Abstract
Spinal cord injury (SCI) causes loss of normal sensation and often leads to debilitating neuropathic pain (NeP). Chronic NeP develops at or below the SCI lesion in as many as 80% of patients with SCI and may be induced by modulators of neuronal excitability released from activated microglia and macrophages. In the inflammatory response after SCI, different microglia/macrophage populations that are classically activated (M1 phenotype) or alternatively activated (M2 phenotype) have become of great interest. Chemokines have also recently attracted attention in neuron-microglia communication. CCL21 is a chemokine that activates microglia in the central nervous system (CNS) and is expressed only in neurons with an insult or mechanical injury. In this study using an SCI model in mutant (plt) mice with deficient CCL21 expression, we assessed post-SCI NeP and expression of microglia/macrophages and inflammatory cytokines at the injured site and lumbar enlargement. SCI-induced hypersensitivities to mechanical and thermal stimulation were relieved in plt mice compared with those in wild-type (C57BL/6) mice, although there was no difference in motor function. Immunohistochemistry and flow cytometry analysis showed that the phenotype of microglia/macrophages was M1 type-dominant in both types of mice at the lesion site and lumbar enlargement. A decrease of M1-type microglia/macrophages was seen in plt mice compared with wild-type, while the number of M2-type microglia/macrophages did not differ between these mice. In immunoblot analysis, expression of M1-induced cytokines [tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ)] was decreased in plt mice, while that of M2-induced cytokines interleukin-4 (IL-4, IL-10) did not differ in the two types of mice. The results of this study indicate that suppression of expression of inflammatory cytokines by decreasing the number of M1-type microglia/macrophages at the injured site and lumbar enlargement is associated with provision of an environment for reduction of NeP. These findings may be useful for the design of new therapies to alleviate NeP after SCI.
Highlights
The International Association for the Study of Pain defines neuropathic pain (NeP) as that associated with anatomical or functional abnormalities of the nervous system (Merskey and Bogduk, 1994)
In a peripheral nerve injury model, CCL21 is only expressed in damaged neurons and induces upregulation of the P2X4 receptor in microglia and macrophages. These P2X4 receptor-expressing cells are activated by adenosine triphosphate (ATP) and release pain-related factors such as brain-derived neurotrophic factors (BDNF) and/or inflammatory cytokines such as tumor necrosis factor-α (TNF-α), IFNγ, and IL-6; and these events promote NeP after Spinal cord injury (SCI) (Figure 1; Biber et al, 2011; Tsuda et al, 2013). These findings indicate that CCL21 has a specific role in neuronmicroglia/macrophage communication and is a potential drug target for prevention of NeP
In NeP after SCI, CCL21 is secreted from damaged neurons and induces P2X4 receptor upregulation in microglia activated by extracellular ATP released from dying cells
Summary
The International Association for the Study of Pain defines neuropathic pain (NeP) as that associated with anatomical or functional abnormalities of the nervous system (Merskey and Bogduk, 1994). Pain at the level of the spinal segment occurs in 37–50% of these patients, while 76–83% have pain below the lesion level (Ravenscroft et al, 2000; Turner et al, 2001; Siddall et al, 2003; Calmels et al, 2009; Jensen and Finnerup, 2014; Nagoshi et al, 2016). These symptoms are associated with significant impairment in health-related quality of life (Woolf and Mannion, 1999; Jensen et al, 2008; Doth et al, 2010; Finnerup et al, 2015; Inoue et al, 2017; Nakajima et al, 2019), but current medications are often ineffective for NeP after SCI. The M2 phenotype is activated via T helper 2 (Th2) cytokines, such as interleukin (IL)-4 and IL-10 (Kigerl et al, 2009; Gordon and Martinez, 2010)
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