Páll Karlsson

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

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

  • Andrew J Shepherd, Department of Pharmacology, The University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
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  • Bryan A Copits, Department of Anesthesiology and Washington University Pain Center, Washington University School of Medicine in St. Louis, MO, 63110, USA.
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  • Aaron D Mickle, Department of Pharmacology, The University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
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  • Páll Karlsson
  • Suraj Kadunganattil, Department of Anesthesiology and Washington University Pain Center, Washington University School of Medicine in St. Louis, MO, 63110, USA.
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  • Simon Haroutounian, Department of Anesthesiology and Washington University Pain Center, Washington University School of Medicine in St. Louis, MO, 63110, USA.
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  • Satya M Tadinada, Department of Pharmacology, The University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
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  • Annette D de Kloet, Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL, 32610, USA.
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  • Manouela V Valtcheva, Department of Anesthesiology and Washington University Pain Center, Washington University School of Medicine in St. Louis, MO, 63110, USA.
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  • Lisa A McIlvried, Department of Anesthesiology and Washington University Pain Center, Washington University School of Medicine in St. Louis, MO, 63110, USA.
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  • Tayler D Sheahan, Department of Anesthesiology and Washington University Pain Center, Washington University School of Medicine in St. Louis, MO, 63110, USA.
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  • Sanjay Jain, Departments of Medicine, Pathology and Immunology, Washington University School of Medicine in St. Louis, MO, 63110, USA.
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  • Pradipta R Ray, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, 75080, USA.
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  • Yuriy M Usachev, Department of Pharmacology, The University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
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  • Gregory Dussor, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, 75080, USA.
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  • Eric G Krause, Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA.
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  • Theodore J Price, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, 75080, USA.
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  • Robert W Gereau, Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine in St. Louis, MO, 63110, USA.
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  • Durga P Mohapatra, Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine in St. Louis, MO, 63110, USA.

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.

OriginalsprogEngelsk
TidsskriftThe Journal of neuroscience : the official journal of the Society for Neuroscience
Vol/bind38
Nummer32
Sider (fra-til)7032-7057
Antal sider26
ISSN0270-6474
DOI
StatusUdgivet - 8 aug. 2018

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