RGD Reference Report - Down-Regulation of CXCL12/CXCR4 Expression Alleviates Ischemia-Reperfusion-Induced Inflammatory Pain via Inhibiting Glial TLR4 Activation in the Spinal Cord. - Rat Genome Database

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

Authors: Li, Xiao-Qian  Zhang, Zai-Li  Tan, Wen-Fei  Sun, Xi-Jia  Ma, Hong 
Citation: Li XQ, etal., PLoS One. 2016 Oct 19;11(10):e0163807. doi: 10.1371/journal.pone.0163807. eCollection 2016.
RGD ID: 12910551
Pubmed: PMID:27760212   (View Abstract at PubMed)
PMCID: PMC5070836   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pone.0163807   (Journal Full-text)

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-1ß 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.



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Gene Ontology Annotations    Click to see Annotation Detail View

Objects Annotated

Genes (Rattus norvegicus)
Cxcl12  (C-X-C motif chemokine ligand 12)
Cxcr4  (C-X-C motif chemokine receptor 4)
Tlr4  (toll-like receptor 4)

Genes (Mus musculus)
Cxcl12  (C-X-C motif chemokine ligand 12)
Cxcr4  (C-X-C motif chemokine receptor 4)
Tlr4  (toll-like receptor 4)

Genes (Homo sapiens)
CXCL12  (C-X-C motif chemokine ligand 12)
CXCR4  (C-X-C motif chemokine receptor 4)
TLR4  (toll like receptor 4)


Additional Information