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bioRxiv · 10.1101/696542

PI16 is a non-neuronal regulator of neuropathic pain

Singhmar, P.·Trinh, R. T. P.·Ma, J.·Huo, X.·Peng, B.·Heijnen, C. J.·Kavelaars, A.
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Abstract

Chronic pain is a major clinical problem of which the mechanisms are incompletely understood. Here we describe the concept that PI16, a protein of unknown function mainly produced by fibroblasts, controls neuropathic pain. The spared nerve injury model of neuropathic pain increases PI16 protein levels in fibroblasts in DRG meninges and in the epi/perineurium of the sciatic nerve. We did not detect PI16 expression in neurons or glia in spinal cord, DRG and nerve. Mice deficient in PI16 are protected against neuropathic pain. In vitro, PI16 promotes trans-endothelial leukocyte migration. In vivo, PI16-/- mice show reduced endothelial barrier permeability, lower leukocyte infiltration and reduced activation of the endothelial barrier regulator MLCK and reduced phosphorylation of its substrate MLC2 in response to SNI. In summary, our findings support a model in which PI16 promotes neuropathic pain by mediating a cross talk between fibroblasts and the endothelial barrier leading to barrier opening, cellular influx and increased pain. Its key role in pain and its limited cellular and tissue distribution makes PI16 an attractive target for pain management.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=128 HEIGHT=200 SRC=\"FIGDIR/small/696542v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (22K):\norg.highwire.dtl.DTLVardef@172f530org.highwire.dtl.DTLVardef@3f62a8org.highwire.dtl.DTLVardef@16606ccorg.highwire.dtl.DTLVardef@1485156_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Singhmar, P., Trinh, R. T. P., Ma, J., Huo, X., Peng, B., Heijnen, C. J., Kavelaars, A.. 2019-07-22. PI16 is a non-neuronal regulator of neuropathic pain. https://doi.org/10.1101/696542

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