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Angiotensin II Triggers Peripheral Macrophage-to-Sensory Neuron Redox Crosstalk to Elicit Pain. J Neurosci 2018 Aug 08;38(32):7032-7057

Date

07/07/2018

Pubmed ID

29976627

Pubmed Central ID

PMC6083458

DOI

10.1523/JNEUROSCI.3542-17.2018

Scopus ID

2-s2.0-85051586513 (requires institutional sign-in at Scopus site)   84 Citations

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.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.

Author List

Shepherd AJ, Copits BA, Mickle AD, Karlsson P, Kadunganattil S, Haroutounian S, Tadinada SM, de Kloet AD, Valtcheva MV, McIlvried LA, Sheahan TD, Jain S, Ray PR, Usachev YM, Dussor G, Krause EG, Price TJ, Gereau RW 4th, Mohapatra DP

Author

Aaron D. Mickle PhD Associate Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Angiotensin II
Angiotensin Receptor Antagonists
Animals
Cell Communication
Cells, Cultured
Female
Ganglia, Spinal
Genes, Reporter
Humans
Hyperalgesia
Imidazoles
Macrophage Activation
Macrophages, Peritoneal
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Neuralgia
Neutrophil Activation
Oxidation-Reduction
Pyridines
Receptor, Angiotensin, Type 2
Sensory Receptor Cells
Skin
TRPA1 Cation Channel
Tacrolimus