Synaptotagmin XI Regulates Phagocytosis and Cytokine Secretion in Macrophages

Duque, Guillermo Arango; Fukuda, Mitsunori; Descoteaux, Albert

doi:10.4049/jimmunol.1202500

Cited by 50 publications

(49 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We previously characterized Syt XI as a negative regulator of cytokine secretion and of phagosome maturation (26). In this work, we demonstrated that Syt XI is both degraded by the zinc metalloprotease GP63, and excluded from the phagosome by LPG.…”

Section: Discussionmentioning

confidence: 80%

“…We previously discovered that Syt XI negatively regulates cytokine secretion and modulates phagosome maturation (26). Because Leishmania affects these processes, we postulated that this parasite may alter Syt XI integrity and function.…”

Section: Resultsmentioning

confidence: 99%

“…The mouse macrophage cell line RAW264.7 and RAW264.7 cells expressing the FLAG-Syt XI-GFP construct (26) were cultured in complete DMEM with L-glutamine (Life Technologies) and complemented with 10% heat-inactivated FBS (PAA Laboratories), 10 mM HEPES (Bioshop) at pH 7.4, and antibiotics (Life Technologies) in a 37˚C incubator with 5% CO 2 . Bone marrow-derived macrophages (BMM) were extracted from the bone marrow (48) of 6-to 8-wk-old female BALB/c mice (Charles River Laboratories), and differentiated with complete DMEM supplemented with 15% v/v L929 cell-conditioned medium as a source of CSF 1.…”

Section: Cell Culturementioning

confidence: 99%

“…For synchronized phagocytosis using zymosan or parasites, macrophages were incubated at 4˚C for 15 min (26). Macrophages were washed with cold complete DMEM to remove excess particles, and internalization was triggered by transferring cells to 37˚C for the required times (27).…”

Section: Synchronized Phagocytosis Assaysmentioning

confidence: 99%

“…In this regard, we recently reported that Leishmania targets Synaptotagmin (Syt) V-a regulator of particle uptake and phagosome maturation-by impeding the recruitment of this Syt to phagocytic cups via LPG (23,24). Syts constitute a large family of membrane-associated proteins that regulate vesicle-associated processes ranging from exocytosis (25,26) to phagocytosis (27,28). Because of the roles of Syts in vesicle trafficking, they are attractive targets for pathogens.…”

mentioning

confidence: 99%

See 4 more Smart Citations

Leishmania Promastigotes Induce Cytokine Secretion in Macrophages through the Degradation of Synaptotagmin XI

Duque

Fukuda

Turco

et al. 2014

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Synaptotagmins (Syts) are type-I membrane proteins that regulate vesicle docking and fusion in processes such as exocytosis and phagocytosis. We recently discovered that Syt XI is a recycling endosome- and lysosome-associated protein that negatively regulates the secretion of TNF and IL-6. In this study, we show that Syt XI is directly degraded by the zinc metalloprotease GP63 and excluded from Leishmania parasitophorous vacuoles by the promastigotes surface glycolipid lipophosphoglycan. Infected macrophages were found to release TNF and IL-6 in a GP63-dependent manner. To demonstrate that cytokine release was dependent on GP63-mediated degradation of Syt XI, small interfering RNA-mediated knockdown of Syt XI before infection revealed that the effects of small interfering RNA knockdown and GP63 degradation were not cumulative. In mice, i.p. injection of GP63-expressing parasites led to an increase in TNF and IL-6 secretion and to an augmented influx of neutrophils and inflammatory monocytes to the inoculation site. Both of these cell types have been shown to be infection targets and aid in the establishment of infection. In sum, our data revealed that GP63 induces proinflammatory cytokine release and increases infiltration of inflammatory phagocytes. This study provides new insight on how Leishmania exploits the immune response to establish infection.

show abstract

Section: Discussionmentioning

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Section: Cell Culturementioning

confidence: 99%

Section: Synchronized Phagocytosis Assaysmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Leishmania Promastigotes Induce Cytokine Secretion in Macrophages through the Degradation of Synaptotagmin XI

Duque

Fukuda

Turco

et al. 2014

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

Synaptotagmin‐11 inhibits cytokine secretion and phagocytosis in microglia

Wang

Zhang

et al. 2017

Glia

View full text Add to dashboard Cite

Cytokine secretion and phagocytosis are key functions of activated microglia. However, the molecular mechanisms underlying their regulation in microglia remain largely unknown. Here, we report that synaptotagmin-11 (Syt11), a non-Ca -binding Syt implicated in Parkinson disease and schizophrenia, inhibits cytokine secretion and phagocytosis in microglia. We found Syt11 expression in microglia in brain slices and primary microglia. Interestingly, Syt11-knockdown (KD) increased cytokine secretion and NO release in primary microglia both in the absence and presence of lipopolysaccharide. NF-κB was activated in untreated KD microglia together with enhanced synthesis of IL-6, TNF-α, IL-1β, and iNOS. When the release capacity was assessed by the ratio of extracellular to intracellular levels, only the IL-6 and TNF-α secretion capacity was increased in Syt11-KD cells, suggesting that Syt11 specifically regulates conventional secretion. Consistently, Syt11 localized to the trans-Golgi network and recycling endosomes. In addition, Syt11 was recruited to phagosomes and its deficiency enhanced microglial phagocytosis. All the KD phenotypes were rescued by expression of an shRNA-resistant Syt11, while overexpression of Syt11 suppressed cytokine secretion and phagocytosis. Importantly, Syt11 also inhibited microglial phagocytosis of α-synuclein fibrils, supporting its association with Parkinson disease. Taken together, we propose that Syt11 suppresses microglial activation under both physiological and pathological conditions through the inhibition of cytokine secretion and phagocytosis.

show abstract

Revisiting the role of calcium in phagosome formation and maturation

Westman

Grinstein

Maxson

2019

Journal of Leukocyte Biology

View full text Add to dashboard Cite

Like other membrane receptor-mediated responses, execution of phagocytosis requires the transduction of signals to cytoplasmic effectors. Signaling in this case is particularly complex as the process involves not only the formation of phagosomes but also their subsequent maturation and resolution. Transient increases in cytosolic calcium, which mediate a variety of other transduction pathways, also feature prominently in phagocytosis. However, despite intensive study over the course of nearly 30 years, the occurrence, source, and functional relevance of such calcium bursts remain the subject of debate. Here, we have attempted to consolidate the information that was reviewed in the past with more recent studies in an effort to shed some light on the existing controversies. K E Y W O R D Sfluorescence, calcium, phagocytosis, phagosome maturation, membrane fusion summarized in Table 1 upward of 80% of the studies reported that an elevation in [Ca 2+ ] cyt accompanied phagosome formation. Yet a significant

show abstract

Synaptotagmin XI Regulates Phagocytosis and Cytokine Secretion in Macrophages

Cited by 50 publications

References 54 publications

Leishmania Promastigotes Induce Cytokine Secretion in Macrophages through the Degradation of Synaptotagmin XI

Leishmania Promastigotes Induce Cytokine Secretion in Macrophages through the Degradation of Synaptotagmin XI

Synaptotagmin‐11 inhibits cytokine secretion and phagocytosis in microglia

Revisiting the role of calcium in phagosome formation and maturation

Contact Info

Product

Resources

About