Transgenic mice with a global depletion of toll-like receptor type 4 are largely protected from peripheral and...

Experimental bone fracture induces a posttraumatic inflammatory reaction which is characterized by local swelling, increased temperature, tenderness, thermal hypersensitivity and pain at the lesion site. As a consequence, some patients develop complex regional pain syndrome (CRPS), a chronic pain condition which often starts with exacerbating inflammation of the limb. The transmembrane receptor Toll-like receptor type 4 (TLR4) plays a central role in the innate immune response and not only engages with extracellular but also intracellular ligands, initiating intricate intracellular signaling cascades promoting inflammation. Depletion of TLR4 specifically in microglia attenuates posttraumatic pain, especially in males. Here, it is shown that male mice lacking TLR4 develop less inflammation after distal bone fracture, with attenuated swelling, local warming, macrophage invation into the dorsal root ganglion and spinal activation of microglia. Furthermore, expression of neuroinflammatory markers such as NGF, TNFα, ATF3 and Il4rα, is reduced in dorsal root ganglia. Together, the results support a proinflammatory role of TLR4 after distal bone fracture possibly initiating mechanisms leading to complex regional pain syndrome development in some patients which may be a promising novel for analgesic drug development. PERSPECTIVE: TLR4 is causally involved in the development of posttraumatic neuroinflammation characterised by upregulation of inflammatory mediators, invasion of macrophages into the dorsal root ganglion, as well as activation of microglia changes in the spinal dorsal horn in a murine model of human complex regional pain syndrome.