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Effect of tolytoxin on tunneling nanotube formation and function.

ABSTRACT: Tunneling nanotubes (TNTs) are actin-containing membrane protrusions that play an essential role in long-range intercellular communication. They are involved in development of various diseases by allowing transfer of pathogens or protein aggregates as well as organelles such as mitochondria. Increase in TNT formation has been linked to many pathological conditions. Here we show that nM concentrations of tolytoxin, a cyanobacterial macrolide that targets actin by inhibition of its polymerization, significantly decrease the number of TNT-connected cells, as well as transfer of mitochondria and α-synuclein fibrils in two different cell lines of neuronal (SH-SY5Y) and epithelial (SW13) origin. As the cytoskeleton of the tested cell remain preserved, this macrolide could serve as a valuable tool for future therapies against diseases propagated by TNTs.

SUBMITTER: Dilsizoglu Senol A

PROVIDER: S-EPMC6450976 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Effect of tolytoxin on tunneling nanotube formation and function.

Dilsizoglu Senol Aysegul A Pepe Anna A Grudina Clara C Sassoon Nathalie N Reiko Ueoka U Bousset Luc L Melki Ronald R Piel Jörn J Gugger Muriel M Zurzolo Chiara C

Scientific reports 20190405 1

Tunneling nanotubes (TNTs) are actin-containing membrane protrusions that play an essential role in long-range intercellular communication. They are involved in development of various diseases by allowing transfer of pathogens or protein aggregates as well as organelles such as mitochondria. Increase in TNT formation has been linked to many pathological conditions. Here we show that nM concentrations of tolytoxin, a cyanobacterial macrolide that targets actin by inhibition of its polymerization, ...[more]

PMID: 30952909

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Project description:Tunneling nanotubes (TNTs) are cellular extensions enabling cytosol-to-cytosol intercellular interaction between numerous cell types including macrophages. Previous studies of hematopoietic stem and progenitor cell (HSPC) transplantation for the lysosomal storage disorder cystinosis have shown that HSPC-derived macrophages form TNTs to deliver cystinosin-bearing lysosomes to cystinotic cells, leading to tissue preservation. Here, we explored if macrophage polarization to either proinflammatory M1-like M(LPS/IFNγ) or anti-inflammatory M2-like M(IL-4/IL-10) affected TNT-like protrusion formation, intercellular transport and, ultimately, the efficacy of cystinosis prevention. We designed new automated image processing algorithms used to demonstrate that LPS/IFNγ polarization decreased bone marrow-derived macrophages (BMDMs) formation of protrusions, some of which displayed characteristics of TNTs, including cytoskeletal structure, 3D morphology and size. In contrast, co-culture of macrophages with cystinotic fibroblasts yielded more frequent and larger protrusions, as well as increased lysosomal and mitochondrial intercellular trafficking to the diseased fibroblasts. Unexpectedly, we observed normal protrusion formation and therapeutic efficacy following disruption of anti-inflammatory IL-4/IL-10 polarization in vivo by transplantation of HSPCs isolated from the Rac2-/- mouse model. Altogether, we developed unbiased image quantification systems that probe mechanistic aspects of TNT formation and function in vitro, while HSPC transplantation into cystinotic mice provides a complex in vivo disease model. While the differences between polarization cell culture and mouse models exemplify the oversimplicity of in vitro cytokine treatment, they simultaneously demonstrate the utility of our co-culture model which recapitulates the in vivo phenomenon of diseased cystinotic cells stimulating thicker TNT formation and intercellular trafficking from macrophages. Ultimately, we can use both approaches to expand the utility of TNT-like protrusions as a delivery system for regenerative medicine.

Dataset Information

Effect of tolytoxin on tunneling nanotube formation and function.

Publications

Effect of tolytoxin on tunneling nanotube formation and function.

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