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- Title
Angiotensin II Triggers Peripheral Macrophage-to-Sensory Neuron Redox Crosstalk to Elicit Pain.
- Authors
Shepherd, Andrew J.; Copits, Bryan A.; Mickle, Aaron D.; Karlsson, Páll; Kadunganattil, Suraj; Haroutounian, Simon; Tadinada, Satya M.; de Kloet, Annette D.; Valtcheva, Manouela V.; McIlvried, Lisa A.; Sheahan, Tayler D.; Jain, Sanjay; Ray, Pradipta R.; Usachev, Yuriy M.; Dussor, Gregory; Krause, Eric G.; Price, Theodore J.; Gereau, Robert W.; Mohapatra, Durga P.
- Abstract
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.
- Subjects
ALLERGIES; SENSORY receptors; ANGIOTENSIN II; INFLAMMATION; GANGLIA
- Publication
Journal of Neuroscience, 2018, Vol 38, Issue 32, p7032
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.3542-17.2018