Endocytosis of GM-CSF receptor β is essential for signal transduction regulating mesothelial-macrophage transition

Zsiros, Viktória; Katz, Sándor; Dóczi, Nikolett; Kiss, Anna L.

doi:10.1016/j.bbamcr.2019.06.005

Cited by 6 publications

(14 citation statements)

References 42 publications

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“…The exact mechanisms by which GM-CSF induces CD103 expression remain unknown, but binding of GM-CSF to its receptor (GM-CSFR) leads to a signaling cascade that is mediated in part by GM-CSFR internalization ( Broughton et al., 2012 ; Zsiros et al., 2019 ). To first test whether GM-CSFR internalization is indeed involved in GM-CSF-induced cDC CD103 expression, FLT3L–BMDCs were pre-treated with Dynasore, a dynamin inhibitor that blocks internalization of receptor–ligand complex, prior to GM-CSF stimulations ( Macia et al., 2006 ; Zsiros et al., 2019 ). Pre-treatment with Dynasore blocked CD103 expression on FLT3L-BMDCs suggesting that GM-CSFR internalization is required for its expression on cDCs ( Figure 4A ).…”

Section: Resultsmentioning

confidence: 99%

“…Our results linking the GM-CSFR internalization to CD103 expression were obtained using Dynasore a GTPase inhibitor that inhibits dynamin activity, which prevents endocytosis. Although this inhibitor is frequently used to block GM-CSFR internalization ( Katz et al., 2016 ; Zsiros et al., 2019 ), Dynasore could also exert other effects. For instance, the presence of Dynasore could also block the internalization of other receptors, such as TLR4, express by cDCs ( Kagan et al., 2008 ).…”

Section: Discussionmentioning

confidence: 99%

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Exposure to the Gram-Negative Bacteria Pseudomonas aeruginosa Influences the Lung Dendritic Cell Population Signature by Interfering With CD103 Expression

Brassard

Roy

Lemay

et al. 2021

Front. Cell. Infect. Microbiol.

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Lung dendritic cells (DCs) are divided into two major populations, which include CD103+XCR1+ cDC1s and CD11b+Sirpα+ cDC2s. The maintenance of their relative proportions is dynamic and lung inflammation, such as caused by exposure to lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria, can have a significant impact on the local cDC signature. Alterations in the lung cDC signature could modify the capacity of the immune system to respond to various pathogens. We consequently aimed to assess the impact of the Gram-negative bacteria Pseudomonas aeruginosa on lung cDC1 and cDC2 populations, and to identify the mechanisms leading to alterations in cDC populations. We observed that exposure to P. aeruginosa decreased the proportions of CD103+XCR1+ cDC1s, while increasing that of CD11b+ DCs. We identified two potential mechanisms involved in this modulation of lung cDC populations. First, we observed an increase in bone marrow pre-DC IRF4 expression suggesting a higher propensity of pre-DCs to differentiate towards the cDC2 lineage. This observation was combined with a reduced capacity of lung XCR1+ DC1s to express CD103. In vitro, we demonstrated that GM-CSF-induced CD103 expression on cDCs depends on GM-CSF receptor internalization and RUNX1 activity. Furthermore, we observed that cDCs stimulation with LPS or P. aeruginosa reduced the proportions of intracellular GM-CSF receptor and decreased RUNX1 mRNA expression. Altogether, these results suggest that alterations in GM-CSF receptor intracellular localization and RUNX1 signaling could be involved in the reduced CD103 expression on cDC1 in response to P. aeruginosa. To verify whether the capacity of cDCs to express CD103 following P. aeruginosa exposure impacts the immune response, WT and Cd103-/- mice were exposed to P. aeruginosa. Lack of CD103 expression led to an increase in the number of neutrophils in the airways, suggesting that lack of CD103 expression on cDC1s could favor the innate immune response to this bacterium.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Exposure to the Gram-Negative Bacteria Pseudomonas aeruginosa Influences the Lung Dendritic Cell Population Signature by Interfering With CD103 Expression

Brassard

Roy

Lemay

et al. 2021

Front. Cell. Infect. Microbiol.

