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Published on: July 26, 2017
Toll-like receptor 2 activation by bacterial peptidoglycan-associated lipoprotein activates cardiomyocyte
Xinsheng Zhu1, Aranya Bagchi, Huailong Zhao
1Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Objective:
Although cardiac dysfunction plays an important role in the pathogenesis of sepsis, the mechanisms that underlie cardiac dysfunction in sepsis remain poorly understood. Bacterial peptidoglycan-associated lipoprotein (PAL), an outer-membrane protein of Gram-negative bacteria, was recently found to be released into the bloodstream in sepsis and to cause inflammation and death in mice. The present studies assessed the effects of PAL on cardiomyocyte function and its signal transduction in cardiomyocytes.
Design:
Randomized prospective animal study.
Setting:
Research laboratory.
Subjects:
Male C57BL/6 mice, B6;129S-Tnfrsf1a(tm1Imx) Tnfrsf1b(tm1Imx)/J knockout mice, Toll-like receptor 2 (TLR2) knockout mice, and myeloid differentiation factor 88 (MyD88) knockout mice.
Interventions:
None.
Measurements And Results:
Immunohistochemical staining and immunoblot analysis indicated that intravenously injected PAL bound to myocardium. Injection of PAL decreased cardiac function in vivo. Challenge with PAL altered cell shortening and Ca2+ transients in isolated mouse cardiomyocytes but not in cardiomyocytes isolated from TLR2 -/- and MyD88 -/- mice. Cytokine profiling arrays demonstrated that tumor necrosis factor-alpha (TNFalpha), granulocyte colony-stimulating factor, and interferon-gamma-production were elevated in PAL-treated cardiomyocytes. Increased TNFalpha production was abolished in MyD88 -/- cardiomyocytes but restored by adenovirally mediated expression of MyD88. PAL did not affect cell shortening and Ca2+ cycling in cardiomyocytes obtained from mice deficient for TNFalpha receptor (TNFR) 1 and TNFR2 (TNFR1/2 -/-).
Conclusion:
Our data reveal that PAL uses the TLR2/MyD88 signaling cascade to induce cardiomyocyte dysfunction and inflammatory responses and that TNFalpha is a major mediator of PAL-induced dysfunction in cardiomyocytes. These studies suggest that circulating PAL and other TLR2 agonists may contribute to cardiac dysfunction in sepsis.
Insights
Bacterial peptidoglycan-associated lipoprotein (PAL) triggers cardiac dysfunction in sepsis via the Toll-like receptor 2 (TLR2)/MyD88 pathway. Tumor necrosis factor-alpha (TNFalpha) is a key mediator, highlighting PAL
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Medicine
Background:
- Sepsis-induced cardiac dysfunction is a significant clinical problem.
- The precise mechanisms underlying sepsis-related heart dysfunction remain unclear.
- Bacterial peptidoglycan-associated lipoprotein (PAL) is implicated in sepsis pathogenesis.
Purpose of the Study:
- To investigate the effects of PAL on cardiomyocyte function.
- To elucidate the signal transduction pathways involved in PAL-induced cardiac dysfunction.
Main Methods:
- Utilized a randomized prospective animal study design.
- Employed knockout mouse models deficient in Toll-like receptor 2 (TLR2) and myeloid differentiation factor 88 (MyD88).
- Assessed cardiomyocyte function, Ca2+ transients, and cytokine production.
Main Results:
- Intravenously injected PAL localized to the myocardium and impaired cardiac function in vivo.
- PAL treatment altered cardiomyocyte function and Ca2+ transients, dependent on TLR2 and MyD88.
- Elevated levels of tumor necrosis factor-alpha (TNFalpha) were observed in PAL-treated cardiomyocytes.
- TNFalpha mediated PAL-induced cardiac dysfunction, as blocking TNFalpha receptors prevented these effects.
Conclusions:
- PAL induces cardiomyocyte dysfunction and inflammation through the TLR2/MyD88 signaling cascade.
- TNFalpha is a critical mediator of PAL-induced cardiac dysfunction.
- Circulating PAL and other TLR2 agonists may contribute to cardiac dysfunction during sepsis.
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