TY - JOUR

T1 - Angiotensin II triggers peripheral macrophage-to-sensory neuron redox crosstalk to elicit pain

AU - Shepherd, Andrew J

AU - Copits, Bryan A

AU - Mickle, Aaron D

AU - Karlsson, Páll

AU - Kadunganattil, Suraj

AU - Haroutounian, Simon

AU - Tadinada, Satya M

AU - de Kloet, Annette D

AU - Valtcheva, Manouela V

AU - McIlvried, Lisa A

AU - Sheahan, Tayler D

AU - Jain, Sanjay

AU - Ray, Pradipta R

AU - Usachev, Yuriy M

AU - Dussor, Gregory

AU - Krause, Eric G

AU - Price, Theodore J

AU - Gereau, Robert W

AU - Mohapatra, Durga P

N1 - Copyright © 2018 the authors.

PY - 2018/8/8

Y1 - 2018/8/8

N2 - Injury, inflammation, and nerve damage initiate a wide variety of cellular and molecular processes that culminate in hyperexcitation of sensory nerves, which underlies chronic inflammatory and neuropathic pain. Using be avioral readouts of pain hypersensitivity induced by angiotensin II (Ang II) injection into mouse hindpaws, our study shows that activation of the type 2 Ang II receptor (AT2R) and the cell-damage-sensing ion channel TRPA1 are required for peripheral mechanical pain sensitization induced by Ang II in male and female mice. However, we show that AT2R is not expressed in mouse and human dorsal root ganglia (DRG) sensory neurons. Instead, expression/ activation of AT2R on peripheral/skin macrophages (Mɸs) constitutes a critical trigger of mouse and human DRG sensory neuron excitation. Ang II-induced peripheral mechanical pain hypersensitivity can be atten ated by chemogenetic depletion of peripheralM_s. Furthermore, AT2R activation in Mɸs triggers production of reactive oxygen/nitrogen species, which trans-activate TRPA1 on mouse and human DRG sensory neurons via cysteine modification of the channel. Our study thus identifies a translatable immune cell-tosensory neuron signaling crosstalk underlying peripheral nociceptor sensitization. This form of cell-to-cell signaling represents a critical peripheral mechanism for chronic pain and thus identifies multiple druggable analgesic targets.

AB - Injury, inflammation, and nerve damage initiate a wide variety of cellular and molecular processes that culminate in hyperexcitation of sensory nerves, which underlies chronic inflammatory and neuropathic pain. Using be avioral readouts of pain hypersensitivity induced by angiotensin II (Ang II) injection into mouse hindpaws, our study shows that activation of the type 2 Ang II receptor (AT2R) and the cell-damage-sensing ion channel TRPA1 are required for peripheral mechanical pain sensitization induced by Ang II in male and female mice. However, we show that AT2R is not expressed in mouse and human dorsal root ganglia (DRG) sensory neurons. Instead, expression/ activation of AT2R on peripheral/skin macrophages (Mɸs) constitutes a critical trigger of mouse and human DRG sensory neuron excitation. Ang II-induced peripheral mechanical pain hypersensitivity can be atten ated by chemogenetic depletion of peripheralM_s. Furthermore, AT2R activation in Mɸs triggers production of reactive oxygen/nitrogen species, which trans-activate TRPA1 on mouse and human DRG sensory neurons via cysteine modification of the channel. Our study thus identifies a translatable immune cell-tosensory neuron signaling crosstalk underlying peripheral nociceptor sensitization. This form of cell-to-cell signaling represents a critical peripheral mechanism for chronic pain and thus identifies multiple druggable analgesic targets.

KW - AT2R

KW - Angiotensin II

KW - Neuroimmune interaction

KW - Oxidative stress

KW - Pain

KW - TRPA1

KW - pain

KW - HORMONE-RELATED PEPTIDE

KW - THERMAL HYPERALGESIA

KW - PROTEIN-KINASE

KW - TYPE-2 RECEPTOR

KW - neuroimmune interaction

KW - MECHANICAL HYPERSENSITIVITY

KW - NEUROPATHIC PAIN

KW - angiotensin II

KW - INFLAMMATORY PAIN

KW - VANILLOID RECEPTOR TRPV1

KW - ION CHANNELS

KW - UP-REGULATION

KW - oxidative stress

U2 - 10.1523/JNEUROSCI.3542-17.2018

DO - 10.1523/JNEUROSCI.3542-17.2018

M3 - Journal article

C2 - 29976627

VL - 38

SP - 7032

EP - 7057

JO - The Journal of neuroscience : the official journal of the Society for Neuroscience

JF - The Journal of neuroscience : the official journal of the Society for Neuroscience

SN - 0270-6474

IS - 32

ER -