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Extracellular Vesicles Derived From Ex Vivo Expanded Regulatory T Cells Modulate In Vitro and In Vivo Inflammation.

ABSTRACT: Extracellular vehicles (EVs) are efficient biomarkers of disease and participate in disease pathogenesis; however, their use as clinical therapies to modify disease outcomes remains to be determined. Cell-based immune therapies, including regulatory T cells (Tregs), are currently being clinically evaluated for their usefulness in suppressing pro-inflammatory processes. The present study demonstrates that ex vivo expanded Tregs generate a large pool of EVs that express Treg-associated markers and suppress pro-inflammatory responses in vitro and in vivo. Intravenous injection of Treg EVs into an LPS-induced mouse model of inflammation reduced peripheral pro-inflammatory transcripts and increased anti-inflammatory transcripts in myeloid cells as well as Tregs. Intranasal administration of enriched Treg EVs in this model also reduced pro-inflammatory transcripts and the associated neuroinflammatory responses. In a mouse model of amyotrophic lateral sclerosis, intranasal administration of enriched Treg EVs slowed disease progression, increased survival, and modulated inflammation within the diseased spinal cord. These findings support the therapeutic potential of expanded Treg EVs to suppress pro-inflammatory responses in human disease.

SUBMITTER: Thome AD

PROVIDER: S-EPMC9258040 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Extracellular Vesicles Derived From Ex Vivo Expanded Regulatory T Cells Modulate In Vitro and In Vivo Inflammation.

Thome Aaron D AD Thonhoff Jason R JR Zhao Weihua W Faridar Alireza A Wang Jinghong J Beers David R DR Appel Stanley H SH

Frontiers in immunology 20220622

Extracellular vehicles (EVs) are efficient biomarkers of disease and participate in disease pathogenesis; however, their use as clinical therapies to modify disease outcomes remains to be determined. Cell-based immune therapies, including regulatory T cells (Tregs), are currently being clinically evaluated for their usefulness in suppressing pro-inflammatory processes. The present study demonstrates that ex vivo expanded Tregs generate a large pool of EVs that express Treg-associated mark ...[more]

PMID: 35812435

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Project description:Extracellular vesicles (EVs) mediate cell-to-cell communication by horizontally transferring biological materials from host cells to target cells. During exposure to pathogens, pathogen-associated molecular patterns (e.g., lipopolysaccharide, LPS) get in contact with endothelial cells and stimulate the secretion of endothelial cell-derived EVs (E-EVs). The triggered EVs secretion is known to have a modulating influence on the EVs-receiving cells. Macrophages, a major component of innate immunity, are polarized upon receiving external inflammatory stimuli, in which toll-like receptor4 (TLR4)-nuclear factor kappa B (NFκB) pathway plays a key role. However, the functions of LPS-induced E-EVs (ELPS-EVs) in modulating macrophage phenotype and activation remain elusive. We collected the EVs from quiescent endothelial cells (ENor-EVs) and ELPS-EVs to detect their stimulatory role on NR8383 macrophages. Isolated EVs were characterized by transmission electron microscopy (TEM), western blot assay, and nanoparticle tracking analysis (NTA). NR8383 macrophages were stimulated with ELPS-EVs, ENor-EVs, or PBS for 24 h. Hereafter, the uptake of EVs by the macrophages was investigated. Upon EVs stimulation, cellular viability was determined by MTT assay, while macrophage phenotype was analyzed by flow cytometry and immunofluorescence analysis. Furthermore, a western blot assay was conducted to evaluate the potentially involved TLR4-NFκB pathway. Interestingly, upon exposure to LPS, endothelial cells secreted significantly higher amounts of EVs (i.e., ELPS-EVs) when compared to quiescent cells or cells in PBS. The ELPS-EVs were also better internalized by NR8383 macrophages than ENor-EVs. The cellular viability of ELPS-EVs-treated macrophages was 1.2 times higher than those in the ENor-EVs and PBS groups. In addition, ELPS-EVs modulated NR8383 macrophages towards a proinflammatory macrophage M1-like phenotype. This was indicated by the significantly upregulated expressions of proinflammatory macrophage biomarkers CD86 and inducible nitric oxide synthase (iNOS) observed in ELPS-EVs-treated macrophages. The TLR4-NFκB signaling pathway was substantially activated in ELPS-EVs-treated macrophages, indicated by the elevated expressions of makers TLR4 and phosphorylated form of nuclear factor kappa B p65 subunit (p-NFκBp65). Overall, our results indicate that E-EVs play a crucial role in macrophage phenotype modulation under inflammatory conditions.

Dataset Information

Extracellular Vesicles Derived From Ex Vivo Expanded Regulatory T Cells Modulate In Vitro and In Vivo Inflammation.

Publications

Extracellular Vesicles Derived From <i>Ex Vivo</i> Expanded Regulatory T Cells Modulate <i>In Vitro</i> and <i>In Vivo</i> Inflammation.

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