Chronic Activation of The Innate Immune Receptor Toll-Like Receptor 4 Drives Peripheral Nerve Fiber Loss but Not Pain-Like Behavior

The most prevalent complication of diabetes is the development of pain, numbness, and tingling in the distal extremities due to nerve degeneration – referred to as diabetic peripheral neuropathy (DPN). Although DPN significantly decreases patients’ quality of life, there have been significant challenges in understanding its pathogenesis and developing targeted interventions. Because diabetes is a chronic inflammatory condition, we explored how the innate immune receptor toll-like receptor 4 (TLR4) contributes to DPN. TLR4 can be activated by various agonists present in diabetes and promotes the expression of downstream inflammatory mediators. 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, we intraperitoneally injected the TLR4 agonist lipopolysaccharide (LPS) into wild-type mice over 3 weeks. We quantified intraepidermal nerve fiber density and assessed mechanical and thermal sensation. We found that 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. This suggests that TLR4-mediated neuroimmune interactions contribute to the integrity of peripheral nerve innervation but may not be sufficient to affect sensation. These findings suggest an unrecognized function of c-fibers to act as “immunoceptors” that orchestrate a degenerative response to immune threats and coordinate a neuroimmune reaction. Current experiments are exploring the mechanism by which TLR4 contributes to IENFD loss and testing whether blocking TLR4 may be an effective pharmacological intervention in DPN.