TY - JOUR
T1 - Schwann cell TRPA1 mediates neuroinflammation that sustains macrophage-dependent neuropathic pain in mice
AU - De Logu, Francesco
AU - Nassini, Romina
AU - Materazzi, Serena
AU - Carvalho Gonçalves, Muryel
AU - Nosi, Daniele
AU - Rossi Degl'Innocenti, Duccio
AU - Marone, Ilaria M.
AU - Ferreira, Juliano
AU - Li Puma, Simone
AU - Benemei, Silvia
AU - Trevisan, Gabriela
AU - Souza Monteiro De Araújo, Daniel
AU - Patacchini, Riccardo
AU - Bunnett, Nigel W.
AU - Geppetti, Pierangelo
N1 - Funding Information:
We thank A.H. Morice (University of Hull, UK) for the hTRPA1-HEK293 cells and D. Preti (University of Ferrara, Italy) for providing HC-030031. We also thank Mary K. Lokken for her expert English revision. This work was supported by grants from Istituto Toscano Tumori (ITT), grant 2014 and Regione Toscana, grant Nutraceuticals 2014, ‘POFCADT’ (to P. Geppetti).
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85037052367&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85037052367&partnerID=8YFLogxK
U2 - 10.1038/s41467-017-01739-2
DO - 10.1038/s41467-017-01739-2
M3 - Article
C2 - 29192190
AN - SCOPUS:85037052367
VL - 8
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1887
ER -