TLR3 contributes to persistent autophagy and heart failure in mice after myocardial infarction

Abstract

Toll‐like receptors (TLRs) are essential immunoreceptors involved in host defence against invading microbes. Recent studies indicate that certain TLRs activate immunological autophagy to eliminate microbes. It remains unknown whether TLRs regulate autophagy to play a role in the heart. This study examined this question. The activation of TLR3 in cultured cardiomyocytes was observed to increase protein levels of autophagic components, including LC3‐II, a specific marker for autophagy induction, and p62/SQSTM1, an autophagy receptor normally degraded in the final step of autophagy. The results of transfection with a tandem mRFP‐GFP‐LC3 adenovirus and use of an autophagic flux inhibitor chloroquine both suggested that TLR3 in cardiomyocytes promotes autophagy induction without affecting autophagic flux. Gene‐knockdown experiments showed that the TRIF‐dependent pathway mediated the autophagic effect of TLR3. In the mouse model of chronic myocardial infarction, persistent autophagy was observed, concomitant with up‐regulated TLR3 expression and increased TLR3‐Trif signalling. Germline knockout (KO) of TLR3 inhibited autophagy, reduced infarct size, attenuated heart failure and improved survival. These protective effects were abolished by in vivo administration of an autophagy inducer rapamycin. Similar to the results obtained in cultured cardiomyocytes, TLR3‐KO did not prevent autophagic flux in mouse heart. Additionally, this study failed to detect the involvement of inflammation in TLR3‐KO‐derived protection, as wild‐type and TLR3‐KO hearts were comparable in inflammatory activity. It is concluded that up‐regulated TLR3 expression and signalling contributes to persistent autophagy following MI, which promotes heart failure and lethality.

FOXC1 up‐regulates the expression of toll‐like receptors in myocardial ischaemia

“…Fallach et al reported increased immunohistochemical staining for TLR4 in ischaemic mouse heart. Our published data showed increases in mRNAs and proteins for TLR2, TLR3 and TLR4 in cultured cardiomyocytes exposed to ischaemia, as well as heart tissue subjected to ischaemia . As a fact, we have examined more members of TLR family and have obtained data, which are presented herein, showing universal increases in Tlr mRNAs in ischaemic cardiomyocytes and myocardium.…”

“…Our published data showed increases in mRNAs and proteins for TLR2, TLR3 and TLR4 in cultured cardiomyocytes exposed to ischaemia, as well as heart tissue subjected to ischaemia. [7][8][9] As a fact, we have examined more members of TLR family and have obtained data, which are presented herein, showing universal increases in Tlr mRNAs in ischaemic cardiomyocytes and myocardium. To uncover the underlying mechanism stimulating Tlr expression in cardiomyocytes, the present study screened transcription factors (TFs) that potentially regulate TLR gene transcription, and identified forkhead box C1 (FOXC1) as an ischaemia-responsive TF that up-regulates the expression of TLR members in myocardial ischaemia.…”

“…The neonatal rat ventricular myocytes (NRVMs) and H9c2 rat ventricular cell line were cultured as we described previously . NRVMs were prepared from neonatal Sprague Dawley rats.…”

“…The neonatal rat ventricular myocytes (NRVMs) and H9c2 rat ventricular cell line were cultured as we described previously. 7,20 NRVMs were prepared from neonatal Sprague Dawley rats. Briefly, the neonatal rats were killed by decapitation; then, the ventricles were removed, rinsed, minced and digested with 0.2% trypsin in Ca 2+ -and Mg 2+ -free Hanks solution for repeated short time periods.…”

Toll‐like receptor 3 controls QT interval on the electrocardiogram by targeting the degradation of Kv4.2/4.3 channels in the endoplasmic reticulum

“…Tlr3 ‐deficient mice also exhibited more severe pulmonary hypertension following exposure to chronic hypoxia (13). However, TLR3 represents an injurious factor during I/R injury (14) and myocardial infarction (15). And it also plays a deleterious role in mediating cardiac dysfunction in sepsis (16).…”