Neuronal Injury Induces Cytokine-Induced Neutrophil Chemoattractant-1 (CINC-1) Production in Astrocytes

Cao

et al. 2013

Pain

217

248

Recent studies have indicated an important role of chemokines such as CCL2 in the development of chronic pain. However, the distinct roles of different chemokines in the development and maintenance of neuropathic pain and in their interactions with neurons have not been clearly elucidated. We found that spinal nerve ligation (SNL) not only induced persistent neuropathic pain symptoms including mechanical allodynia and heat hyperalgesia but also produced sustained CXCL1 upregulation in the spinal cord. Double staining of immunofluorescence and in situ hybridization revealed that CXCL1 was primarily induced in spinal astrocytes. In cultured astrocytes, TNF-α induced robust CXCL1 expression, via the activation of the c-jun N-terminal kinase (JNK). Intrathecal administration of CXCL1 neutralizing antibody transiently reduced SNL-induced pain hypersensitivity, suggesting an essential role of CXCL1 in neuropathic pain sensitization. In particular, intraspinal delivery of CXCL1 shRNA lentiviral vectors, either before or after SNL, persistently attenuated SNL-induced pain hypersensitivity. Spinal application of CXCL1 not only elicited pain hypersensitivity but also induced rapid neuronal activation, as indicated by the expression of phosphorylated ERK and CREB (pERK and pCREB) and c-Fos in spinal cord neurons. Interestingly, CXCR2, the primary receptor of CXCL1, was upregulated in dorsal horn neurons after SNL, and the CXCR2 antagonist SB225002 completely blocked the CXCL1-induced heat hyperalgesia. SB225002 also attenuated SNL-induced pain hypersensitivity. Collectively, our results have demonstrated a novel form of chemokine-mediated glial-neuronal interaction in the spinal cord that can drive neuropathic pain. Inhibition of the CXCL1-CXCR2 signaling may offer a new therapy for neuropathic pain management.

Section: Discussionmentioning

confidence: 99%

Chemokine contribution to neuropathic pain: Respective induction of CXCL1 and CXCR2 in spinal cord astrocytes and neurons

Cao

et al. 2013

Pain

217

248

“…CINC1 is produced by astrocytes in response to various noxious stimuli, including oxidative stress (68). Elevated serum levels of fibrinogen, a plasma glycoprotein, are another indication of altered microcirculation and inflammation; increased levels of fibrinogen can increase blood viscosity as well as vascular permeability (69, 70).…”

Section: Discussionmentioning

confidence: 99%

The Temporal Pattern of Changes in Serum Biomarker Levels Reveals Complex and Dynamically Changing Pathologies after Exposure to a Single Low-Intensity Blast in Mice

et al. 2015

Time-dependent changes in blood-based protein biomarkers can help identify the pathological processes in blast-induced traumatic brain injury (bTBI), assess injury severity, and monitor disease progression. We obtained blood from control and injured mice (exposed to a single, low-intensity blast) at 2-h, 1-day, 1–week, and 1-month post-injury. We then determined the serum levels of biomarkers related to metabolism (4-HNE, HIF-1α, ceruloplasmin), vascular function (AQP1, AQP4, VEGF, vWF, Flk-1), inflammation (OPN, CINC1, fibrinogen, MIP-1a, OX-44, p38, MMP-8, MCP-1 CCR5, CRP, galectin-1), cell adhesion and the extracellular matrix (integrin α6, TIMP1, TIMP4, Ncad, connexin-43), and axonal (NF-H, Tau), neuronal (NSE, CK-BB) and glial damage (GFAP, S100β, MBP) at various post-injury time points. Our findings indicate that the exposure to a single, low-intensity blast results in metabolic and vascular changes, altered cell adhesion, and axonal and neuronal injury in the mouse model of bTBI. Interestingly, serum levels of several inflammatory and astroglial markers were either unchanged or elevated only during the acute and subacute phases of injury. Conversely, serum levels of the majority of biomarkers related to metabolic and vascular functions, cell adhesion, as well as neuronal and axonal damage remained elevated at the termination of the experiment (1 month), indicating long-term systemic and cerebral alterations due to blast. Our findings show that the exposure to a single, low-intensity blast induces complex pathological processes with distinct temporal profiles. Hence, monitoring serum biomarker levels at various post-injury time points may provide enhanced diagnostics in blast-related neurological and multi-system deficits.

“…Pineau et al reported that CXCL1 mRNA is upregulated in spinal astrocytes after spinal cord injury in mice (Pineau et al, 2010). CXCL1 is also induced in brain astrocytes by neuronal injury and intracerebroventricular administration of endothelin-1 (Katayama et al, 2009; Koyama et al, 2007). In humans, CXCL1 is selectively expressed in hypertropic astrocytes after active multiple sclerosis lesions (Omari et al, 2006; Omari et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Chemokine CXCL1 enhances inflammatory pain and increases NMDA receptor activity and COX-2 expression in spinal cord neurons via activation of CXCR2

Cao

Xie

et al. 2014

Experimental Neurology

111

Recent studies have shown that CXCL1 upregulation in spinal astrocytes is involved in the maintenance of neuropathic pain. However, whether and how CXCL1 regulates inflammatory pain remains unknown. Here we show that intraplantar injection of CFA increased mRNA and protein expressions of CXCL1 and its major receptor CXCR2 in the spinal cord at 6 hours and 3 days after the injection. Immunofluorescence double staining showed that CXCL1 and CXCR2 were expressed in spinal astrocytes and neurons, respectively. Intrathecal injection of CXCL1 neutralizing antibody or CXCR2 antagonist SB225002 attenuated CFA-induced mechanical and heat hypersensitivity on post-CFA day 3. Patch-clamp recordings showed that CXCL1 potentiated NMDA-induced currents in lamina II neurons via CXCR2, and this potentiation was further increased in CFA-treated mice. Furthermore, intrathecal injection of CXCL1 increased COX-2 expression in dorsal horn neurons, which was blocked by pretreatment with SB225002 or MEK (ERK kinase) inhibitor PD98059. Finally, pretreatment with SB225002 or PD98059 decreased CFA-induced heat hyperalgesia and COX-2 mRNA/protein expression and ERK activation in the spinal cord. Taken together, our data suggest that CXCL1, upregulated and released by spinal astrocytes after inflammation, acts on CXCR2-expressing spinal neurons to increase ERK activation, synaptic transmission and COX-2 expression in dorsal horn neurons and contributes to the pathogenesis of inflammatory pain.