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

Andrew J. Shepherd, Bryan A. Copits, Aaron D. Mickle, Páll Karlsson, Suraj Kadunganattil, Simon Haroutounian, Satya M. Tadinada, Annette D. De Kloet, Manouela V. Valtcheva, Lisa A. McIlvried, Tayler D. Sheahan, Sanjay Jain, Pradipta R. Ray, Yuriy M. Usachev, Gregory Dussor, Eric G. Krause, Theodore J. Price, Robert W. Gereau, Durga P. Mohapatra

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


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.

Original languageEnglish
Pages (from-to)7032-7057
Number of pages26
JournalJournal of Neuroscience
Issue number32
StatePublished - Aug 8 2018


  • AT2R
  • Angiotensin II
  • Neuroimmune interaction
  • Oxidative stress
  • Pain
  • TRPA1


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