title: Peripheral NLCR4 inflammasome participates in the genesis of acute inflammatory pain.
abstract: Inflammatory hyperalgesia is a complex process that depends on the sensitization of primary nociceptive neurons triggered by proinflammatory mediators, such as interleukin 1β (IL-1β). Recently, the peripheral activation of caspase-1 (previously known as IL-1β-converting enzyme) was implicated in the induction of acute inflammatory pain by promoting the processing of IL-1β from its precursor form, pro-IL-1β. Caspase-1 activation in several systems requires the assembly of an intracellular molecular platform called an inflammasome. Inflammasomes consist of 1 nucleotide-binding oligomerization domain-like receptor (NLR), the adapter molecule apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC), and caspase-1. NLRP3 and NLRC4 inflammasomes are well described. However, the identity of the inflammasome that is involved in the peripheral activation of caspase-1 that accounts for acute inflammatory hyperalgesia has not been described. The present findings demonstrated that mice deficient in NLRC4 or ASC, but not in NLRP3, present reduced mechanical and thermal acute inflammatory hyperalgesia induced by carrageenan. The reduced hyperalgesia was accompanied by significant impairments in the levels of mature forms of IL-1β (p17) and caspase-1 (p20) compared to wild-type mice at the inflammatory site. Therefore, these results identified the inflammasome components NLRC4 and ASC as the molecular platform involved in the peripheral activation of caspase-1 and IL-1β maturation, which are responsible for the induction of acute inflammatory pain. In conclusion, our study provides new therapeutic targets for the control of acute inflammatory pain.
authors: Department of Pharmacology, Ribeirao Preto Medical School, University of São Paulo, Ribeirao Preto, São Paulo, Brazil Departamento de Ciências Patológicas, Universidade Estadual de Londrina, Centro de Ciências Biológicas, Londrina, Paraná, Brazil Department of Cell Biology, Ribeirao Preto Medical School, University of São Paulo, Ribeirao Preto, São Paulo, Brazil University of Orleans and CNRS UMR7355, Experimental and Molecular Immunology and Neurogenetics, Orleans, France.
authors: Alexandre H
authors: AH
authors: Lopes
authors: Jhimmy
authors: J
authors: Talbot
authors: Rangel L
authors: RL
authors: Silva
authors: Jonilson B
authors: JB
authors: Lima
authors: Rafael O
authors: RO
authors: França
authors: Waldiceu A
authors: WA
authors: Verri
authors: Danielle P
authors: DP
authors: Mascarenhas
authors: Bernhard
authors: B
authors: Ryffel
authors: Fernando Q
authors: FQ
authors: Cunha
authors: Dario S
authors: DS
authors: Zamboni
authors: Thiago M
authors: TM
authors: Cunha
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000172:deficiency / Q000235:genetics; D020169:Caspases / Q000172:deficiency / Q000235:genetics; D053471:Caspases, Initiator; D016207:Cytokines / Q000378:metabolism*; D015232:Dinoprostone / Q000633:toxicity; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D006930:Hyperalgesia / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000150:complications* / Q000209:etiology; D053583:Interleukin-1beta / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010146:Pain / Q000209:etiology* / Q000378:metabolism*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D009195:Peroxidase / Q000378:metabolism; D053573:Receptors, Interleukin-1 Type I / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D016207:Cytokines; D053583:Interleukin-1beta; C512299:Ipaf protein, mouse; D053573:Receptors, Interleukin-1 Type I; D009195:Peroxidase; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1; D015232:Dinoprostone