Toll-like receptor 5 deficiency diminishes doxorubicin-induced acute cardiotoxicity in mice
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Updated: Dec 6, 2025
A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
Zhen-Guo Ma1,2, Chun-Yan Kong1,2, Hai-Ming Wu1,2
1Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, RP China.
Abstract:
Rationale: Clinical application of doxorubicin (DOX) is limited by its toxic cardiovascular side effects. Our previous study found that toll-like receptor (TLR) 5 deficiency attenuated cardiac fibrosis in mice. However, the role of TLR5 in DOX-induced cardiotoxicity remains unclear. Methods: To further investigate this, TLR5-deficient mice were subjected to a single intraperitoneal injection of DOX to mimic an acute model. Results: Here, we reported that TLR5 expression was markedly increased in response to DOX injection. Moreover, TLR5 deficiency exerted potent protective effects against DOX-related cardiac injury, whereas activation of TLR5 by flagellin exacerbated DOX injection-induced cardiotoxicity. Mechanistically, the effects of TLR5 were largely attributed to direct interaction with spleen tyrosine kinase to activate NADPH oxidase (NOX) 2, increasing the production of superoxide and subsequent activation of p38. The toxic effects of TLR5 activation in DOX-related acute cardiac injury were abolished by NOX2 deficiency in mice. Our further study showed that neutralizing antibody-mediated TLR5 depletion also attenuated DOX-induced acute cardiotoxicity. Conclusion: These findings suggest that TLR5 deficiency attenuates DOX-induced cardiotoxicity in mice, and targeting TLR5 may provide feasible therapies for DOX-induced acute cardiotoxicity.
Insights
Toll-like receptor (TLR) 5 deficiency protects against doxorubicin (DOX)-induced heart damage. Targeting TLR5 may offer new therapies for DOX cardiotoxicity, reducing severe side effects.
Area of Science:
- Cardiology
- Immunology
- Pharmacology
Background:
- Doxorubicin (DOX) chemotherapy causes cardiotoxicity, limiting its clinical use.
- Toll-like receptor (TLR) 5 deficiency previously showed protective effects against cardiac fibrosis.
- The specific role of TLR5 in DOX-induced cardiotoxicity requires further investigation.
Purpose of the Study:
- To elucidate the role of TLR5 in acute doxorubicin-induced cardiotoxicity.
- To investigate the protective potential of TLR5 deficiency against DOX-induced cardiac injury.
- To identify the molecular mechanisms underlying TLR5's involvement in DOX cardiotoxicity.
Main Methods:
- Utilized TLR5-deficient mice subjected to acute doxorubicin injection.
- Administered flagellin to activate TLR5 and assessed exacerbation of cardiotoxicity.
- Investigated molecular pathways involving spleen tyrosine kinase, NADPH oxidase 2 (NOX2), and p38 activation.
- Employed NOX2-deficient mice and TLR5-neutralizing antibodies to validate findings.
Main Results:
- Doxorubicin injection significantly increased TLR5 expression in mice.
- TLR5 deficiency markedly attenuated DOX-induced cardiac injury and fibrosis.
- TLR5 activation by flagellin worsened DOX cardiotoxicity.
- The protective effects of TLR5 deficiency were dependent on NOX2, implicating the TLR5-spleen tyrosine kinase-NOX2 pathway.
- TLR5 depletion using neutralizing antibodies also reduced DOX cardiotoxicity.
Conclusions:
- TLR5 deficiency confers significant protection against acute doxorubicin-induced cardiotoxicity in mice.
- The TLR5-mediated cardiotoxicity involves the activation of spleen tyrosine kinase and NOX2.
- Targeting TLR5 presents a promising therapeutic strategy to mitigate doxorubicin's cardiovascular side effects.
