Macrophage-to-sensory neuron crosstalk mediated by Angiotensin II type-2 receptor elicits neuropathic pain

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Krause, Eric ; Shepherd, Andrew ; Mickle, Aaron ; Copits, Bryan ; Karlsson, Pall ; Kadunganattil, Suraj ; Golden, Judith ; Tadinada, Satya ; Mack, Madison ; Haroutounian, Simon ; De Kloet, Annette ; Samineni, Vijay ; Valtcheva, Manouela ; Mcilvried, Lisa ; Sheahan, Tayler ; Jain, Sanjay ; Ray, Pradipta ; Usachev, Yuriy ; Dussor, Gregory ; Kim, Brian ; Price, Theodore ; Gereau, Robert ; Mohapatra, Durga (2017)

Peripheral nerve damage initiates a complex series of cellular and structural processes that culminate in chronic neuropathic pain. Our study defines local angiotensin signaling via activation of the Angiotensin II (Ang II) type-2 receptor (AT2R) on macrophages as the critical trigger of neuropathic pain. An AT2R-selective antagonist attenuates neuropathic, but not inflammatory pain hypersensitivity in mice, and requires the cell damage-sensing ion channel transient receptor potential family-A member-1 (TRPA1). Mechanical and cold pain hypersensitivity that are characteristic of neuropathic conditions can be attenuated by chemogenetic depletion of peripheral macrophages and AT2R-null hematopoietic cell transplantation. Our findings show no AT2R expression in mouse or human sensory neurons, rather AT2R expression and activation in macrophages triggers production of reactive oxygen/nitrogen species, which trans-activate TRPA1 on sensory neurons. Our study defines the precise neuro-immune crosstalk underlying nociceptor sensitization at the site of nerve injury. This form of cell-to-cell signaling represents a critical peripheral mechanism for chronic neuropathic pain, and therefore identifies multiple analgesic targets.