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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 340; no. 3; pp. 577 - 587
• Main Authors: Kiguchi, Norikazu, Kobayashi, Yuka, Maeda, Takehiko, Fukazawa, Yohji, Tohya, Kazuo, Kimura, Michio, Kishioka, Shiroh
• Format: Journal Article
• Language: English
• Published: United States 01.03.2012
• Subjects: Acetylation; Animals; Chemokine CXCL2 - genetics; Chemokine CXCL2 - physiology; Epigenesis, Genetic; Histones - metabolism; Male; Mice; Mice, Inbred ICR; Neuralgia - etiology; Neutrophil Infiltration; Peripheral Nerve Injuries - physiopathology; Promoter Regions, Genetic; Receptors, Interleukin-8B - genetics; Receptors, Interleukin-8B - physiology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.111.187724

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)-N'-(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.