Fusion protein vesicle-associated membrane protein 2 is implicated in IFN-γ–induced piecemeal degranulation in human eosinophils from atopic individuals

Lacy, Paige; Logan, Michael; Bablitz, Ben; Moqbel, Redwan

doi:10.1067/mai.2001.113562

Cited by 63 publications

(50 citation statements)

References 31 publications

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“…It is also interesting to note that CCL5/ RANTES is colocalized with vesicle-associated membrane protein 2 (VAMP-2) in eosinophils. VAMP-2 is an important component of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes, which regulate membrane vesicle fusion and exocytosis (Lacy et al, 2001). Because the formation of mHtt aggregates has been suggested to cause abnormalities in the SNARE machinery (Morton and Edwardson, 2001;Molinari and Sitia, 2005), a defect in the SNARE machinery might account for the impairment of CCL5/RANTES secretion in R6/2 astrocytes.…”

Section: Discussionmentioning

confidence: 99%

Expanded-Polyglutamine Huntingtin Protein Suppresses the Secretion and Production of a Chemokine (CCL5/RANTES) by Astrocytes

Chou¹,

Weng²,

Lai³

et al. 2008

J. Neurosci.

100

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Huntington's disease (HD) is a hereditary neurological disease caused by expended CAG repeats in the HD gene, which codes for a protein called Huntingtin (Htt). The resultant mutant Huntingtin (mHtt) forms aggregates in neurons and causes neuronal dysfunction. In astrocytes, the largest population of brain cells, mHtt also exists. We report herein that astrocyte-conditioned medium (ACM) collected from astrocytes of R6/2 mice (a mouse model of HD) caused primary cortical neurons to grow less-mature neurites, migrate more slowly, and exhibit lower calcium influx after depolarization than those maintained in wild-type (WT) ACM. Using a cytokine antibody array and ELISA assays, we demonstrated that the amount of a chemokine [chemokine (C-C motif) ligand 5 (CCL5)/regulated on activation normal T cell expressed and secreted (RANTES)] released by R6/2 astrocytes was much less than that by WT astrocytes. When cortical neurons were treated with the indicated ACM, supplementation with recombinant CCL5/RANTES ameliorated the neuronal deficiency caused by HD-ACM, whereas removing CCL5/RANTES from WT-ACM using an anti-CCL5/RANTES antibody mimicked the effects evoked by HD-ACM. Quantitative PCR and promoter analyses demonstrated that mHtt hindered the activation of the CCL5/RANTES promoter by reducing the availability of nuclear factor B-p65 and, hence, reduced the transcript level of CCL5/RANTES. Moreover, ELISA assays and immunocytochemical staining revealed that mHtt retained the residual CCL5/RANTES inside R6/2 astrocytes. In line with the above findings, elevated cytosolic CCL5/RANTES levels were also observed in the brains of two mouse models of HD [R6/2 and Hdh (CAG)150 ] and human HD patients. These findings suggest that mHtt hinders one major trophic function of astrocytes which might contribute to the neuronal dysfunction of HD.

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Section: Discussionmentioning

confidence: 99%

Expanded-Polyglutamine Huntingtin Protein Suppresses the Secretion and Production of a Chemokine (CCL5/RANTES) by Astrocytes

Chou¹,

Weng²,

Lai³

et al. 2008

J. Neurosci.

100

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“…58 Our recent studies have shown that human peripheral blood eosinophils express members of the SNARE fusion complex, including VAMP-2, 59 syntaxin-4, 60 and SNAP-23. 61 In addition to SNAREs, members of Rho-related GTPases, including Rac-2, have been identified in eosinophils and shown to be critical in the assembly of NADPH oxidase complex prior to the generation of superoxide.…”

Section: Discussionmentioning

confidence: 99%

Translocation of the tetraspanin CD63 in association with human eosinophil mediator release

