| First Author | Shen J | Year | 2020 |
| Journal | Cell Death Dis | Volume | 11 |
| Issue | 11 | Pages | 958 |
| PubMed ID | 33161415 | Mgi Jnum | J:313492 |
| Mgi Id | MGI:6799872 | Doi | 10.1038/s41419-020-03157-7 |
| Citation | Shen J, et al. (2020) Membrane nanotubes facilitate the propagation of inflammatory injury in the heart upon overactivation of the beta-adrenergic receptor. Cell Death Dis 11(11):958 |
| abstractText | Acute sympathetic stress quickly induces cardiac inflammation and injury, suggesting that pathogenic signals rapidly spread among cardiac cells and that cell-to-cell communication may play an important role in the subsequent cardiac injury. However, the underlying mechanism of this response is unknown. Our previous study demonstrated that acute beta-adrenergic receptor (beta-AR) signaling activates inflammasomes in the heart, which triggers the inflammatory cascade. In the present study, beta-AR overactivation induced inflammasome activation in both the cardiomyocytes and cardiac fibroblasts (CFs) of mice hearts following a subcutaneous injection of isoproterenol (ISO, 5 mg/kg body weight), a selective agonist of beta-AR. In isolated cardiac cells, ISO treatment only activated the inflammasomes in the cardiomyocytes but not the CFs. These results demonstrated that inflammasome activation was propagated from cardiomyocytes to CFs in the mice hearts. Further investigation revealed that the inflammasomes were activated in the cocultured CFs that connected with cardiomyocytes via membrane nanotubes (MNTs), a novel membrane structure that mediates distant intercellular connections and communication. Disruption of the MNTs with the microfilament polymerization inhibitor cytochalasin D (Cyto D) attenuated the inflammasome activation in the cocultured CFs. In addition, the MNT-mediated inflammasome activation in the CFs was blocked by deficiency of the inflammasome component NOD-like receptor protein 3 (NLRP3) in the cardiomyocytes, but not NLRP3 deficiency in the CFs. Moreover, ISO induced pyroptosis in the CFs cocultured with cardiomyocytes, and this process was inhibited by disruption of the MNTs with Cyto D or by the NLRP3 inhibitor MCC950 and the caspase-1 inhibitor Z-YVAD-FMK (FMK). Our study revealed that MNTs facilitate the rapid propagation of inflammasome activation among cardiac cells to promote pyroptosis in the early phase of beta-adrenergic insult. Therefore, preventing inflammasome transfer is a potential therapeutic strategy to alleviate acute beta-AR overactivation-induced cardiac injury. |
