PT  - JOURNAL ARTICLE
AU  - Andrew J. Shepherd
AU  - Bryan A. Copits
AU  - Aaron D. Mickle
AU  - Páll Karlsson
AU  - Suraj Kadunganattil
AU  - Simon Haroutounian
AU  - Satya M. Tadinada
AU  - Annette D. de Kloet
AU  - Manouela V. Valtcheva
AU  - Lisa A. McIlvried
AU  - Tayler D. Sheahan
AU  - Sanjay Jain
AU  - Pradipta R. Ray
AU  - Yuriy M. Usachev
AU  - Gregory Dussor
AU  - Eric G. Krause
AU  - Theodore J. Price
AU  - Robert W. Gereau IV
AU  - Durga P. Mohapatra
TI  - Angiotensin II Triggers Peripheral Macrophage-to-Sensory Neuron Redox Crosstalk to Elicit Pain
AID  - 10.1523/JNEUROSCI.3542-17.2018
DP  - 2018 Aug 08
TA  - The Journal of Neuroscience
PG  - 7032--7057
VI  - 38
IP  - 32
4099  - http://www.jneurosci.org/content/38/32/7032.short
4100  - http://www.jneurosci.org/content/38/32/7032.full
SO  - J. Neurosci.2018 Aug 08; 38
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 behavioral 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 (MΦs) constitutes a critical trigger of mouse and human DRG sensory neuron excitation. Ang II-induced peripheral mechanical pain hypersensitivity can be attenuated by chemogenetic depletion of peripheral MΦs. Furthermore, AT2R activation in MΦs 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-to-sensory 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.SIGNIFICANCE STATEMENT Pain is a widespread health problem that is undermanaged by currently available analgesics. Findings from a recent clinical trial on a type II angiotensin II receptor (AT2R) antagonist showed effective analgesia for neuropathic pain. AT2R antagonists have been shown to reduce neuropathy-, inflammation- and bone cancer-associated pain in rodents. We report that activation of AT2R in macrophages (MΦs) that infiltrate the site of injury, but not in sensory neurons, triggers an intercellular redox communication with sensory neurons via activation of the cell damage/pain-sensing ion channel TRPA1. This MΦ-to-sensory neuron crosstalk results in peripheral pain sensitization. Our findings provide an evidence-based mechanism underlying the analgesic action of AT2R antagonists, which could accelerate the development of efficacious non-opioid analgesic drugs for multiple pain conditions.