Mahmudi‐Azer

Downey

Moqbel

2002

Blood

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The tetraspanin CD63 (also known as LAMP-3) has been implicated in phagocytic and intracellular lysosome-phagosome fusion events. It is also present in eosinophils, with predominant expression on crystalloid granule membrane. However, its role in eosinophil function is obscure. We hypothesized that CD63 is associated with intracellular events involved in eosinophil activation and mediator release. We used a combination of confocal immunofluorescence microscopy, flow cytometry, and secretion assays, including ␤-hexosaminidase, eosinophil peroxidase, and RANTES, to examine CD63 expression, intracellular localization, and its association with cell activation and mediator release. In resting eosinophils, CD63 immunoreactivity was localized to plasma and crystalloid granule membranes. In interferon-␥ (IFN-␥)-or C5a/CB-stimulated cells (10 minutes), intracellular CD63 appeared to shift to the cell periphery and plasma membrane, while stimulation with a cocktail of interleukin-3 (IL-3)/IL-5/granulocyte-macrophage colony-stimulating factor induced the appearance of discrete intracellular clusters of CD63 immunoreactivity. IFN-␥ induced mobilization of CD63 to the cell periphery, which coincided with selective mobilization of RANTES prior to its release, implying CD63 association with piecemeal degranulation. Agonist-induced CD63 mobilization and cell surface upregulation was associated with ␤-hexosaminidase, eosinophil peroxidase, and RANTES release. Dexamethasone as well as genistein (a broad-spectrum inhibitor of tyrosine kinases) inhibited agonistinduced intracellular mobilization of CD63 and RANTES together with cell surface up-regulation of CD63 and mediator release. This is the first report of an association between CD63 mobilization and agonist-induced selective mediator release, which may imply the involvement of CD63 in eosinophil activation and piecemeal degranulation. IntroductionEosinophils are major effector cells in allergic inflammation and asthma. 1-3 They synthesize, store, and release a wide range of proinflammatory mediators, including at least 4 cationic proteins 1,2 and up to 23 cytokines and growth factors. 4,5 Eosinophils contain different populations of mediator-storage organelles, including small secretory vesicles as well as crystalloid granules. The latter secretory granules are the site of storage of cytotoxic cationic proteins as well as a number of cytokines, chemokines, and growth factors. 6,7 The membrane-bound crystalloid granule comprises 2 compartments: an electron-dense crystalline core (internum) where major basic protein (MBP) 8,9 is stored and an electron-lucent matrix 6 where 3 cationic proteins-namely, eosinophil cationic protein, eosinophil peroxidase (EPO), and eosinophil-derived neurotoxin 1,8 -together with a number of other cytokines, including interleukin-6 (IL-6) 10 and RANTES (regulated on activation normal T cells expressed and secreted), 11 are stored. Among eosinophilderived mediators, ␤-hexosaminidase (␤-hex) has been shown to localize to both small secretory vesicle...

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“…68 Some of the trafficking machinery governing piecemeal degranulation of CCL5/RANTES in eosinophils has been characterized, using a pathway that depends on the membrane fusion R-SNARE protein, VAMP-2 (synaptobrevin-2), and the Q-SNAREs syntaxin-4 and SNAP-23 ( Figure 4). 9,15 Human eosinophils express VAMP-2 in small secretory vesicles containing CCL5/RANTES, which translocate to the cell surface on stimulation by IFN␥ (Figure 4). Syntaxin-4 and SNAP-23 localize to the cell surface where they function as putative cognate intracellular receptors for VAMP-2, allowing the vesicles to fuse with the cell surface.…”

Section: Regulated and Constitutive Exocytosis Of Cytokines In Granulmentioning

confidence: 99%

Cytokine release from innate immune cells: association with diverse membrane trafficking pathways

Lacy

Stow

2011

Blood

Self Cite

324

261

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Fusion protein vesicle-associated membrane protein 2 is implicated in IFN-γ–induced piecemeal degranulation in human eosinophils from atopic individuals

Cited by 63 publications

References 31 publications

Expanded-Polyglutamine Huntingtin Protein Suppresses the Secretion and Production of a Chemokine (CCL5/RANTES) by Astrocytes

Expanded-Polyglutamine Huntingtin Protein Suppresses the Secretion and Production of a Chemokine (CCL5/RANTES) by Astrocytes

Translocation of the tetraspanin CD63 in association with human eosinophil mediator release

Cytokine release from innate immune cells: association with diverse membrane trafficking pathways

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