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Published on: February 22, 2017
Exosomal RNF144A Derived From Mesenchymal Stem Cells Ameliorates LPS-induced Pneumonia in Experimental Models By
Yonggang Wang1, Tao Xu2, Daowei Li3
1Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
Abstract:
Exosomes derived from mesenchymal stem cells (MSC EXO) have emerged as promising therapeutic candidates for pneumonia. However, the molecular mechanisms underlying MSC EXO-mediated pneumonia protection remain incompletely elucidated. WI-38 fibroblasts were exposed to lipopolysaccharide (LPS) in vitro, while an animal model of pneumonia was generated through intratracheal LPS administration in mice. MSC EXO were isolated and used to treat the pneumonia models. The efficacy of MSC EXO was evaluated by detecting cell viability, proliferation, apoptosis, and pro-inflammatory cytokine secretion. Glutathione S-transferase (GST) pull-down, co-immunoprecipitation (Co-IP), and immunoprecipitation (IP) assays were performed to verify the RNF144A/thyroid-stimulating hormone receptor (TSHR) interaction. TSHR was upregulated in pneumonia serum samples and LPS-stimulated WI-38 fibroblasts. TSHR knockdown attenuated LPS-triggered apoptosis and inflammatory damage in WI-38 fibroblasts. Moreover, ring finger protein 144A (RNF144A) destabilized TSHR through ubiquitination in WI-38 cells. MSC EXO increased RNF144A expression in LPS-stimulated WI-38 fibroblasts. Downregulation of RNF144A diminished the protective effects of MSC EXO against LPS-triggered damage in WI-38 fibroblasts and LPS-induced pneumonia in mice. Additionally, re-expression of TSHR reversed the protective effects of MSC EXO against LPS-triggered injuries in WI-38 fibroblasts. Our findings suggest that MSC EXO protect against LPS-triggered injuries in WI-38 fibroblasts and LPS-evoked pneumonia in mice through RNF144A upregulation-mediated suppression of TSHR expression. This study provides a novel theoretical foundation for the application of MSC EXO in pneumonia treatment.
Insights
Mesenchymal stem cell exosomes (MSC EXO) treat pneumonia by increasing RNF144A, which reduces the harmful TSHR protein. This mechanism protects against lung injury and inflammation in pneumonia models.
Area of Science:
- Biomedical research
- Cell biology
- Immunology
Background:
- Mesenchymal stem cell exosomes (MSC EXO) show therapeutic potential for pneumonia.
- The precise molecular mechanisms of MSC EXO's protective effects against pneumonia are not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanisms by which MSC EXO protect against lipopolysaccharide (LPS)-induced pneumonia.
- To investigate the role of RNF144A and TSHR in MSC EXO-mediated pneumonia treatment.
Main Methods:
- In vitro LPS-induced WI-38 fibroblast model and in vivo LPS-induced mouse pneumonia model.
- MSC EXO isolation and treatment, cell viability, proliferation, apoptosis, and cytokine assays.
- GST pull-down, Co-IP, IP assays, TSHR knockdown, and RNF144A expression analysis.
Main Results:
- TSHR was upregulated in pneumonia models and contributed to LPS-induced damage.
- RNF144A destabilized TSHR via ubiquitination, and MSC EXO increased RNF144A expression.
- RNF144A upregulation by MSC EXO suppressed TSHR, mitigating pneumonia-related injury and apoptosis.
Conclusions:
- MSC EXO exert protective effects against pneumonia by upregulating RNF144A, leading to TSHR degradation.
- This RNF144A/TSHR pathway offers a novel therapeutic target for pneumonia treatment using MSC EXO.
