Fig. 1

All TLRs signal through the common MyD88-dependent pathway. MyD88 signals via downstream kinases eventually leading to the activation of NF-κB and inflammatory cytokine production. TLR preconditioning triggers cross activation of both MyD88-dependent and Trif-dependent pathways with PI3K/Akt to protect the heart against I/R injury. TLR activation initiates an adaptive immune respons to maintain organ function through both the PI3K survival and NF-κB signaling pathways and moderate expression of proinflammatory cytokines IL-1 ß, IL-6, and TNF-α. Activation of PI3K/Akt signaling limits pro-inflammatory and apoptotic events induced by TLR-NF-κB pathway through an endogenous compensatory mechanism and protects against I/R injuries. But, exaggerated activation of TLRs leads to a positive-feedback-regulation loop in inflammatory pathway and robuset activation of TLR-NF-κB, which subsequently results in cardiac injury and heart impairment