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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.
Pubmed ID: 29976627 RIS Download
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View all literature mentionsMus musculus with name C57BL/6J from IMSR.
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View all literature mentionsThis monoclonal targets Mapk14
View all literature mentionsThis polyclonal targets GFP (FITC)
View all literature mentionsThis polyclonal targets p38 MAPK
View all literature mentionsThis monoclonal targets Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204) (E10) Mouse mAb
View all literature mentionsThis unknown targets IgG1
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
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View all literature mentionsThis monoclonal targets CD68
View all literature mentionsThis monoclonal targets GFP
View all literature mentionsThis monoclonal targets F4/80
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View all literature mentionsThis polyclonal secondary targets IgG
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View all literature mentionsThis polyclonal targets donkey anti-goat IgG-HRP
View all literature mentionsThis polyclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsThis monoclonal targets Neurofilament 200 (Phos. and Non-Phos.) antibody produced in mouse
View all literature mentionsThis monoclonal targets Ly6g
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View all literature mentionsThis polyclonal targets AT2 (C-18)
View all literature mentionsCell line U-937 is a Cancer cell line with a species of origin Homo sapiens (Human)
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View all literature mentionsAllele Detail: QTL This is a legacy resource.
View all literature mentionsAllele Detail: Targeted This is a legacy resource.
View all literature mentionsMus musculus with name C57BL/6J from IMSR.
View all literature mentionsThis polyclonal targets Angiotensin II Type 2 Receptor antibody
View all literature mentionsCell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line J774A1 is a Cancer cell line with a species of origin Mus musculus
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