title: Functional recovery after peripheral nerve injury is dependent on the pro-inflammatory cytokines IL-1β and TNF: implications for neuropathic pain.
abstract: IL-1β and TNF are potential targets in the management of neuropathic pain after injury. However, the importance of the IL-1 and TNF systems for peripheral nerve regeneration and the mechanisms by which these cytokines mediate effects are to be fully elucidated. Here, we demonstrate that mRNA and protein levels of IL-1β and TNF are rapidly upregulated in the injured mouse sciatic nerve. Mice lacking both IL-1β and TNF, or both IL-1 type 1 receptor (IL-1R1) and TNF type 1 receptor (TNFR1), showed reduced nociceptive sensitivity (mechanical allodynia) compared with wild-type littermates after injury. Microinjecting recombinant IL-1β or TNF at the site of sciatic nerve injury in IL-1β- and TNF-knock-out mice restored mechanical pain thresholds back to levels observed in injured wild-type mice. Importantly, recovery of sciatic nerve function was impaired in IL-1β-, TNF-, and IL-1β/TNF-knock-out mice. Notably, the infiltration of neutrophils was almost completely prevented in the sciatic nerve distal stump of mice lacking both IL-1R1 and TNFR1. Systemic treatment of mice with an anti-Ly6G antibody to deplete neutrophils, cells that play an essential role in the genesis of neuropathic pain, did not affect recovery of neurological function and peripheral axon regeneration. Together, these results suggest that targeting specific IL-1β/TNF-dependent responses, such as neutrophil infiltration, is a better therapeutic strategy for treatment of neuropathic pain after peripheral nerve injury than complete blockage of cytokine production.
authors: Centre de recherche du Centre hospitalier de l'Université Laval and Department of Molecular Medicine, Université Laval, Québec, G1V 4G2, Canada.
authors: Sylvain
authors: S
authors: Nadeau
authors: Mohammed
authors: M
authors: Filali
authors: Ji
authors: J
authors: Zhang
authors: Bradley J
authors: BJ
authors: Kerr
authors: Serge
authors: S
authors: Rivest
authors: Denis
authors: D
authors: Soulet
authors: Yoichiro
authors: Y
authors: Iwakura
authors: Juan Pablo
authors: JP
authors: de Rivero Vaccari
authors: Robert W
authors: RW
authors: Keane
authors: Steve
authors: S
authors: Lacroix
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D000950:Antigens, Ly / Q000276:immunology; D039481:CD11b Antigen / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000502:physiology; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D021621:Imaging, Three-Dimensional; D019410:Interleukin-16 / Q000378:metabolism; D053583:Interleukin-1beta / Q000172:deficiency / Q000378:metabolism* / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000378:metabolism*; D020127:Recovery of Function / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D012584:Sciatic Nerve / Q000637:transplantation; D012585:Sciatica / Q000188:drug therapy* / Q000503:physiopathology / Q000601:surgery; D013997:Time Factors
chemical_list: D000906:Antibodies; D000950:Antigens, Ly; D039481:CD11b Antigen; D019410:Interleukin-16; D053583:Interleukin-1beta; C480309:Ly6G antigen, mouse; D017472:Receptors, Interleukin-1; D047888:Receptors, Tumor Necrosis Factor, Type I