Schwann cell TRPA1 mediates neuroinflammation that sustains macrophage-dependent neuropathic pain in mice

Francesco De Logu,Juliano Ferreira,Pierangelo Geppetti,Simone Li Puma,Ilaria M Marone,Serena Materazzi,Daniele Nosi,Duccio Rossi Degl’Innocenti,Romina Nassini,Gabriela Trevisan,Muryel Carvalho Gonçalves,Riccardo Patacchini,Silvia Benemei,Nigel W Bunnett,Daniel Souza Monteiro De Araújo

doi:10.1038/s41467-017-01739-2

Abstract

It is known that transient receptor potential ankyrin 1 (TRPA1) channels, expressed by nociceptors, contribute to neuropathic pain. Here we show that TRPA1 is also expressed in Schwann cells. We found that in mice with partial sciatic nerve ligation, TRPA1 silencing in nociceptors attenuated mechanical allodynia, without affecting macrophage infiltration and oxidative stress, whereas TRPA1 silencing in Schwann cells reduced both allodynia and neuroinflammation. Activation of Schwann cell TRPA1 evoked NADPH oxidase 1 (NOX1)-dependent H2O2 release, and silencing or blocking Schwann cell NOX1 attenuated nerve injury-induced macrophage infiltration, oxidative stress and allodynia. Furthermore, the NOX2-dependent oxidative burst, produced by macrophages recruited to the perineural space activated the TRPA1–NOX1 pathway in Schwann cells, but not TRPA1 in nociceptors. Schwann cell TRPA1 generates a spatially constrained gradient of oxidative stress, which maintains macrophage infiltration to the injured nerve, and sends paracrine signals to activate TRPA1 of ensheathed nociceptors to sustain mechanical allodynia.

Highlights

It is known that transient receptor potential ankyrin 1 (TRPA1) channels, expressed by nociceptors, contribute to neuropathic pain
We report the discovery of a role for TRPA1 in Schwann cells in neuroinflammation and ensuing neuropathic pain
The established capacity of TRPA1 to sense oxidative stress[15,18,19,22], and recent data obtained in a model of neuropathic pain caused by trigeminal nerve injury[30], led to the hypothesis that mechanical allodynia is sustained by the oxidative burden generated by infiltrating macrophages that continuously target TRPA1 in nerve fibers

Summary

Introduction

It is known that transient receptor potential ankyrin 1 (TRPA1) channels, expressed by nociceptors, contribute to neuropathic pain. We found that in mice with partial sciatic nerve ligation, TRPA1 silencing in nociceptors attenuated mechanical allodynia, without affecting macrophage infiltration and oxidative stress, whereas TRPA1 silencing in Schwann cells reduced both allodynia and neuroinflammation. Schwann cell TRPA1 generates a spatially constrained gradient of oxidative stress, which maintains macrophage infiltration to the injured nerve, and sends paracrine signals to activate TRPA1 of ensheathed nociceptors to sustain mechanical allodynia. The infiltration of macrophages into the damaged nerve trunk is known to induce mechanical allodynia in mice with sciatic nerve injury[6,7,8,9], the precise pathway by which inflammatory cells cause persistent allodynia is only partially defined. Oxidative stress contributes to neuropathic pain, since antioxidants attenuate mechanical hypersensitivity in mouse models, including chronic constriction of the sciatic nerve[12] and spinal nerve ligation[13]

Methods

Results

Conclusion