Jing Li1, Shujuan Tian2, Hualong Wang1, Yanyong Wang1, Chongbo Du1, Jiyu Fang1, Xiaoxiao Wang3, Yufeng Wang4, Zhexuan Gong4, Baoyong Yan5, Mingwei Wang6. 1. Department of Neurology, the First Hospital of Hebei Medical University, Shijiazhuang, Hebei, China; Brain Aging and Cognitive Neuroscience Key Laboratory of Hebei Province, Shijiazhuang, Hebei, China. 2. Department of Neurology, the First Hospital of Hebei Medical University, Shijiazhuang, Hebei, China; Brain Aging and Cognitive Neuroscience Key Laboratory of Hebei Province, Shijiazhuang, Hebei, China. Electronic address: jtian72@126.com. 3. Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei, China. 4. Basic Medical College, Hebei Medical University, Shijiazhuang, Hebei, China. 5. Cell Therapy Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei, China. Electronic address: yanby7001@163.com. 6. Department of Neurology, the First Hospital of Hebei Medical University, Shijiazhuang, Hebei, China; Brain Aging and Cognitive Neuroscience Key Laboratory of Hebei Province, Shijiazhuang, Hebei, China. Electronic address: mingweiwang88@163.com.
Abstract
BACKGROUND: Hyperactivation of complement C3 and inflammation-related activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome are implicated in the etiology of stress-related disorders. Studies have shown that human umbilical cord mesenchymal stromal cells (hUC-MSCs) have immunomodulatory and anti-inflammatory effects; however, the mechanism remains unclear. METHODS: hUC-MSCs were administered to chronic unpredictable mild stress (CUMS) model mice once a week for four weeks. After the administration of hUC-MSCs, several parameters were assessed, including behavioral performance, synapse-related proteins, complement C3 receptors (C3aR) in neurons, and the NLRP3 inflammasome. Then, CUMS mice were injected with SB290157, a complement C3aR antagonist, and the behavioral index and NLRP3 inflammasome activation were tested. RESULTS: The open-field and forced swimming behavioral tests showed an improvement in depression-like behaviors in the CUMS-exposed mice after the administration of hUC-MSCs. Treatment with hUC-MSCs significantly decreased the neuronal C3aR levels and alleviated synaptic damage. Furthermore, the levels of the NLRP3 inflammasome and inflammatory factors were reduced after hUC-MSC administration. In particular, treatment with a C3aR antagonist also decreased NLRP3 inflammasome expression and inflammation, which was consistent with the observed improvements after hUC-MSC treatment. CONCLUSION: hUC-MSCs can attenuate NLRP3 activation in CUMS-induced mice, which may be correlated with C3aR in neurons.
BACKGROUND:Hyperactivation of complement C3 and inflammation-related activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome are implicated in the etiology of stress-related disorders. Studies have shown that human umbilical cord mesenchymal stromal cells (hUC-MSCs) have immunomodulatory and anti-inflammatory effects; however, the mechanism remains unclear. METHODS: hUC-MSCs were administered to chronic unpredictable mild stress (CUMS) model mice once a week for four weeks. After the administration of hUC-MSCs, several parameters were assessed, including behavioral performance, synapse-related proteins, complement C3 receptors (C3aR) in neurons, and the NLRP3 inflammasome. Then, CUMS mice were injected with SB290157, a complement C3aR antagonist, and the behavioral index and NLRP3 inflammasome activation were tested. RESULTS: The open-field and forced swimming behavioral tests showed an improvement in depression-like behaviors in the CUMS-exposed mice after the administration of hUC-MSCs. Treatment with hUC-MSCs significantly decreased the neuronal C3aR levels and alleviated synaptic damage. Furthermore, the levels of the NLRP3 inflammasome and inflammatory factors were reduced after hUC-MSC administration. In particular, treatment with a C3aR antagonist also decreased NLRP3 inflammasome expression and inflammation, which was consistent with the observed improvements after hUC-MSC treatment. CONCLUSION: hUC-MSCs can attenuate NLRP3 activation in CUMS-induced mice, which may be correlated with C3aR in neurons.