Non-neuronal cells, including glia and leukocytes contribute to chronic pain. Here we identify fibroblasts secreting the protein PI16 as novel regulator of neuropathic pain. Mice deficient in PI16, a member of the CAP superfamily of proteases, are protected against neuropathic pain induced by spared nerve injury (SNI) or paclitaxel. SNI increases PI16 in fibroblasts and in vitro myofiborblast differentiation increases PI16 expression and secretion. In vitro, PI16 conditioned medium promotes migration of immune cells across the endothelial layer. Consistently, protection against neuropathic pain in PI16-/- mice was associated with reduced endothelial barrier permeability, lower leukocyte infiltration and reduced activation of the endothelial barrier regulator MLCK. Collectively our findings indicate that the fibroblast- derived protein PI16 promotes neuropathic pain by increasing vascular permeability and cellular infiltration. Due to its key role in pain and limited cellular distribution PI16 is an attractive novel target for pain management.

This work was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health RO1 NS073939 and RO1 NS074999.