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“…We suppose that the activation of STAT5 occurs in early endosomes as well. Until the inflammation is maintained the receptor can be detected in recycling endosomes, indicating that the receptor can turn back to the cell surface, and taking part in another endocytic cycle the signaling is maintained [33] To study whether internalization of the receptor/ligand complex is really necessary for the signaling, we used dynasore. Dynasore is a potent inhibitor of the small GTPase, dynamin, and efficiently inhibits the pinching off of vesicles from the plasma membrane [34], blocking both caveolin-and clathrin-mediated endocytosis.…”

Section: Internalization Of Receptor-ligand Complex Is Essential For mentioning

confidence: 99%

“…Dynasore is a potent inhibitor of the small GTPase, dynamin, and efficiently inhibits the pinching off of vesicles from the plasma membrane [34], blocking both caveolin-and clathrin-mediated endocytosis. When the internalization of membrane-connected caveolae was blocked, GM-CSF treatment could not result in EMT, there was no ED1 expression and by blocking the receptor internalization the STAT5 signaling could not occur in mesothelial cells [14,33].…”

Section: Internalization Of Receptor-ligand Complex Is Essential For mentioning

confidence: 99%

Section: Internalization Of Receptor-ligand Complex Is Essential For mentioning

confidence: 99%

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Cellular and molecular events of inflammation induced transdifferentiation (EMT) and regeneration (MET) in mesenteric mesothelial cells

Zsiros

Kiss

2020

Inflamm. Res.

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In this review we summarize the cellular and molecular events of inflammation induced epithelial-to-mesenchymal (EMT) and mesothelial-to-macrophage transition (MET) during regeneration. Since the receptor transmits the environmental stimulus, downregulating or upregulating the process on an epigenetic level, the intracellular localization of receptors (signaling organelles: early endosomes or lysosomal degradation: late endosomes) plays a crucial role in the signaling events regulating inflammation and regeneration. Therefore, we focused on the internalization of the receptors as well as the intracellular compartmentalization of signaling molecules during EMT and MET. The review draws the reader’s attention to the plasticity of mesothelial cells and supports the idea that during inflammation an ambient macrophage population might derive from mesothelial cells.

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Selective activation of STAT3 and STAT5 dictates the fate of myeloid progenitor cells

et al. 2023

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The molecular programs that govern the directed differentiation of myeloid progenitor cells are still poorly defined. Using a previously established immortalized, phenotypically normal myeloid progenitor cell model mEB8-ER, we unveil a new mechanism mediated by STAT5 and STAT3 at a bifurcation point of myeloid progenitor cell-fate specification. We find that myeloid progenitor cells can spontaneously differentiate into neutrophils with a basal level of STAT3 phosphorylation, which is enhanced by G-CSF treatment or STAT3 over-expression, leading to elevated neutrophil differentiation. Reduced STAT3 phosphorylation caused by GM-CSF treatment, STAT3 specific inhibitor, or STAT3 depletion leads to attenuated myeloid differentiation into neutrophils, while elevating differentiation into monocytes/macrophages. In contrast, STAT5 appears to have an antagonistic function to STAT3. When activated by GM-CSF, STAT5 promotes myeloid differentiation into monocytes/macrophages but inhibits neutrophil differentiation. At the mechanistic level, GM-CSF activates STAT5 to up-regulate SOCS3, which attenuates STAT3 phosphorylation and consequently neutrophil differentiation, while enhancing monocyte/macrophage differentiation. Furthermore, inhibition of STAT5 and STAT3 in primary myeloid progenitors recapitulates the results from the mEB8-ER model. Together, our findings provide new mechanistic insights into myeloid differentiation and may prove useful for the diagnosis and treatment of diseases related to abnormal myeloid differentiation.

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Endocytosis of GM-CSF receptor β is essential for signal transduction regulating mesothelial-macrophage transition

Cited by 6 publications

References 42 publications

Exposure to the Gram-Negative Bacteria Pseudomonas aeruginosa Influences the Lung Dendritic Cell Population Signature by Interfering With CD103 Expression

Exposure to the Gram-Negative Bacteria Pseudomonas aeruginosa Influences the Lung Dendritic Cell Population Signature by Interfering With CD103 Expression

Cellular and molecular events of inflammation induced transdifferentiation (EMT) and regeneration (MET) in mesenteric mesothelial cells

Selective activation of STAT3 and STAT5 dictates the fate of myeloid progenitor cells

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