Down-Regulation of CXCL12/CXCR4 Expression Alleviates Ischemia-Reperfusion-Induced Inflammatory Pain via Inhibiting Glial TLR4 Activation in the Spinal Cord

Autor: Xi-Jia Sun, Wen-Fei Tan, Zai-Li Zhang, Hong Ma, Xiao-Qian Li
Rok vydání: 2016
Předmět:
0301 basic medicine
Chemokine
Benzylamines
Macroglial Cells
Physiology
lcsh:Medicine
Pharmacology
Cyclams
Pathology and Laboratory Medicine
Nervous System
Immune Receptors
Biochemistry
Rats
Sprague-Dawley
Chemokine receptor
0302 clinical medicine
Heterocyclic Compounds
Animal Cells
Immune Physiology
Medicine and Health Sciences
Enzyme-Linked Immunoassays
lcsh:Science
Immune Response
Toll-like Receptors
Sulfonamides
Innate Immune System
Multidisciplinary
CXCR4 antagonist
Immune System Proteins
Microglia
biology
Behavior
Animal
Chemotaxis
Cell Motility
medicine.anatomical_structure
Spinal Cord
Hyperalgesia
Reperfusion Injury
Cytokines
medicine.symptom
Anatomy
Cellular Types
Chemokines
Research Article
Signal Transduction
Receptors
CXCR4
Immunology
Down-Regulation
Pain
Glial Cells
Research and Analysis Methods
Proinflammatory cytokine
03 medical and health sciences
Signs and Symptoms
Diagnostic Medicine
medicine
Animals
Immunoassays
Microglial Cells
Inflammation
business.industry
lcsh:R
Biology and Life Sciences
Proteins
Cell Biology
Molecular Development
Spinal cord
Chemokine CXCL12
Rats
Toll-Like Receptor 4
Neuroanatomy
030104 developmental biology
Astrocytes
Immune System
biology.protein
TLR4
Immunologic Techniques
lcsh:Q
business
030217 neurology & neurosurgery
Neuroscience
Developmental Biology
Zdroj: PLoS ONE
PLoS ONE, Vol 11, Iss 10, p e0163807 (2016)
ISSN: 1932-6203
Popis: Toll-like receptor 4 (TLR4) is important for the pathogenesis of inflammatory reactions and the promotion of pain processing after ischemia/reperfusion (IR) in spinal cord. Recently, C-X-C chemokine ligand 12 (CXCL12) and its receptor, C-X-C chemokine receptor 4 (CXCR4), were demonstrated to be simultaneously critical for inflammatory reactions, thereby facilitating glial activation. However, whether CXCL12/CXCR4 expression can contribute to IR-induced inflammatory pain via spinal TLR4 remained unclear. A rat model was established by 8 min of aortic arch occlusion. The effects of CXCL12/CXCR4 expression and TLR4 activation on inflammatory hyperalgesia were investigated by pretreatments with CXCL12-neutralizing antibody, CXCR4 antagonist (AMD3100) and TLR4 antagonist (TAK-242) for 5 consecutive days before surgery. The results indicated that IR induced significant and sustained inflammatory pain, observed as decreases in paw withdrawal threshold (PWT) and paw withdrawal latency (PWL), throughout the post-injury period. The increased levels of TLR4 and proinflammatory chemokine CXCL12, as well as its receptor, CXCR4, were closely correlated with the PWT and PWL trends. Double immunostaining further suggested that TLR4, which is mainly expressed on astrocytes and microglia, was closely co-localized with CXCL12 and CXCR4 in spinal dorsal horn. As expected, intrathecal pretreatment with the TLR4 antagonist, TAK-242 markedly ameliorated pain by inhibiting astrocytic and microglial activation, as shown by decreases in TLR4 immunoreactivity and the percentage of double-labeled cells. These protective effects were likely due in part to the reduced production of the downstream cytokines IL-1β and TNF-α, as well as for the recruitment of CXCL12 and CXCR4. Additionally, intrathecal pretreatment with CXCL12-neutralizing antibody and AMD3100 resulted in similar analgesic and anti-inflammatory effects as those receiving TAK-242 pretreatment. These results suggest that intrathecal blockade of CXCL12/CXCR4 expression may attenuate IR-induced pain sensation and the release of inflammatory cytokines by limiting glial TLR4 activation in spinal cord.
Databáze: OpenAIRE
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