Abstract
Myocardial ischemia/reperfusion (I/R) injury has been extensively studied, yet the underlying neuroinflammatory mechanisms are not fully understood. While toll-like receptor 4 (TLR4) is known to be involved in neuropathic pain and neurodegeneration, its role in the central nervous system during myocardial I/R injury, as well as how it modulates neuronal activity to influence cardiac function, remains unclear. In this study, we established a rodent model of myocardial I/R injury by ligating the left anterior descending artery. We found that myocardial I/R injury significantly upregulated TLR4 expression in the spinal dorsal horn, with enhanced TLR4 levels predominantly localized to spinal neurons rather than astrocytes or microglia. Upregulation of TLR4 exhibited functional crosstalk with the calcitonin gene-related peptide (CGRP) receptor, facilitating the transmission of nociceptive signals from the injured myocardium and leading to hyperexcitation of spinal neurons. Both pharmacological inhibition and genetic manipulation of TLR4 signaling resulted in a marked reduction in neuronal activity and attenuated myocardial ischemic injury, accompanied by decreased nociceptive input from the heart to the spinal dorsal horn. Collectively, our findings reveal classic neuroinflammatory signals derived from TLR4 that contribute to neuronal hyperexcitation following myocardial I/R injury. Targeting spinal neuronal TLR4 signaling represents a promising therapeutic strategy for patients with acute myocardial injury.