title: NLRP3 Inflammasome Involvement in the Organ Damage and Impaired Spermatogenesis Induced by Testicular Ischemia and Reperfusion in Mice.
abstract: We investigated the role of the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome during testis ischemia and reperfusion injury (TI/R) in wild-type (WT) and NLRP3 knock-out (KO) mice. WT and KO mice underwent 1 hour testicular ischemia followed by 4 hours and 1 and 7 days of reperfusion or a sham TI/R. Furthermore, two groups of WT mice were treated at the beginning of reperfusion and up to 7 days with two inflammasome inhibitors, BAY 11-7082 (20 mg/kg i.p.) or Brilliant Blue G (45.5 mg/kg i.p.), or vehicle. Animals were killed with a pentobarbital sodium overdose at 4 hours and 1 and 7 days, and bilateral orchidectomies were performed. Biochemical and morphologic studies were carried out in all groups. TI/R in WT mice significantly increased caspase-1 and interleukin (IL)-1β mRNA after 4 hours and IL-18 mRNA at 1 day of reperfusion (P ≤ 0.05). There was also a significant increase in caspase-3 and terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling-positive cells, marked histologic damage, and altered spermatogenesis in WT mice in both testes after 1 and 7 days of reperfusion. KO TI/R mice, WT TI/R BAY 11-7082, and Brilliant Blue G treated mice showed a significant reduced IL-1β and IL-18 mRNA expression, blunted caspase-1 and -3 expression, minor histologic damages, low terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling activity, and preserved spermatogenesis. These data suggest that the activation of NLRP3 plays a key role in TI/R, and its inhibition might represent a therapeutic target for the management of patients with unilateral testicular torsion.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (L.M., N.I., M.R., A.B., H.M., G.P., F.S.); Department of Paediatric, Gynaecological, Microbiological, and Biomedical Sciences, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (P.A., C.R., D.A.); Department of Biomedical Sciences and Morphofunctional Imaging, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (A.P., G.S., D.P., A.M.); and Department of Human Pathology, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (C.M.).
authors.forename: Letteria
authors.initials: L
authors.lastname: Minutoli
authors.affiliation: Department of Clinical and Experimental Medicine, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (L.M., N.I., M.R., A.B., H.M., G.P., F.S.); Department of Paediatric, Gynaecological, Microbiological, and Biomedical Sciences, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (P.A., C.R., D.A.); Department of Biomedical Sciences and Morphofunctional Imaging, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (A.P., G.S., D.P., A.M.); and Department of Human Pathology, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (C.M.).
authors.forename: Pietro
authors.initials: P
authors.lastname: Antonuccio
authors.affiliation: Department of Clinical and Experimental Medicine, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (L.M., N.I., M.R., A.B., H.M., G.P., F.S.); Department of Paediatric, Gynaecological, Microbiological, and Biomedical Sciences, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (P.A., C.R., D.A.); Department of Biomedical Sciences and Morphofunctional Imaging, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (A.P., G.S., D.P., A.M.); and Department of Human Pathology, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (C.M.).
authors.forename: Natasha
authors.initials: N
authors.lastname: Irrera
authors.affiliation: Department of Clinical and Experimental Medicine, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (L.M., N.I., M.R., A.B., H.M., G.P., F.S.); Department of Paediatric, Gynaecological, Microbiological, and Biomedical Sciences, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (P.A., C.R., D.A.); Department of Biomedical Sciences and Morphofunctional Imaging, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (A.P., G.S., D.P., A.M.); and Department of Human Pathology, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (C.M.).
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Rinaldi
authors.affiliation: Department of Clinical and Experimental Medicine, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (L.M., N.I., M.R., A.B., H.M., G.P., F.S.); Department of Paediatric, Gynaecological, Microbiological, and Biomedical Sciences, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (P.A., C.R., D.A.); Department of Biomedical Sciences and Morphofunctional Imaging, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (A.P., G.S., D.P., A.M.); and Department of Human Pathology, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (C.M.).
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bitto
authors.affiliation: Department of Clinical and Experimental Medicine, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (L.M., N.I., M.R., A.B., H.M., G.P., F.S.); Department of Paediatric, Gynaecological, Microbiological, and Biomedical Sciences, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (P.A., C.R., D.A.); Department of Biomedical Sciences and Morphofunctional Imaging, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (A.P., G.S., D.P., A.M.); and Department of Human Pathology, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (C.M.).
authors.forename: Herbert
authors.initials: H
authors.lastname: Marini
authors.affiliation: Department of Clinical and Experimental Medicine, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (L.M., N.I., M.R., A.B., H.M., G.P., F.S.); Department of Paediatric, Gynaecological, Microbiological, and Biomedical Sciences, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (P.A., C.R., D.A.); Department of Biomedical Sciences and Morphofunctional Imaging, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (A.P., G.S., D.P., A.M.); and Department of Human Pathology, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (C.M.).
