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

Francesco De Logu, Romina Nassini, Serena Materazzi, Muryel Carvalho Gonçalves, Daniele Nosi, Duccio Rossi Degl’Innocenti, Ilaria M. Marone, Juliano Ferreira, Simone Li Puma, Silvia Benemei, Gabriela Trevisan, Daniel Souza Monteiro de Araújo, Riccardo Patacchini, Nigel W. Bunnett and Pierangelo Geppetti ()
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Francesco De Logu: Section of Clinical Pharmacology and Oncology, University of Florence
Romina Nassini: Section of Clinical Pharmacology and Oncology, University of Florence
Serena Materazzi: Section of Clinical Pharmacology and Oncology, University of Florence
Muryel Carvalho Gonçalves: Section of Clinical Pharmacology and Oncology, University of Florence
Daniele Nosi: Section of Anatomy and Histology, University of Florence
Duccio Rossi Degl’Innocenti: Section of Clinical Pharmacology and Oncology, University of Florence
Ilaria M. Marone: Section of Clinical Pharmacology and Oncology, University of Florence
Juliano Ferreira: Federal University of Santa Catarina
Simone Li Puma: Section of Clinical Pharmacology and Oncology, University of Florence
Silvia Benemei: Section of Clinical Pharmacology and Oncology, University of Florence
Gabriela Trevisan: Graduate Program in Pharmacology, Federal University of Santa Maria (UFSM)
Daniel Souza Monteiro de Araújo: Section of Clinical Pharmacology and Oncology, University of Florence
Riccardo Patacchini: Chiesi Farmaceutici SpA
Nigel W. Bunnett: Columbia University
Pierangelo Geppetti: Section of Clinical Pharmacology and Oncology, University of Florence

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01739-2

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