Chronic Activation of Toll-Like Receptor 4 Decreases Peripheral Nerve Integrity

Despite its prevalence and impact on quality of life, understanding the pathogenesis of Diabetic peripheral neuropathy (DPN) and developing targeted interventions has been challenging. Sarah Crowards, a PhD student from Dr Douglas Wright's lab at the University of Kansas Medical Center, presented her research on Toll-like receptor 4 (TLR4) and its involvement in peripheral neuropathy, including diabetic neuropathy, during the Education Day at the 2024 Peripheral Nerve System (PNS) Annual Meeting in Montreal, Canada.

DPN is a common complication of diabetes characterized by pain, numbness, and tingling in the distal extremities. Crowards' research focuses on TLR4, an innate immune system receptor that plays a crucial role in these complications. "TLR4 is a receptor of the innate immune system, but they are also found on neurons and the peripheral nervous system," Crowards explained. "What makes it unique is its ability to respond to a wide array of atmospheres compared to other toll-like receptors." A hallmark of DPN is the loss of epidermal axons in the distal limbs. To test whether activation of TLR4 drives the loss of peripheral nerve fibers, Crowards and her team intraperitoneally injected the TLR4 agonist lipopolysaccharide (LPS), a classic strong TLR4 activator into wild-type mice over three weeks. They measured mechanical and thermal thresholds and intraepidermal nerve fiber density (IENFD) weekly. Their results showed a series of LPS injections significantly reduced peptidergic fibers (38 vs. 28 fibers/mm, p = 0.012) but did not significantly alter pain-like behavior. The LPS-injected mice also exhibited increased macrophage presence, suggesting that nerve fiber loss may be linked to macrophage activation and dorsal root ganglion aggregation with potential implications for pain and neurodegeneration.

"We don't know from this data if more macrophages are coming in or just the existing macrophages are spreading out, but we definitely see an increase," Crowards noted. These findings indicate a potential role of TLR4-mediated interactions in maintaining the structural integrity of peripheral nerves, including the epidermal c-fibers, but may not directly impact sensation. Thus, there could be a possibility that epidermal c-fibers can respond to immune threats and inflammation by undergoing neurodegeneration. "This really opens the door to many more questions," Crowards added, "Understanding the mechanisms of this nerve fiber loss and its correlation to pain can help us use TLR4 more smartly as a therapeutic target to prevent neuropathy development."

Current experiments in the Wright lab are focused on identifying TLR4-relevant signaling pathways, innate immune cell involvement, and the time course of TLR4's effects on peripheral nerves and their soma. Crowards' work underscores the importance of continued research and collaboration to understand the TLR4-mediated neuroimmune interactions and leverage the knowledge in developing effective treatments for diabetic neuropathy.