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pizzino
authors.affiliation: Department of Clinical and Experimental Medicine, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (L.M., N.I., M.R., A.B., H.M., G.P., F.S.); Department of Paediatric, Gynaecological, Microbiological, and Biomedical Sciences, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (P.A., C.R., D.A.); Department of Biomedical Sciences and Morphofunctional Imaging, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (A.P., G.S., D.P., A.M.); and Department of Human Pathology, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (C.M.).
authors.forename: Carmelo
authors.initials: C
authors.lastname: Romeo
authors.affiliation: Department of Clinical and Experimental Medicine, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (L.M., N.I., M.R., A.B., H.M., G.P., F.S.); Department of Paediatric, Gynaecological, Microbiological, and Biomedical Sciences, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (P.A., C.R., D.A.); Department of Biomedical Sciences and Morphofunctional Imaging, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (A.P., G.S., D.P., A.M.); and Department of Human Pathology, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (C.M.).
authors.forename: Antonina
authors.initials: A
authors.lastname: Pisani
authors.affiliation: Department of Clinical and Experimental Medicine, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (L.M., N.I., M.R., A.B., H.M., G.P., F.S.); Department of Paediatric, Gynaecological, Microbiological, and Biomedical Sciences, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (P.A., C.R., D.A.); Department of Biomedical Sciences and Morphofunctional Imaging, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (A.P., G.S., D.P., A.M.); and Department of Human Pathology, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (C.M.).
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Santoro
authors.affiliation: Department of Clinical and Experimental Medicine, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (L.M., N.I., M.R., A.B., H.M., G.P., F.S.); Department of Paediatric, Gynaecological, Microbiological, and Biomedical Sciences, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (P.A., C.R., D.A.); Department of Biomedical Sciences and Morphofunctional Imaging, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (A.P., G.S., D.P., A.M.); and Department of Human Pathology, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (C.M.).
authors.forename: Domenico
authors.initials: D
authors.lastname: Puzzolo
authors.affiliation: Department of Clinical and Experimental Medicine, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (L.M., N.I., M.R., A.B., H.M., G.P., F.S.); Department of Paediatric, Gynaecological, Microbiological, and Biomedical Sciences, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (P.A., C.R., D.A.); Department of Biomedical Sciences and Morphofunctional Imaging, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (A.P., G.S., D.P., A.M.); and Department of Human Pathology, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (C.M.).
authors.forename: Carlo
authors.initials: C
authors.lastname: Magno
authors.affiliation: Department of Clinical and Experimental Medicine, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (L.M., N.I., M.R., A.B., H.M., G.P., F.S.); Department of Paediatric, Gynaecological, Microbiological, and Biomedical Sciences, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (P.A., C.R., D.A.); Department of Biomedical Sciences and Morphofunctional Imaging, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (A.P., G.S., D.P., A.M.); and Department of Human Pathology, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (C.M.) Francesco.Squadrito@unime.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Squadrito
authors.affiliation: Department of Clinical and Experimental Medicine, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (L.M., N.I., M.R., A.B., H.M., G.P., F.S.); Department of Paediatric, Gynaecological, Microbiological, and Biomedical Sciences, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (P.A., C.R., D.A.); Department of Biomedical Sciences and Morphofunctional Imaging, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (A.P., G.S., D.P., A.M.); and Department of Human Pathology, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (C.M.).
authors.forename: Antonio
authors.initials: A
authors.lastname: Micali
authors.affiliation: Department of Clinical and Experimental Medicine, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (L.M., N.I., M.R., A.B., H.M., G.P., F.S.); Department of Paediatric, Gynaecological, Microbiological, and Biomedical Sciences, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (P.A., C.R., D.A.); Department of Biomedical Sciences and Morphofunctional Imaging, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (A.P., G.S., D.P., A.M.); and Department of Human Pathology, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Messina, Italy (C.M.).
authors.forename: Domenica
authors.initials: D
authors.lastname: Altavilla
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics*; D020170:Caspase 1 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D058847:Inflammasomes / Q000235:genetics*; D020382:Interleukin-18 / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009570:Nitriles / Q000494:pharmacology; D009919:Orchiectomy; D015427:Reperfusion Injury / Q000235:genetics* / Q000473:pathology*; D012394:Rosaniline Dyes / Q000494:pharmacology; D013091:Spermatogenesis / Q000235:genetics*; D013450:Sulfones / Q000494:pharmacology; D013733:Testicular Diseases / Q000235:genetics* / Q000473:pathology*; D013737:Testis / Q000473:pathology
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D002352:Carrier Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009570:Nitriles; C492716:Nlrp3 protein, mouse; D012394:Rosaniline Dyes; D013450:Sulfones; D053148:Caspase 3; D020170:Caspase 1; C004692:coomassie Brilliant Blue