The DOI matches its Crossref record; 27 of the 28 references it cites were found in a registry or an index.
The t-SNARE Syntaxin 4 Is Regulated during Macrophage Activation to Function in Membrane Traffic and Cytokine Secretion
Open accessAbstract
Activation of macrophages with lipopolysaccharide (LPS) induces the rapid synthesis and secretion of proinflammatory cytokines, such as tumor necrosis factor (TNFalpha), for priming the immune response. TNFalpha plays a key role in inflammatory disease; yet, little is known of the intracellular trafficking events leading to its secretion. In order to identify molecules involved in this secretory pathway, we asked whether any of the known trafficking proteins are regulated by LPS. We found that the levels of SNARE proteins were rapidly and significantly up- or downregulated during macrophage activation. A subset of t-SNAREs (Syntaxin 4/SNAP23/Munc18c) known to control regulated exocytosis in other cell types was substantially increased by LPS in a temporal pattern coinciding with peak TNFalpha secretion. Syntaxin 4 formed a complex with Munc18c at the cell surface of macrophages. Functional studies involving the introduction of Syntaxin 4 cDNA or peptides into macrophages implicate this t-SNARE in a rate-limiting step of TNFalpha secretion and in membrane ruffling during macrophage activation. We conclude that, in macrophages, SNAREs are regulated in order to accommodate the rapid onset of cytokine secretion and for membrane traffic associated with the phenotypic changes of immune activation. This represents a novel regulatory role for SNAREs in regulated secretion and in macrophage-mediated host defense.
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In the citing paper
“In macrophages, TNF is released to the extracellular milieu via the constitutive secretion pathway, and its trafficking is the best understood of all cytokines (9, 17, 18).”
From Macrophage Cytokines: Involvement in Immunity and Infectious Diseases (2014) · cites this paper as [18]
In the citing paper
“Thence, the Stx4/SNAP23/VAMP3 complex facilitates the passage of TNF from recycling endosomes to the cell membrane (17, 18).”
From Macrophage Cytokines: Involvement in Immunity and Infectious Diseases (2014) · cites this paper as [18]
In the citing paper
“Moreover, LPS was found to increase the expression of vesicle trafficking proteins that regulate TNF trafficking (17, 18).”
From Macrophage Cytokines: Involvement in Immunity and Infectious Diseases (2014) · cites this paper as [18]
In the citing paper
“The post-Golgi trafficking of IL-6 follows a route that is also dependent on Stx6 and Vti1b, which form a complex with cognate SNARE VAMP3 at recycling endosomes (17, 18).”
From Macrophage Cytokines: Involvement in Immunity and Infectious Diseases (2014) · cites this paper as [18]
Citations
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“Here it was observed that stimulation with TNP-BSA + SCF + IL-33 resulted in a drastic increase of IL-6, IL-13, TNF, CCL1, CCL2 and CCL3 compared to IL-33 + mSCF and TNP-334 BSA + SCF, indicating that IL-33 does amplify the inflammatory response at sites of allergen exposure.”
