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Published on: June 3, 2018
M1 macrophage-derived exosomes inhibit cardiomyocyte proliferation through delivering miR-155
Xiaoqing He1, Shan Liu1, Zhanyu Zhang1
1Department of Cardiology, Guangdong Key Laboratory of Vascular Diseases, The Second Affiliated Hospital, Guangzhou Institute of Cardiovascular Disease, Guangzhou Medical University, Guangzhou, 510260, People's Republic of China.
Background:
M1 macrophages are closely associated with cardiac injury after myocardial infarction (MI). Increasing evidence shows that exosomes play a key role in pathophysiological regulation after MI, but the role of M1 macrophage-derived exosomes (M1-Exos) in myocardial regeneration remains unclear. In this study, we explored the impact of M1 macrophage-derived exosomes on cardiomyocytes regeneration in vitro and in vivo.
Methods:
M0 macrophages were induced to differentiate into M1 macrophages with GM-CSF (50 ng/mL) and IFN-γ (20 ng/mL). Then M1-Exos were isolated and co-incubated with cardiomyocytes. Cardiomyocyte proliferation was detected by pH3 or ki67 staining. Quantitative real-time PCR (qPCR) was used to test the level of miR-155 in macrophages, macrophage-derived exosomes and exosome-treated cardiomyocytes. MI model was constructed and LV-miR-155 was injected around the infarct area, the proliferation of cardiomyocytes was counted by pH3 or ki67 staining. The downstream gene and pathway of miR-155 were predicted and verified by dual-luciferase reporter gene assay, qPCR and immunoblotting analysis. IL-6 (50 ng/mL) was added to cardiomyocytes transfected with miR-155 mimics, and the proliferation of cardiomyocytes was calculated by immunofluorescence. The protein expressions of IL-6R, p-JAK2 and p-STAT3 were detected by Western blot.
Results:
The results showed that M1-Exos suppressed cardiomyocytes proliferation. Meanwhile, miR-155 was highly expressed in M1-Exos and transferred to cardiomyocytes. miR-155 inhibited the proliferation of cardiomyocytes and antagonized the pro-proliferation effect of interleukin 6 (IL-6). Furthermore, miR-155 targeted gene IL-6 receptor (IL-6R) and inhibited the Janus kinase 2(JAK)/Signal transducer and activator of transcription (STAT3) signaling pathway.
Conclusion:
M1-Exos inhibited cardiomyocyte proliferation by delivering miR-155 and inhibiting the IL-6R/JAK/STAT3 signaling pathway. This study provided new insight and potential treatment strategy for the regulation of myocardial regeneration and cardiac repair by macrophages.
Insights
M1 macrophage-derived exosomes (M1-Exos) deliver miR-155 to inhibit cardiomyocyte proliferation by targeting the IL-6 receptor and JAK/STAT3 pathway, impacting cardiac repair after myocardial infarction.
Area of Science:
- Cardiovascular Biology
- Cellular and Molecular Medicine
- Immunology
Background:
- M1 macrophages are implicated in cardiac injury following myocardial infarction (MI).
- Exosomes play a significant role in post-MI pathophysiological regulation.
- The specific function of M1 macrophage-derived exosomes (M1-Exos) in myocardial regeneration is not well understood.
Purpose of the Study:
- To investigate the impact of M1-Exos on cardiomyocyte regeneration.
- To elucidate the underlying molecular mechanisms of M1-Exos in cardiac repair.
Main Methods:
- M1 macrophages were differentiated and M1-Exos isolated.
- Cardiomyocyte proliferation was assessed in vitro and in vivo.
- miR-155 levels, exosome transfer, and the IL-6R/JAK/STAT3 pathway were analyzed.
Main Results:
- M1-Exos suppressed cardiomyocyte proliferation.
- miR-155 was transferred from M1-Exos to cardiomyocytes, inhibiting proliferation.
- miR-155 targeted IL-6 receptor (IL-6R) and suppressed the JAK/STAT3 signaling pathway.
Conclusions:
- M1-Exos inhibit cardiomyocyte proliferation via miR-155 delivery, targeting the IL-6R/JAK/STAT3 pathway.
- This study offers novel insights into macrophage-mediated myocardial regeneration and potential therapeutic strategies for cardiac repair.
