The role of cell-specific TLR4 in Diabetic Peripheral Neuropathy

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Abstract With an annual occurrence of over 200,000 cases per year, painful diabetic peripheral neuropathy is a leading debilitating disorder in the United States. The mechanisms that underlay its development are highly sought after, because current therapeutics fail to offer relief in over half of patients. A high-fat western diet and obesity play crucial roles in neuronal hyperexcitability that lead to painful diabetic peripheral neuropathy. In certain instances, evidence dissociates diet, diabetes, and obesity, and understanding these disparate mechanisms of action will play a divisive role in identifying therapeutic targets that can modulate neuronal activity. Peripheral sensory neurons express toll-like receptor 4 (TLR4), a receptor whose agonist are dietary free fatty acids, dietary sugar metabolites (methylglyoxal), and danger-associated molecular pattern (DAMPs) expressed during diabetes (HMGB1). This suggests that neurons can be directly activated by TLR4 agonists from various sources to play a role in plasticity leading to painful states during diabetic peripheral neuropathy. Moreover, macrophages are closely situated next to peripheral sensory neurons, express TLR4, and release additional pro-nociceptive factors that sensitize neurons. This study will focus on the peripheral nervous system, utilizing genetic tools to clarify the minimum circuitry necessary to mediate TLR4-dependent activation of DRG nociceptive neurons in developing diet-induced/diabetic neuropathic pain. A key feature of this proposal is that we will study the physiological relevance of TLR4 in specific cell populations in vivo to determine whether nociceptor or macrophage TLR4 is sufficient for the development of diabetic neuropathic pain. We will take advantage of the cre-lox transgenic system offering cell-specific reactivation of TLR4 using newly developed null-reactivatable mice. We have crossed these animals with Nav1.8-cre (sensory neuron) and LysM-cre (macrophage) animals to assess these particular populations in developing neuropathic pain in response to diabetes, diet, or obesity. Our research is aimed at understanding mechanisms driving chronic pain and moving these molecular insights toward new therapeutic strategies for pain alleviation. To accomplish these goals we propose the following specific aims: 1) Determine the role of neuron-specific vs. macrophage-specific TLR4 to develop neuropathic pain and 2) Determine the contribution of dietary components as cell-specific TLR4 agonists to induce sensitization and pain states. These studies will hopefully point to novel therapeutic avenues for the treatment and prevention of diabetic pain by targeting nociceptor and macrophage TLR4 signaling and identify elusive mechanisms through, diet, obesity or diabetes.