TRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins.
Gram-negative bacterial infections are accompanied by inflammation and somatic or visceral pain. These symptoms are generally attributed to sensitization of nociceptors by inflammatory mediators released by immune cells. Nociceptor sensitization during inflammation occurs through activation of the Toll-like receptor 4 (TLR4) signalling pathway by lipopolysaccharide (LPS), a toxic by-product of bacterial lysis. Here we show that LPS exerts fast, membrane delimited, excitatory actions via TRPA1, a transient receptor potential cation channel that is critical for transducing environmental irritant stimuli into nociceptor activity. Moreover, we find that pain and acute vascular reactions, including neurogenic inflammation (CGRP release) caused by LPS are primarily dependent on TRPA1 channel activation in nociceptive sensory neurons, and develop independently of TLR4 activation. The identification of TRPA1 as a molecular determinant of direct LPS effects on nociceptors offers new insights into the pathogenesis of pain and neurovascular responses during bacterial infections and opens novel avenues for their treatment.
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández y CSIC, Alicante E-03550, Spain.
Victor
V
Meseguer
Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine and TRP Research Platform Leuven (TRPLe), Leuven B-3000, Belgium.
Yeranddy A
YA
Alpizar
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández y CSIC, Alicante E-03550, Spain.
Enoch
E
Luis
Departamento de Bioquímica y Biología Molecular y Fisiología e Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid y CSIC, Valladolid E-47003, Spain.
Sendoa
S
Tajada
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández y CSIC, Alicante E-03550, Spain.
Bristol
B
Denlinger
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández y CSIC, Alicante E-03550, Spain.
Otto
O
Fajardo
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández y CSIC, Alicante E-03550, Spain.
Jan-Albert
JA
Manenschijn
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández y CSIC, Alicante E-03550, Spain.
Carlos
C
Fernández-Peña
1] Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine and TRP Research Platform Leuven (TRPLe), Leuven B-3000, Belgium [2] Vicepresidencia de Investigaciones. Instituto Finlay, 11600 La Habana, Cuba.
Arturo
A
Talavera
Institute of Physiology and Pathophysiology, University of Erlangen-Nuremberg, Erlangen D-91054, Germany.
Tatiana
T
Kichko
Department of Physiology, CIMUS, University of Santiago de Compostela, Santiago de Compostela E-15782, Spain.
Belén
B
Navia
Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine and TRP Research Platform Leuven (TRPLe), Leuven B-3000, Belgium.
Alicia
A
Sánchez
Department of Physiology, CIMUS, University of Santiago de Compostela, Santiago de Compostela E-15782, Spain.
Rosa
R
Señarís
Institute of Physiology and Pathophysiology, University of Erlangen-Nuremberg, Erlangen D-91054, Germany.
Peter
P
Reeh
Departamento de Bioquímica y Biología Molecular y Fisiología e Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid y CSIC, Valladolid E-47003, Spain.
María Teresa
MT
Pérez-García
Departamento de Bioquímica y Biología Molecular y Fisiología e Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid y CSIC, Valladolid E-47003, Spain.
José Ramón
JR
López-López
Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine and TRP Research Platform Leuven (TRPLe), Leuven B-3000, Belgium.
Thomas
T
Voets
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández y CSIC, Alicante E-03550, Spain.
Carlos
C
Belmonte
1] Instituto de Neurociencias de Alicante, Universidad Miguel Hernández y CSIC, Alicante E-03550, Spain [2] Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine and TRP Research Platform Leuven (TRPLe), Leuven B-3000, Belgium [3].
Karel
K
Talavera
1] Instituto de Neurociencias de Alicante, Universidad Miguel Hernández y CSIC, Alicante E-03550, Spain [2].
Félix
F
Viana
D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004926:Escherichia coli / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008050:Lipid A / Q000737:chemistry; D008070:Lipopolysaccharides / Q000009:adverse effects*; D008564:Membrane Potentials / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020078:Neurogenic Inflammation / Q000378:metabolism* / Q000473:pathology; D009479:Neuropeptides / Q000378:metabolism; D009619:Nociceptors / Q000378:metabolism; D010146:Pain / Q000378:metabolism* / Q000473:pathology; D011984:Sensory Receptor Cells / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D000074025:TRPA1 Cation Channel; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D050051:Transient Receptor Potential Channels / Q000819:agonists / Q000378:metabolism*
D008050:Lipid A; D008070:Lipopolysaccharides; D009479:Neuropeptides; D000074025:TRPA1 Cation Channel; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse