Late Endosome/Lysosome-Localized Rab7b Suppresses TLR9-Initiated Proinflammatory Cytokine and Type I IFN Production in Macrophages

Yao, Ming; Liu, Xingguang; Li, Dong; Chen, Taoyong; Cai, Zhen; Cao, Xuetao

doi:10.4049/jimmunol.0900249

Cited by 64 publications

(50 citation statements)

References 39 publications

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“…For example, Golgi-associated Rab39A in the THP-1 human acute monocytic leukemia cell line is involved in IL-1b secretion [24]. Endosome/lysosome-localized Rab7B negatively regulated TLR4 signaling [25] and TLR9-triggered production of TNF-a, IL-6, and IFN-b in macrophages [26]. In the present study, we showed further that attenuation of Rab37 mRNA expression in activated macrophages led to diminished TNF-a secretion ( Fig.…”

Section: Inflammationsupporting

confidence: 59%

Release of TNF‐α from macrophages is mediated by small GTPase Rab37

et al. 2011

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Activated macrophages at wound sites release many cytokines which positively affect skin wound healing. However, the molecular mechanisms controlling cytokine secretion from macrophages have not been elucidated. In the present study, we performed an RT-PCR analysis and found that 19 small GTPase Rab isoforms were expressed at skin wound sites, with six of them (i.e. Rab3B, Rab27B, Rab30, Rab33A, Rab37, and Rab40C) being upregulated during the inflammation and proliferation/migration phase of skin repair. We also found that gene expression of Rab37 in murine primary and RAW264.7 macrophages was significantly induced after stimulation with LPS. Overexpression of wild type and constitutively active Rab37 in RAW264.7 cells significantly increased TNF-a secretion, whereas knockdown of Rab37 by siRNA significantly decreased it. We also identified 29 putative Rab37-interacting proteins, including the membrane fusion regulating Munc13-1, using liquid chromatography/ linear ion trap mass spectrometry (LC-MS/MS). Immunocytochemical analysis further revealed that TNF-a-containing vesicles were colocalized with both Rab37 and Munc13-1 in activated macrophages. Knockdown of Munc13-1 by siRNA significantly decreased TNF-a secretion. Taken together, these findings demonstrate that Rab37 interacts with Munc13-1 to control TNF-a secretion from activated macrophages.Key words: Macrophage . Munc13-1 . Rab37 . Skin wound healing . TNF-a Supporting Information available online IntroductionIn response to skin tissue damage, inflammatory cells rapidly infiltrate the wound site to protect against infection. In the acute phase of inflammation, neutrophils, the first responder inflammatory cells, migrate toward wound sites to internalize and eliminate pathogens. Subsequently, macrophages preferentially infiltrate to wound sites after neutrophil recruitment, where they release cytokines, chemokines, and growth factors to control skin wound healing by stimulating the activation and proliferation of fibroblasts and keratinocytes, and by promoting wound contraction and angiogenesis [1]. Although this inflammatory response 3230is part of the wound-healing process, wound models in several organisms have shown that the inflammatory response can cause fibrotic diseases (i.e. scarring) in the skin and other organs [2]. Recently, we have shown that osteopontin is secreted by activated fibroblasts in response to platelet-derived growth factor secreted from macrophages, and that silencing of osteopontin at skin wound sites reduces scarring and improves the quality of healing in vivo [3]. Therefore, the pathways controlling inflammatory mediator secretion could provide novel molecular therapeutic targets [4].One such inflammatory mediator, TNF-a, is a pleiotropic proinflammatory cytokine expressed by macrophages and neutrophils at skin wound sites [5,6]. It has been reported that signaling via TNF-a negatively regulates skin wound healing, because TNF-a receptor p55 KO mice showed rapid skin wound healing coincident with reduced inflammatory respons...

