Sparcl1/Hevin drives pathological pain through spinal cord astrocyte and NMDA receptor signaling.
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2022-10
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Abstract
Hevin/Sparcl1 is an astrocyte-secreted protein and regulates synapse formation. Here we show that astrocytic hevin signaling plays a critical role in maintaining chronic pain. Compared to wild-type mice, hevin-null mice exhibited normal mechanical and heat sensitivity but reduced inflammatory pain. Interestingly, hevin-null mice have faster recovery than wild-type mice from neuropathic pain after nerve injury. Intrathecal injection of wild-type hevin was sufficient to induce persistent mechanical allodynia in naïve mice. In hevin-null mice with nerve injury, AAV-mediated re-expression of hevin in GFAP-expressing spinal cord astrocytes could reinstate neuropathic pain. Mechanistically, hevin is crucial for spinal cord NMDA receptor (NMDAR) signaling. Hevin potentiated NMDA currents mediated by the GluN2B-containing NMDARs. Furthermore, intrathecal injection of a neutralizing antibody against hevin alleviated acute and persistent inflammatory pain, postoperative pain, and neuropathic pain. Secreted hevin was detected in mouse cerebrospinal fluid (CSF) and nerve injury significantly increased CSF hevin abundance. Finally, neurosurgery caused rapid and substantial increases in SPARCL1/HEVIN levels in human CSF. Collectively, our findings support a critical role of hevin and astrocytes in the maintenance of chronic pain. Neutralizing of secreted hevin with monoclonal antibody may provide a new therapeutic strategy for treating acute and chronic pain and NMDAR-medicated neurodegeneration.
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Chen, Gang, Jing Xu, Hao Luo, Xin Luo, Sandeep K Singh, Juan J Ramirez, Michael L James, Joseph P Mathew, et al. (2022). Sparcl1/Hevin drives pathological pain through spinal cord astrocyte and NMDA receptor signaling. JCI insight. p. e161028. 10.1172/jci.insight.161028 Retrieved from https://hdl.handle.net/10161/26120.
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Scholars@Duke
Michael Lucas James
With a clinical background in neuroanesthesia and neurointensive care, I have a special interest in translational research in intracerebral hemorrhage and traumatic brain injury. I am fortunate to be part of a unique team of highly motivated and productive individuals who allow me to propel ideas from bench to bedside and the ability to reverse translate ideas from the bedside back to the bench.
Joseph P. Mathew
Current research interests include:
1. The relationship between white matter patency, functional connectivity (fMRI) and neurocognitive function following cardiac surgery.
2. The relationship between global and regional cortical beta-amyloid deposition and postoperative cognitive decline.
3. The effect of lidocaine infusion upon neurocognitive function following cardiac surgery.
4. The association between genotype and outcome after cardiac surgery.
5. Atrial fibrillation following cardiopulmonary bypass.
Cagla Eroglu
Ru-Rong Ji
I have been doing neuroscience and pain research for over 25 years in multiple academic institutes, including Duke University (2012-current), Harvard Medical School (1998-2012), Johns Hopkins Medical School, Karolinska Institute, and Peking University. The long-term goal of my lab is to identify molecular and cellular mechanisms that underlie the induction and resolution of pathological pain and develop novel pain therapeutics that can target these mechanisms, with specific focus on neuroimmune interactions. We are interested in the following scientific questions. (1) How does inflammation induce and resolve pain via immune cell interaction with primary sensory neurons? (2) How does neuroinflammation drive chronic pain via activation of glial cells in the CNS (microglia and astrocytes) and PNS (satellite glial cells) and regulation of sensory neuron plasticity (peripheral sensitization) and spinal cord synaptic plasticity (central sensitization)? (3) How do specialized pro-resolution mediators (SPMs, e.g., resolvins, protectins, and maresins) control pain via GPCR signaling? (4) How do immunotherapies through the PD-L1/PD-1 and STING/IFN pathways regulate pain, cognition, and neuronal activities? (5) How do secreted miRNAs regulate pain and itch via direct activation of surface receptors and ion channels? (6) How do nerve terminals interact with cancers in chronic pain and itch? (7) How do Toll-like receptors (TLR) in primary sensory neurons sense danger signals and regulate pain and itch? (8) How do regenerative approaches such as autologous conditioned serum (ACS) and bone marrow stromal cells (MSCs) produce long-term pain relief via secreting anti-inflammatory factors and exosomes? We employ a multidisciplinary approach that covers in vitro, ex vivo, and in vivo studies for animal behaviors, electrophysiology, molecular biology, cell biology, and transgenic animals. We have identified numerous therapeutic targets and filed many patents for translational studies. As the Director of the Center for Translational Pain Medicine (CTPM) and a highly cited researcher (Cross Field, Clarivate), I have both administrative and scientific leadership for successful completion of many research projects.
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