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Differential Role of Toll‐like Receptors in Elicitation of Cardiac Innate Response to IL‐10
Author(s) -
Bagchi Ashim,
Akolkar Gauri,
Mandal Soma,
Gao Xiaoling,
Yang Xi,
Singal Pawan
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.46.7
Subject(s) - tlr2 , tlr4 , receptor , toll like receptor , cytokine , signal transduction , microbiology and biotechnology , reperfusion injury , tumor necrosis factor alpha , medicine , innate immune system , immunology , chemistry , biology , ischemia
Pattern recognition receptors such as toll‐like receptor 2 (TLR2) and 4 (TLR4), are associated with myocardial ischemia/reperfusion (I/R) injury. Recently, it was suggested that TLR2 is detrimental whereas TLR4 promotes IL‐10‐mediated cardiac cell survival. However the mechanism of molecular balance between these two innate signaling molecules has not been elucidated. We explored the significance of these TLRs in response to IL‐10 in myocardial I/R injury using ex‐vivo, knockout (KO) and shRNA approaches. The ex‐vivo myocardial I/R injury model showed a marked expression of TLR2 and studies in the IL‐10 gene KO (IL‐10 ‐/‐ ) heart indicated a negative regulation of TLR2 by IL‐10. However, 40min reperfusion with IL‐10 after ischemia triggered TLR4 elevation. Inhibition of TLR4 activity using MyD88‐shRNA suggests a MyD88 adaptor molecule dependent activation of TLR4. Increased interleukin‐1 receptor‐associated kinase‐M (IRAK‐M) during I/R injury upregulates IRAK‐2, indicating IRAK‐M/IRAK‐2 requirement in TLR2 signaling. IL‐10 altered these changes significantly, suggesting that IL‐10 dissociates IRAK4 into IRAK 1. Circulating and myocardial levels of TNF‐α were higher in hearts with I/R injury. Consequently, TLR2‐mediated TNF‐α gene activation led to increased apoptosis by TLR2‐mediated IRAK‐M/IRAK‐2 activation. IL‐10 reduced the TNF‐α receptor‐associated increase in TRAIP/TRADD‐induced cell apoptosis during ischemia injury which led to an increase in IL‐1β to mitigate TGF‐βRII‐mediated fibrosis. Our results suggest that this cytokine may be a key therapeutic molecule in restoring heart health from ischemia injury via TLR4 innate signaling pathway (supported by CIHR).