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Section: Inflammationsupporting

confidence: 59%

Release of TNF‐α from macrophages is mediated by small GTPase Rab37

et al. 2011

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“…There is mounting evidence that both subcellular localization and endosomal pH can influence the ability of endosomal TLRs to signal. For example, the TLR9 response to exogenous CpG DNA is dependent on specific endosomal localization and acidification (Guiducci et al , 2006; Yao et al , 2009; Okuya et al , 2010; Hazeki et al , 2013; Duhamel et al , 2016). Sasai et al (2010) showed TLR9 signaling leading to activation of type I IFN but not pro‐inflammatory cytokine genes require TLR9 trafficking from endosomes to a specialized lysosome‐related organelle dependent on AP‐3.…”

Section: Discussionmentioning

confidence: 99%

Snapin promotes HIV ‐1 transmission from dendritic cells by dampening TLR 8 signaling

et al. 2017

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HIV‐1 traffics through dendritic cells (DCs) en route to establishing a productive infection in T lymphocytes but fails to induce an innate immune response. Within DC endosomes, HIV‐1 somehow evades detection by the pattern‐recognition receptor (PRR) Toll‐like receptor 8 (TLR8). Using a phosphoproteomic approach, we identified a robust and diverse signaling cascade triggered by HIV‐1 upon entry into human DCs. A secondary siRNA screen of the identified signaling factors revealed several new mediators of HIV‐1 trans‐infection of CD4+ T cells in DCs, including the dynein motor protein Snapin. Inhibition of Snapin enhanced localization of HIV‐1 with TLR8+ early endosomes, triggered a pro‐inflammatory response, and inhibited trans‐infection of CD4+ T cells. Snapin inhibited TLR8 signaling in the absence of HIV‐1 and is a general regulator of endosomal maturation. Thus, we identify a new mechanism of innate immune sensing by TLR8 in DCs, which is exploited by HIV‐1 to promote transmission.

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“…LPS and OVA protein were from Sigma-Aldrich (St. Louis, MO). Phosphorothioate-modified CpG-ODN was synthesized by Shenggong (Shanghai, China), and its sequence was described previously (30). Endotoxin in these ODNs was removed using endotoxin-removal solution (Sigma-Aldrich).…”

Section: Methodsmentioning

confidence: 99%

Integrin CD11b Negatively Regulates TLR9-Triggered Dendritic Cell Cross-Priming by Upregulating microRNA-146a

Bai

Qian

et al. 2012

The Journal of Immunology

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Dendritic cells (DCs) play critical roles in cross-priming to induce the CTL response against infection; however, the molecular mechanisms for the regulation of DC cross-priming need to be investigated further, which may help to improve the potency of DC vaccines through engineering modifications. Our previous studies showed that β2 integrin CD11b could control TLR-triggered NK cell cytotoxicity and macrophage inflammatory responses. CD11b is also abundantly expressed in DCs, but it is unknown whether CD11b participates in the regulation of DC cross-priming for the CTL response. Also, because microRNAs (miRNAs) are important regulators of the immune response, it remains unclear whether miRNAs are regulated by CD11b in DCs. In this study, we showed that CD11b deficiency upregulated TLR9-triggered, but not TLR4-triggered, IL-12p70 production in DCs, subsequently promoting DC cross-priming of the CTL response. Further experiments showed that CD11b selectively promoted TLR9-triggered miR-146a upregulation in DCs by sustaining late-phase NF-κB activation. Additionally, Notch1, a known positive regulator of IL-12p70 production in DCs, was confirmed to be directly targeted by miR-146a. miR-146a upregulation and Notch1 repression were determined to be responsible for the reduced IL-12p70 production in TLR9-triggered wild-type DCs compared with that in CD11b-deficient DCs. Therefore, CD11b and downstream miR-146a may be new negative regulators for DC cross-priming by suppressing Notch1 expression and IL-12p70 production. Our data indicate a new mechanism for the regulation of DC cross-priming through integrins and miRNAs.

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Late Endosome/Lysosome-Localized Rab7b Suppresses TLR9-Initiated Proinflammatory Cytokine and Type I IFN Production in Macrophages

Cited by 64 publications

References 39 publications

Release of TNF‐α from macrophages is mediated by small GTPase Rab37

Release of TNF‐α from macrophages is mediated by small GTPase Rab37

Snapin promotes HIV ‐1 transmission from dendritic cells by dampening TLR 8 signaling

Integrin CD11b Negatively Regulates TLR9-Triggered Dendritic Cell Cross-Priming by Upregulating microRNA-146a

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