BackgroundInfluentialJuvenal, G. D. A., Meinerz, C., Ayupe, A. C., Campos, H. C., Reis, E. M., Longo, B. M., Pillat, M. M., & Ulrich, H. (2024) · Figshare · doi:10.6084/m9.figshare.26061505
Juvenal, G. D. A., Meinerz, C., Ayupe, A. C., Campos, H. C., Reis, E. M., Longo, B. M., Pillat, M. M., & Ulrich, H. (2024) · Figshare · doi:10.6084/m9.figshare.26735733
Juvenal, G. D. A., Meinerz, C., Ayupe, A. C., Campos, H. C., Reis, E. M., Longo, B. M., Pillat, M. M., & Ulrich, H. (2024) · Figshare · doi:10.6084/m9.figshare.26735739
Juvenal, G. D. A., Meinerz, C., Ayupe, A. C., Campos, H. C., Reis, E. M., Longo, B. M., Pillat, M. M., & Ulrich, H. (2024) · Figshare · doi:10.6084/m9.figshare.26735730
Juvenal, G. D. A., Meinerz, C., Ayupe, A. C., Campos, H. C., Reis, E. M., Longo, B. M., Pillat, M. M., & Ulrich, H. (2024) · Figshare · doi:10.6084/m9.figshare.26735724
Juvenal, G. D. A., Meinerz, C., Ayupe, A. C., Campos, H. C., Reis, E. M., Longo, B. M., Pillat, M. M., & Ulrich, H. (2024) · Figshare · doi:10.6084/m9.figshare.26061538
Juvenal, G. D. A., Meinerz, C., Ayupe, A. C., Campos, H. C., Reis, E. M., Longo, B. M., Pillat, M. M., & Ulrich, H. (2024) · Figshare · doi:10.6084/m9.figshare.26735721
Juvenal, G. D. A., Meinerz, C., Ayupe, A. C., Campos, H. C., Reis, E. M., Longo, B. M., Pillat, M. M., & Ulrich, H. (2024) · Figshare · doi:10.6084/m9.figshare.26735727
Juvenal, G. D. A., Meinerz, C., Ayupe, A. C., Campos, H. C., Reis, E. M., Longo, B. M., Pillat, M. M., & Ulrich, H. (2024) · Figshare · doi:10.6084/m9.figshare.26735736
Wang, Y., Du, Z., Yang, L., Hou, J., Li, X., Fan, M., Yu, C., Sun, J., Zhou, L., Li, L., et al. (2026) · Frontiers in Genetics · doi:10.3389/fgene.2026.1723592
“It plays a pivotal role in macrophage phagocytosis and regulates cytokine secretion, adapting to immune activation changes through modulation of membrane trafficking and cytokine release onset (Veale et al., 2011; Hatsuzawa and Sakurai, 2020; Pagan et al., 2003).”
Lin, W., Sui, W., Deng, Y. X., Chen, J. K., Shao, X., Huang, Z., Wei, W., Liang, C. M., Zhang, X., Hu, R., et al. (2026) · Journal of Translational Medicine · doi:10.1186/s12967-026-08475-6
“…macrophages rapidly upregulates the expression of the Syntaxin 4/SNAP23/ Munc18c complex, which directly controls the rate-limiting secretion of pro-inflammatory cytokines such as TNFα [43]; Syntaxin 12/13, in turn, participates in the regulation of endolysosomal morphology and inflam-maging [44].”
Metadata
- Authors
- Pagan, J. K., Wylie, F. G., Joseph, S., Widberg, C., Bryant, N. J., James, D. E., & Stow, J. L.
- Affiliations
- The University of Queensland (AU)
- Institute for Molecular Bioscience (AU)
- Garvan Institute of Medical Research (AU)
- Corresponding author
- Stow, Jennifer L
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 2003-01
- Volume
- 13
- Issue
- 2
- Pages
- 156-160
- ISSN
- 0960-9822 (ISSN-L)
- OpenAlex
- W2155132039
- Cited by
- 130
- References
- 28
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 11 · 2023: 3 · 2022: 2 · 2021: 5 · 2020: 6 · 2019: 3 · 2018: 3 · 2017: 5 · 2016: 4 · 2015: 9 · 2014: 8 · 2013: 7 · 2012: 7
- FWCI
- 2.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 3850 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Current Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Health and Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Keywords
- syntaxin 4, macrophage activation, lipopolysaccharide, TNF-alpha secretion, regulated exocytosis, membrane traffic, Munc18c, SNAP23, cytokine production, ruffles
- MeSH terms
- Animals, Cell Line, Cell Membrane, Lipopolysaccharides, Macrophage Activation, Membrane Proteins, Tumor Necrosis Factor-alpha, Cytokines, Vesicular Transport Proteins, SNARE Proteins, Qa-SNARE Proteins, Mice
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