Targeting the HMGB1-TLR4 Axis Alleviates Neuropathic Pain-Associated Cognitive Deficits

J Neurosci. 2026 May 8:e2250252026. doi: 10.1523/JNEUROSCI.2250-25.2026. Online ahead of print.

ABSTRACT

Cognitive deficits associated with chronic pain pose a significant burden on a patient's quality of life. Emerging evidence indicates that Toll-like receptor 4 (TLR4), a pattern recognition receptor implicated in neuroinflammatory signaling that can disrupt synaptic plasticity and memory processes. However, the specific involvement of TLR4 in the development of neuropathic pain-related cognitive deficits has not been fully elucidated. In this investigation, we observed an upregulation of TLR4 expression within hippocampal neurons in male mice subjected to chronic constriction injury (CCI) relative to sham group. Notably, in separate experimental cohorts, TLR4-knockout and neuron-specific TLR4-knockdown mice exhibited improved cognitive function compared to wild-type controls, alongside attenuated neuroinflammatory responses, reduced neuronal apoptosis, and enhanced preservation of hippocampal neuroplasticity. Concurrently, elevated concentrations of high-mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) molecule, were detected in the sciatic nerve, serum, and hippocampal tissues following CCI. Furthermore, increased co-localization of HMGB1 with TLR4 was evident in the hippocampus. Exogenous administration of HMGB1 augmented HMGB1 and TLR4 levels in the hippocampus and worsened memory functions that depend on hippocampal integrity. Conversely, inhibition of HMGB1 with glycyrrhizin, which subsequently attenuates TLR4 activation, ameliorated cognitive impairments induced by CCI. Collectively, these results support a model in which HMGB1, elevated during chronic neuropathic pain, contributes to cognitive deficits via a TLR4-dependent mechanism, triggering downstream inflammatory and apoptotic cascades and impairing synaptic plasticity.

Significance Statement Chronic neuropathic pain is frequently accompanied by debilitating cognitive deficits, yet the underlying mechanisms linking peripheral nerve injury to central nervous system dysfunction remain poorly understood, hindering the development of targeted therapies. This study identifies the HMGB1/ TLR4 signaling axis as a critical mediator driving these cognitive impairments. We demonstrate that HMGB1, released after nerve injury, activates hippocampal TLR4, triggering neuroinflammation, neuronal apoptosis, and synaptic deficits. Importantly, genetic deletion or neuronal-specific knockdown of TLR4, as well as pharmacological inhibition of the HMGB1/TLR4 interaction, rescues cognitive function. These findings elucidate a precise molecular pathway connecting peripheral neuropathic pain to cognitive decline and establish the HMGB1/TLR4 axis as a promising therapeutic target for preventing or treating pain-associated cognitive dysfunction.

PMID:42103480 | DOI:10.1523/JNEUROSCI.2250-25.2026