Toll-like receptor 2 dominance over Toll-like receptor 4 in stressful conditions for its detrimental role in the heart

Abstract

It has been suggested that Toll-like receptor (TLR)4 promotes IL-10-mediated cardiac cell survival, whereas another receptor, TLR2, from the same family, is detrimental. Here, we examined the interactive role of these two innate signaling molecules under stressful conditions, including IL-10 knockout (IL-10) mice, global ischemia-reperfusion (I/R) injury in rat hearts, and in vitro short hairpin RNA experimental models in the presence or absence of IL-10 (10 ng/ml). Circulating and myocardial levels of TNF-α as well as apoptosis and fibrosis were higher in IL-10 mice. The increase in TLR2 in IL-10 hearts indicated its negative regulation by IL-10. Ex vivo I/R also caused a marked upregulation of TLR2 and TNF-α as well as apoptotic and fibrotic signals. However, a 40-min reperfusion with IL-10 triggered an increase in TLR4 expression and improved recovery of cardiac function. The increase in IL-1 receptor-associated kinase (IRAK)-M and IRAK-2 activity during I/R injury suggested their role in TLR2 signaling. In vitro inhibition of TLR4 activity as a consequence of RNA inhibition-mediated suppression of myeloid differentiation gene (MyD)88 suggested MyD88-dependent activation of TLR4. The inclusion of IL-10 during reperfusion also downregulated the expression of IRAK-2, TNF-α receptor-associated factor 1-interacting protein (TRAIP) and apoptotic signals, caspase-3, and the Bax-to-Bcl-x ratio. IL-10 reduced the TNF-α receptor-associated increase in TRAIP-induced apoptosis during I/R injury, which led to an increase in IL-1β to mitigate transforming growth factor-β receptor type I-mediated fibrosis. The IL-10 mitigation of these changes suggests that the stimulation through TLR4 signaling promotes IRAK-4 and phosphorylates IRAK-1 instead of IRAK-2 and may be an important therapeutic approach in restoring heart health in stress. Under stress conditions such as downregulation of the IL-10 gene or ischemia-reperfusion injury, Toll-like receptor (TLR)4 and IL-1 receptor-associated kinase (IRAK)-1 activation is suppressed, along with the upregulation of TLR-2 and IRAK-2, resulting in fibrosis and apoptosis. It is suggested that IL-10 helps to maintain heart function during stress via myeloid differentiation gene 88/IRAK-4/IRAK-1-dependent TLR4 signaling.

Down-Regulation of miR-327 Alleviates Ischemia/Reperfusion-Induced Myocardial Damage by Targeting RP105

“…However, the role of TLR2 in MIRI still remains uncertain. Some studies have shown that TLR2 activation may accelerate inflammation, fibrosis, and apoptosis [31,32], while Shishido and colleagues reported that myocardial infarct size and inflammation in infarct area had no difference between wild-type mice and TLR2 deficient mice [33]. Moreover, the MIRI rat model treated with TLR2 ligands (PGN or Pam3CSK4) even induced a cardioprotective effect [34].…”

“…First, the effect of TLR2 signaling in MIRI is controversial [31][32][33][34]; we mainly used adenovirus transfection technology to regulate the expression of miR-327, but did not suppress TLR4 or TLR2 signaling to exam the effect, respectively. Second, we confirmed the effect of miR-327 on myocardium subjected to I/R injury in vivo but did not verify the effect on hypoxia/reoxygenation cardiomyocytes; we intend to conduct these follow-up experiments in future research.…”

Effect of Intermittent and Mild Cold Stimulation on the Immune Function of Bursa in Broilers

“…Additionally, the expression of IL-6 could mitigate the damage from cold stress [45]. According to Bagchi et al [46], changes from the external environment can lead to an increase in pro-inflammatory cytokines. The research from Akihisa Harada et al [47] indicated that IL-8 played a causative role in acute inflammation by recruiting and activating neutrophils.…”

Identification Of Both Shared And Specific Potential Molecular Mechanisms Of Arvc And Dcm Based On A Genome-Wide Microarray Dataset

“…Bagchi AK. et al [35] showed that under stress, IL-10-mediated toll-like receptor 4 (TLR4) signaling suppresses apoptosis as well as brosis, while TLR2 has the opposite effect. Similarly, the hypoxia-inducible factor-1 (HIF-1) signal pathway also takes part in the development of brosis [36].…”