Antibody Receptor Signaling from Spinal Cord Astrocytes Promotes Neuropathic Pain

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      Injury to somatosensory nerves can lead to mechanical allodynia, in which normally innocuous touch is perceived as painful. Inflammatory signaling arising from spinal cord glial cells are thought to promote allodynia, but it is unclear what mechanisms control glial activation after injury. Here we demonstrate that Fc gamma receptor IIa (FcγRIIa), an immune receptor for immunoglobulin G (IgG) antibodies, is expressed by astrocytes in the spinal cord and contributes to the development of mechanical allodynia after neuropathic injury. Neuropathic pain in male and female rats was induced by chronic constriction injury (CCI) of the sciatic nerve. Paw withdrawal to innocuous touch was measured by von Frey filaments and paintbrush assay. Intrathecal injections of IgG immune complex (IgG-IC) were used to activate spinal FcγRs. Viral-mediated CRISPR-Cas9 gene editing was used to disrupt Fcgr2a expression in Gfap+ spinal astrocytes in vivo. Gene and protein expression were measured by in situ hybridization, qRT-PCR, and immunohistochemistry. For in vitro experiments, astrocytes were purified by immunopanning and treated with IgG-IC. Activating FcγRs by spinal administration of IgG-IC produces mechanical allodynia. Fcgr2a RNA expression increases specifically in ipsilateral spinal dorsal horn after CCI, and FcγRIIa protein co-localizes primarily with GFAP+ astrocytes. Genetic disruption of Fcgr2a in Gfap+ spinal astrocytes attenuates mechanical allodynia after CCI. Astrocytes respond to IgG-IC by increasing production of pro-inflammatory mediators, including TNF and IL-1β, which are known to influence nociceptor activity. These data suggest FcγRIIa on spinal astrocytes may be activated following peripheral nerve injury and directly contribute to injury-induced tactile pain. These findings expand our understanding of how neuroimmune signaling from glia contribute to the development of mechanical allodynia and suggest that reducing autoantibody IgG signaling at glial FcγRs could be a novel therapeutic target to alleviate suffering from neuropathic pain. Grant support from U.S. Army Medical Research and Materiel Command grants W81XWH-19-1-0160 and W81XWH-16-1-0717 (PMG) Rita Allen Foundation Award in Pain (PMG) University of Texas System Rising STARs Award (PMG) University of Texas MD Anderson Cancer Center start-up funds (PMG) American Australian Association Sir Keith Murdoch Fellowship (MJL).
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