Epigenetic Augmentation of the Macrophage Inflammatory Protein 2/C-X-C Chemokine Receptor Type 2 Axis through Histone H3 Acetylation in Injured Peripheral Nerves Elicits Neuropathic Pain

Abstract

Although there is growing evidence showing that the involvement of chemokines in the pathogenesis of neuropathic pain is associated with neuroinflammation, the details are unclear. We investigated the C-X-C chemokine ligand type 2 [macrophage inflammatory protein 2 (MIP-2)]/C-X-C chemokine receptor type 2 (CXCR2) axis and epigenetic regulation of these molecules in neuropathic pain after peripheral nerve injury. Expression of MIP-2 and CXCR2 were up-regulated and localized on accumulated neutrophils and macrophages in the injured sciatic nerve (SCN) after partial sciatic nerve ligation (PSL). Perineural injection of MIP-2-neutralizing antibody (anti-MIP-2) or the CXCR2 antagonist N-(2-bromophenyl)-NЈ-(2-hydroxy-4-nitrophenyl)urea (SB225002) prevented PSL-induced tactile allodynia and thermal hyperalgesia. Perineural injection of recombinant MIP-2 elicited neuropathic pain-like behaviors. Anti-MIP-2 suppressed neutrophil accumulation in the SCN after PSL.Neutrophil depletion by intraperitoneal injection of Ly6G antibody attenuated PSL-induced neuropathic pain. Both anti-MIP-2 and SB225002 suppressed up-regulation of inflammatory cytokines and chemokines in the injured SCN. In addition, acetylation of histone H3 [lysine (Lys9)-acetylated histone H3 (AcK9-H3)] on the promoter region of MIP-2 and CXCR2 was increased in the injured SCN after PSL. Expression of AcK9-H3 was observed in the nuclei of neutrophils and macrophages surrounding the epineurium. Administration of the histone acetyltransferase inhibitor anacardic acid suppressed the up-regulation of MIP-2 and CXCR2 in the SCN after PSL and resulted in the prevention of PSL-induced neuropathic pain. Taken together, these results show that augmentation of the MIP-2/CXCR2 axis by hyperacetylation of histone H3 on the promoter region of MIP-2 and CXCR2 located in the injured peripheral nerve elicits chronic neuroinflammation through neutrophil accumulation, leading to neuropathic pain.

CC‐chemokine ligand 4/macrophage inflammatory protein‐1β participates in the induction of neuropathic pain after peripheral nerve injury

“…To eliminate the non-specific effects of immunoglobulin, normal goat IgG was used as a control for anti-MIP-1b. As also described in our previous report, normal IgG had no effect on PSL-induced neuropathic pain (Kiguchi et al, 2012). These results suggest that MIP-1b might enhance the development (early phase) but not the maintenance (late phase) of neuropathic pain.…”

“…In addition to MIP-1b, other chemokines contributes to the development of neuropathic pain. We revealed that perineural injection of recombinant MIP-1a or MIP-2 elicited neuropathic pain-like allodynia and hyperalgesia (Kiguchi et al, 2010b(Kiguchi et al, , 2012. These results suggest that several chemokines including MIP-1b are key molecules of early phase of neuropathic pain.…”

Is there any therapeutic value for the use of histone deacetylase inhibitors for chronic pain?

“…In addition, the up-regulation of chemokine-chemokine receptor systems plays an essential role in chronic pain induction and maintenance (Gao and Ji, 2010;Ji et al, 2014;Marchand et al, 2005). Recent studies indicate that enhanced acetylation in the promoters of the genes encoding CCL2, CCL3, and Chemokine CC motif receptor 2 (CXCR2) may increase their expression under pain conditions (Kiguchi et al, 2012;Kiguchi et al, 2013;Sun et al, 2013). Furthermore, Chiechio and colleagues observed that increased expression of mGluR2 in the spinal cord and DRG is responsible for the analgesic effect of HDACIs (Chiechio et al, 2010;Chiechio et al, 2009).…”

“…Recent studies suggest that the expression of receptors, ion channels, and even cytokines in pain modulation may be regulated by histone acetylation (Chiechio et al, 2009;Chiechio et al, 2010;Kiguchi et al, 2012;Kiguchi et al, 2013). For example, decreased expression of -opioid receptors (MORs) and Na v 1.8 sodium channels in the DRG is thought to be an underlying cause of neuropathic pain symptoms (Uchida et al, 2010).…”

“…In the PSL neuropathic pain model, the HAT inhibitor anacardic acid attenuated thermal hyperalgesia, potentially by facilitating H3K9 hypoacetylation at the macrophage inflammatory protein 2 (MIP-2) and CXC chemokine receptor type 2 promoters in macrophages and neutrophils (Kiguchi et al, 2012).…”