title: 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)-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.
authors.affiliation: Department of Pharmacology, Wakayama Medical University, 811-1 Kimiidera, Wakayama, Wakayama 641-0012, Japan.
authors.forename: Norikazu
authors.initials: N
authors.lastname: Kiguchi
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Takehiko
authors.initials: T
authors.lastname: Maeda
authors.forename: Yohji
authors.initials: Y
authors.lastname: Fukazawa
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tohya
authors.forename: Michio
authors.initials: M
authors.lastname: Kimura
authors.forename: Shiroh
authors.initials: S
authors.lastname: Kishioka
mesh_terms: D000107:Acetylation; D000818:Animals; D054426:Chemokine CXCL2 / Q000235:genetics / Q000502:physiology*; D044127:Epigenesis, Genetic; D006657:Histones / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009437:Neuralgia / Q000209:etiology*; D020556:Neutrophil Infiltration; D059348:Peripheral Nerve Injuries / Q000503:physiopathology*; D011401:Promoter Regions, Genetic; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000502:physiology*
chemical_list: D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D006657:Histones; D023063:Receptors, Interleukin-8B