nicholas D.; Norwood, Suzanne J.; Schoenwaelder, Simone M.; Chen, Kaiwen; Jackson, Shaun P.; Jenkins, Brendan J.; Hartland, Elizabeth L.; Schroder, Kate; Collins, Brett M.; Sweet, Matthew J.; Stow, Jennifer L.

doi:10.1038/ncomms5407

Cited by 120 publications

(192 citation statements)

References 68 publications

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“…Consequently, our novel findings of a beneficial effect of rapamycin on early stage of DN via TLR4 pathway in vivo, confirms a role of TLR4 in renal fibrosis, a dangerous factor of DN. Our findings also support Luo et al who suggest that TLR4-driven mTOR signaling plays a vital role in innate immune responses [39].…”

Section: Tlr-4supporting

confidence: 92%

The Inhibitory Effect of Rapamycin on Toll Like Receptor 4 and Interleukin 17 in the Early Stage of Rat Diabetic Nephropathy

Hong

Villani

et al. 2016

Kidney Blood Press Res

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Background/Aims: There is increasing evidence showing that innate immune responses and inflammatory processes play an important role in the development and progression of diabetic nephropathy (DN). The potential effect of innate immunity in the early stage of DN is still unclear. Toll-Like-Receptor 4 (TLR4) is vigorously involved in the progress of kidney diseases in a sterile environment. The activation of the interleukin 17 (IL-17) pathway produces inflammatory cytokines, appearing in various kidney diseases. Unfortunately the relationship between TLR4 and IL-17 has not been investigated in diabetic nephropathy to date. The aim of this study is to investigate whether mammalian target of rapamycin (mTOR) inhibition may be dependent on TLR4 signaling and the pro-inflammatory factor IL-17 to delay the progression of DN. Methods: Streptozotocin (STZ)-induced diabetic rats were randomly assigned to 3 experimental groups: a diabetic nephropathy group (DN, n = 6); and a diabetic nephropathy treated with rapamycin group (Rapa, n = 6) and a control group (Control, n =6). Body weight, fasting blood sugar, and 24h urine albumin were assessed at week 2, week 4 and week 8. Renal tissues were harvested for H&E, PAS staining, as well as an immunohistochemistry assay for TLR4 and IL-17. TLR4 quantitative expression was measured by Western-Blot analysis and RT-PCR. Results: Our results demonstrated that the expression of both TLR4 and IL-17 were upregulated in early stage DN and reduced by rapamycin. TLR4 and IL-17 both increased and positively related to 24h urinary albumin and kidney/weight ratio. However, neither TLR4 nor IL-17 made a significant difference on fasting blood sugar. Conclusions: Taken together, our results confirm and extend previous studies identifying the significance of the TLR4 and Th17 pathways in development of early stage DN. Furthermore, we suggest this overexpression of TLR4 might be involved in the immunopathogenesis of DN through activation of Th17 cells. Rapamycin may attenuate DN via reduction of the TLR4 signaling pathway and Th17 cells signaling. Although the underlying mechanisms need to be explored, the observed increase of TLR4 and IL-17 during the early stages of DN and their suppression with rapamycin treatment suggest the importance of TLR4 and IL-17 in DN pathophysiology.

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Section: Tlr-4supporting

confidence: 92%

The Inhibitory Effect of Rapamycin on Toll Like Receptor 4 and Interleukin 17 in the Early Stage of Rat Diabetic Nephropathy

Hong

Villani

et al. 2016

Kidney Blood Press Res

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“…Therefore, our findings show that, following CSF-1 receptor activation in macrophages, the majority of macropinocytic activity is derived from dorsal ruffles. This conclusion is consistent with an emerging view that the dorsal surface and ruffles might function as a membrane domain specialised for signalling (Abella et al, 2010;Luo et al, 2014).…”

Section: Discussionsupporting

confidence: 90%

“…Dorsal ruffles have a distinctive circular or curved upright architecture, are very dynamic and appear transiently following receptor activation. In some cells, dorsal ruffles are specialised for initiating receptor signalling (Abella et al, 2010;Luo et al, 2014), for example dorsal ruffles are abundant in macrophages following activation (Patel and Harrison, 2008;Yoshida et al, 2009). Although macropinocytosis has been linked to both peripheral ruffles and dorsal ruffles, some reports have suggested that peripheral ruffles might be more relevant than dorsal ruffles for initiating macropinocytosis (Buccione et al, 2004;Hoon et al, 2012;Suetsugu et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Sorting nexin 5 (SNX5) selectively regulates dorsal ruffle-mediated macropinocytosis in primary macrophages

Lim

Gosavi

Mintern

et al. 2015

Journal of Cell Science

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The regulation of macropinocytosis, a specialised endocytosis pathway, is important for immune cell function. However, it is not known whether the biogenesis of macropinosomes involves one or more distinct pathways. We previously identified sorting nexin 5 (SNX5) as a regulator of macropinocytosis in macrophages. Here, we show that bone-marrow-derived macrophages from SNX5-knockout mice had a 60-70% reduction in macropinocytic uptake of dextran or ovalbumin, whereas phagocytosis and retrograde transport from the plasma membrane to the Golgi was unaffected. In contrast, deficiency of SNX5 had no effect on macropinocytosis or antigen presentation by dendritic cells. Activation of macrophages with CSF-1 resulted in a localisation of SNX5 to actin-rich ruffles in a manner dependent on receptor tyrosine kinases. SNX5-deficient macrophages showed a dramatic reduction in ruffling on the dorsal surface following CSF-1 receptor activation, whereas peripheral ruffling and cell migration were unaffected. We demonstrate that SNX5 is acting upstream of actin polymerisation following CSF-1 receptor activation. Overall, our findings reveal the important contribution of dorsal ruffing to receptoractivated macropinocytosis in primary macrophages and show that SNX5 selectively regulates macropinosomes derived from the dorsal ruffles.

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“…7). It was shown recently that MTs are required for targeting TLR4 to membrane ruffles following LPS activation (85). As stathmin overexpression also reduces membrane ruffles on macrophages, both the TLR4 signaling foci within these membrane structures as well as total surface TLR4 levels are impacted when stabilized MTs are diminished.…”

Section: Discussionmentioning

confidence: 98%

Down-regulation of Stathmin Is Required for the Phenotypic Changes and Classical Activation of Macrophages

Harrison

2015

Journal of Biological Chemistry

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Background: Macrophage activation involves pronounced microtubule (MT) stabilization. Results: Stathmin is degraded to enhance MT stabilization and allow robust activation in IFN␥-LPS-stimulated macrophages. Conclusion: MT stabilization by reduced stathmin levels is required for enhanced phagocytosis, signal transduction, and activation of macrophages. Significance: Understanding the nature and mechanisms of MT stabilization in activated macrophages is important for both immunology and cell biology fields.

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

Cited by 120 publications

References 68 publications

The Inhibitory Effect of Rapamycin on Toll Like Receptor 4 and Interleukin 17 in the Early Stage of Rat Diabetic Nephropathy

The Inhibitory Effect of Rapamycin on Toll Like Receptor 4 and Interleukin 17 in the Early Stage of Rat Diabetic Nephropathy

Sorting nexin 5 (SNX5) selectively regulates dorsal ruffle-mediated macropinocytosis in primary macrophages

Down-regulation of Stathmin Is Required for the Phenotypic Changes and Classical Activation of Macrophages

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