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Proteomic Characterization, Biodistribution, and Functional Studies of Immune-Therapeutic Exosomes: Implications for Inflammatory Lung Diseases #MMPMID33841418
Elashiry M; Elsayed R; Elashiry MM; Rashid MH; Ara R; Arbab AS; Elawady AR; Hamrick M; Liu Y; Zhi W; Lucas R; Vazquez J; Cutler CW
Front Immunol 2021[]; 12 (?): 636222 PMID33841418show ga
Dendritic cell (DC)-derived exosomes (DC EXO), natural nanoparticles of endosomal origin, are under intense scrutiny in clinical trials for various inflammatory diseases. DC EXO are eobiotic, meaning they are well-tolerated by the host; moreover, they can be custom-tailored for immune-regulatory or -stimulatory functions, thus presenting attractive opportunities for immune therapy. Previously we documented the efficacy of immunoregulatory DCs EXO (regDCs EXO) as immunotherapy for inflammatory bone disease, in an in-vivo model. We showed a key role for encapsulated TGFbeta1 in promoting a bone sparing immune response. However, the on- and off-target effects of these therapeutic regDC EXO and how target signaling in acceptor cells is activated is unclear. In the present report, therapeutic regDC EXO were analyzed by high throughput proteomics, with non-therapeutic EXO from immature DCs and mature DCs as controls, to identify shared and distinct proteins and potential off-target proteins, as corroborated by immunoblot. The predominant expression in regDC EXO of immunoregulatory proteins as well as proteins involved in trafficking from the circulation to peripheral tissues, cell surface binding, and transmigration, prompted us to investigate how these DC EXO are biodistributed to major organs after intravenous injection. Live animal imaging showed preferential accumulation of regDCs EXO in the lungs, followed by spleen and liver tissue. In addition, TGFbeta1 in regDCs EXO sustained downstream signaling in acceptor DCs. Blocking experiments suggested that sustaining TGFbeta1 signaling require initial interaction of regDCs EXO with TGFbeta1R followed by internalization of regDCs EXO with TGFbeta1-TGFbeta1R complex. Finally, these regDCs EXO that contain immunoregulatory cargo and showed biodistribution to lungs could downregulate the main severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) target receptor, ACE2 on recipient lung parenchymal cells via TGFbeta1 in-vitro. In conclusion, these results in mice may have important immunotherapeutic implications for lung inflammatory disorders.
|Animals[MESH]
|COVID-19/*immunology[MESH]
|Dendritic Cells/*immunology[MESH]
|Exosomes/*immunology[MESH]
|Mice[MESH]
|Proteome/*immunology[MESH]
|Proteomics[MESH]
|Receptor, Transforming Growth Factor-beta Type I/immunology[MESH]
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Front+Immunol 2021 ; 12 (?): 636222
