Mounting evidences suggests that cancers such as melanoma produce programmed death protein-1 ligand 1 (PD-L1) to suppress T cell activation and immunity via interaction with PD-1 (receptor of PD-L1). Emerging immune therapies such as anti-PD1 and anti-PD-L1 treatments have shown great success in treating cancers, such as melanoma and head and neck cancers. However, the unique role of PD-L1/PD-1 in pain regulation is unknown. Our work in progress has demonstrated the presence of anatomical and functional PD-1 in primary sensory neurons and identified PD-L1 as a novel pain inhibitor, produced not only by cancer cells but also by normal neural tissues. We hypothesize that PD-L1 masks cancer pain and inhibits baseline pain and neuropathic pain via silencing PD-1 expressing nociceptive neurons. We also hypothesize that PD-L1 can inhibit somatic and trigeminal neuropathic pain via suppressing microglial and T-cell activation in the spinal cord and brain stem. Of interest recent studies have shown that microglia and T cells in the spinal cord contribute to neuropathic pain in a sex-dependent manner. Consistently, our pilot study shows that intrathecal inhibition of caspase-6 and p38 signaling inhibits nerve injury-induced mechanical allodynia in male but not female mice. We further hypothesize that PD-L1 inhibits microglial and T-cell activation in a sex-dependent manner. The overall goal of this application is to investigate how the PD-L1/PD-1 pathway can mask cancer pain and also suppress neuropathic pain via regulating the function of neurons, microglia, and T-cells. We will use mouse melanoma and neuropathic pain models of both sexes to test our hypotheses by accomplishing the following 3 specific aims:
Aim 1. Test the hypothesis that the PD-L1/PD-1 pathway can mask skin cancer pain, suppress somatic and trigeminal neuropathic pain, and inhibit baseline pain;
Aim 2. Test the hypothesis that activation of the PD- L1/PD-1 pathway can suppress neuronal excitability in mouse and human DRG/TG neurons and inhibit synaptic plasticity in mouse spinal cord neurons;
Aim 3. Test the hypothesis that the PD-L1/PD-1 pathway can inhibit pain via suppressing microglial and T-cell activation in a sex-dependent manner. This project will identify PD-L1 as a novel endogenous pain inhibitor and provide new insights into neuron-glia, neuron-immune, and neuron- cancer interactions. Manipulation of PD-L1/PD-1 signaling may lead to the development of novel analgesics.
Emerging immune therapies such as anti-PD-L1 (programmed death-ligand 1) and anti-PD-1 treatments have shown great efficacy in treating cancers; however, the unique role of PD-L1 and PD-1 in pain regulation is unknown. The overall goal of this application is to investigate how the PD-L1/PD-1 pathway can mask cancer pain in a melanoma model and also suppress neuropathic pain in somatic and trigeminal regions via neuron-glia, neuron-cancer, and neuron-immune interactions, and furthermore, to define the sex-dependent effects by testing both sexes. This project will identify PD-L1 as a novel endogenous pain inhibitor and provide new insights into neuron-glia, neuron-immune, and neuron-cancer interactions.
|Chen, Gang; Luo, Xin; Qadri, M Yawar et al. (2018) Sex-Dependent Glial Signaling in Pathological Pain: Distinct Roles of Spinal Microglia and Astrocytes. Neurosci Bull 34:98-108|
|Chang, Wonseok; Berta, Temugin; Kim, Yong Ho et al. (2018) Expression and Role of Voltage-Gated Sodium Channels in Human Dorsal Root Ganglion Neurons with Special Focus on Nav1.7, Species Differences, and Regulation by Paclitaxel. Neurosci Bull 34:4-12|
|Luo, Xin; Fitzsimmons, Bethany; Mohan, Apoorva et al. (2018) Intrathecal administration of antisense oligonucleotide against p38? but not p38? MAP kinase isoform reduces neuropathic and postoperative pain and TLR4-induced pain in male mice. Brain Behav Immun 72:34-44|
|Xie, Rou-Gang; Gao, Yong-Jing; Park, Chul-Kyu et al. (2018) Spinal CCL2 Promotes Central Sensitization, Long-Term Potentiation, and Inflammatory Pain via CCR2: Further Insights into Molecular, Synaptic, and Cellular Mechanisms. Neurosci Bull 34:13-21|
|Ji, Ru-Rong; Nackley, Andrea; Huh, Yul et al. (2018) Neuroinflammation and Central Sensitization in Chronic and Widespread Pain. Anesthesiology 129:343-366|
|Ji, Ru-Rong (2018) Recent Progress in Understanding the Mechanisms of Pain and Itch: the Second Special Issue. Neurosci Bull 34:1-3|
|Chen, Gang; Zhang, Yu-Qiu; Qadri, Yawar J et al. (2018) Microglia in Pain: Detrimental and Protective Roles in Pathogenesis and Resolution of Pain. Neuron 100:1292-1311|
|Zhang, Linlin; Terrando, Niccolò; Xu, Zhen-Zhong et al. (2018) Distinct Analgesic Actions of DHA and DHA-Derived Specialized Pro-Resolving Mediators on Post-operative Pain After Bone Fracture in Mice. Front Pharmacol 9:412|
|Chamessian, Alexander; Young, Michael; Qadri, Yawar et al. (2018) Transcriptional Profiling of Somatostatin Interneurons in the Spinal Dorsal Horn. Sci Rep 8:6809|
|Han, Qingjian; Liu, Di; Convertino, Marino et al. (2018) miRNA-711 Binds and Activates TRPA1 Extracellularly to Evoke Acute and Chronic Pruritus. Neuron 99:449-463.e6|
Showing the most recent 10 out of 88 publications