A Partial Toll-like Receptor 4 Agonist Attenuates Pain While Maintaining Immunosufficiency

Activation of Toll-like Receptor 4 (TLR4) from infection or tissue damage/stress is a contributing factor to many diseases including chronic pain. Many of these pain conditions are associated with chronically elevated inflammatory cytokine expression or autoimmune dysregulation (e.g., rheumatoid arthritis, Crohn’s disease). Current treatment includes biologics that target signaling pathways downstream of TLR4. These drugs reduce pain by reducing cytokine detection and function; many target TNF-alpha. The problem with chronically inhibiting cytokine function is a reduction in the body’s ability to appropriately fight infection. Lipopolysaccharide (LPS) from Gram-negative bacteria activates TLR4 signaling pathways to initiate the body’s innate immune response including upregulation of pro-inflammatory cytokines. Notably, structurally engineered LPS components can be used to modulate TLR4 output. Our group has patented a process, bacterial enzymatic combinatorial chemistry (BECC), to produce bacteria that express an engineered LPS molecule that is significantly less toxic than prototypical enteric LPS. We call this molecule ALT (Anti-nociceptive LOS competitive TLR4 ligand). Preliminary data show ALT acts as a partial TLR4 agonist, weakly activating the receptor resulting in an attenuated cytokine response. In several different pain models in mice ALT is antinociceptive, similar to TLR4 antagonists. However, in contrast to TLR4 antagonists, ALT does not interfere with a normal outcome in a lethal endotoxemia model. ALT represents a novel approach to treating chronic pain conditions that are mediated by TLR4 activation. It will improve patient’s quality of life by allowing pain reduction without compromising normal protective immune function, a plague of the current biologic treatments. Supported by Department of Defense Award W81XWH-21-1-0595.