GT1b functions as a novel endogenous agonist of toll‐like receptor 2 inducing neuropathic pain. (6th February 2020)

• Record Type: Journal Article
• Authors: Lim, Hyoungsub; Lee, Jaesung; You, Byunghyun; Oh, Jae Hoon; Mok, Hyuck Jun; Kim, Yoo Sung; Yoon, Bo‐Eun; Kim, Byung Gon; Back, Seung Keun; Park, Jong‐Sang; Kim, Kwang Pyo; Schnaar, Ronald L; Lee, Sung Joong
• Is Part Of: EMBO journal. Volume 39:Number 6(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-02-06
• Subjects: ganglioside -- microglia -- neuropathic pain -- St3gal2 -- toll‐like receptor 2; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2019102214
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: Spinal cord microglia contribute to nerve injury‐induced neuropathic pain. We have previously demonstrated that toll‐like receptor 2 (TLR2) signaling is critical for nerve injury‐induced activation of spinal cord microglia, but the responsible endogenous TLR2 agonist has not been identified. Here, we show that nerve injury‐induced upregulation of sialyltransferase St3gal2 in sensory neurons leads to an increase in expression of the sialylated glycosphingolipid, GT1b. GT1b ganglioside is axonally transported to the spinal cord dorsal horn and contributes to characteristics of neuropathic pain such as mechanical and thermal hypersensitivity. Spinal cord GT1b functions as an TLR2 agonist and induces proinflammatory microglia activation and central sensitization. Pharmacological inhibition of GT1b synthesis attenuates nerve injury‐induced spinal cord microglia activation and pain hypersensitivity. Thus, the St3gal2 ‐GT1b‐TLR2 axis may offer a novel therapeutic target for the treatment of neuropathic pain. Synopsis: Peripheral nerve injury upregulates GT1b in the injured sensory neurons, which is released in the spinal cord and functions as an endogenous agonist of microglial TLR2. Nerve injury upregulates St3gal2 and subsequent GT1b synthesis in injured DRG neurons. GT1b functions as an endogenous agonist of TLR2 to activate microglia. Antagonizing St3gal2 ‐GT1b‐TLR2 signaling attenuates neuropathic pain. Abstract : Upregulation of the sialyated glycosphingolipid GT1b in sensory neurons after peripheral nerve injury leads to TLR‐2 mediated microglia activation and nerve injury‐induced neuropathic pain.