Bruton's Tyrosine Kinase Inhibition Attenuates the Cardiac Dysfunction Caused by Cecal Ligation and Puncture in Mice
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Updated: Jan 19, 2026
Viral Transgene Expression in Rodent Hearts and the Assessment of Cardiac Arrhythmia Risk
Published on: July 27, 2022
Caroline E O'Riordan1, Gareth S D Purvis1, Debora Collotta2
1William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
Insights
Bruton's tyrosine kinase (BTK) inhibitors, ibrutinib and acalabrutinib, attenuated sepsis-induced cardiac dysfunction in mice. These drugs reduced key inflammatory pathways and may offer a new therapeutic approach for sepsis treatment.
Area of Science:
- Cardiology
- Immunology
- Pharmacology
Background:
- Sepsis is a prevalent disease associated with high mortality, often leading to cardiac dysfunction.
- Bruton's tyrosine kinase (BTK) signaling and NLRP3 inflammasome activation are implicated in sepsis pathophysiology and cardiac complications.
Purpose of the Study:
- To investigate the efficacy of pharmacological BTK inhibition using ibrutinib and acalabrutinib in attenuating sepsis-associated cardiac dysfunction in a mouse model.
- To assess the impact of these inhibitors on inflammatory pathways, including BTK, NF-κB, and NLRP3 inflammasome activation, as well as serum cytokine levels.
Main Methods:
- Male C57BL/6 mice underwent cecal ligation and puncture (CLP) or sham surgery.
- Mice received vehicle, ibrutinib (30 mg/kg), or acalabrutinib (3 mg/kg) intravenously 1 hour after surgery.
- Cardiac function was evaluated by echocardiography, and cardiac tissue was analyzed for protein activation via Western blot. Serum cytokine levels were measured using a multiplex assay.
Main Results:
- CLP surgery significantly reduced cardiac function (ejection fraction, fractional shortening) and increased BTK, NF-κB, and NLRP3 inflammasome activation.
- CLP induced a significant increase in serum pro-inflammatory cytokines and chemokines.
- Ibrutinib and acalabrutinib administration attenuated cardiac dysfunction, reduced inflammatory pathway activation, and suppressed serum cytokine release.
Conclusions:
- Delayed administration of ibrutinib or acalabrutinib effectively mitigated sepsis-induced cardiac dysfunction in mice.
- BTK inhibition by these drugs reduced NF-κB and inflammasome activation and suppressed the release of sepsis-associated cytokines.
- Acalabrutinib demonstrated greater potency than ibrutinib, suggesting that FDA-approved BTK inhibitors could be repurposed for sepsis treatment.
Abstract:
Sepsis is one of the most prevalent diseases in the world. The development of cardiac dysfunction in sepsis results in an increase of mortality. It is known that Bruton's tyrosine kinase (BTK) plays a role in toll-like receptor signaling and NLRP3 inflammasome activation, two key components in the pathophysiology of sepsis and sepsis-associated cardiac dysfunction. In this study we investigated whether pharmacological inhibition of BTK (ibrutinib 30 mg/kg and acalabrutinib 3 mg/kg) attenuates sepsis associated cardiac dysfunction in mice. 10-week old male C57BL/6 mice underwent CLP or sham surgery. One hour after surgery mice received either vehicle (5% DMSO + 30% cyclodextrin i.v.), ibrutinib (30 mg/kg i.v.), or acalabrutinib (3 mg/kg i.v.). Mice also received antibiotics and an analgesic at 6 and 18 h. After 24 h, cardiac function was assessed by echocardiography in vivo. Cardiac tissue underwent western blot analysis to determine the activation of BTK, NLRP3 inflammasome and NF-κB pathway. Serum analysis of 33 cytokines was conducted by a multiplex assay. When compared to sham-operated animals, mice subjected to CLP demonstrated a significant reduction in ejection fraction (EF), fractional shortening (FS), and fractional area change (FAC). The cardiac tissue from CLP mice showed significant increases of BTK, NF-κB, and NLRP3 inflammasome activation. CLP animals resulted in a significant increase of serum cytokines and chemokines (TNF-α, IL-6, IFN-γ, KC, eotaxin-1, eotaxin-2, IL-10, IL-4, CXCL10, and CXCL11). Delayed administration of ibrutinib and acalabrutinib attenuated the decline of EF, FS, and FAC caused by CLP and also reduced the activation of BTK, NF-κB, and NLRP3 inflammasome. Both ibrutinib and acalabrutinib significantly suppressed the release of cytokines and chemokines. Our study revealed that delayed intravenous administration of ibrutinib or acalabrutinib attenuated the cardiac dysfunction associated with sepsis by inhibiting BTK, reducing NF-κB activation and the activation of the inflammasome. Cytokines associated with sepsis were significantly reduced by both BTK inhibitors. Acalabrutinib is found to be more potent than ibrutinib and could potentially prove to be a novel therapeutic in sepsis. Thus, the FDA-approved BTK inhibitors ibrutinib and acalabrutinib may be repurposed for the use in sepsis.
