title: Interleukin-18 modulation in autism spectrum disorders.
abstract: BACKGROUND
  Autism spectrum disorder (ASD) is a neurodevelopmental disease which affects 1 in 88 children. Its etiology remains basically unknown, but it is apparent that neuroinflammation is involved in disease development. Great attention has been focused on pro-inflammatory cytokines, and several studies have reported their dysfunction unbalance in serum as well as in the brain. The present work aimed at evaluating putative dysregulation of interleukin-18 (IL-18), a pro-inflammatory cytokine of the IL-1 family in the sera of patients with ASD of different grades, compared to healthy controls, as well as in postmortem brain samples obtained from patients with tuberous sclerosis as well as acute inflammatory diseases. Moreover, quantitative analysis of IL-18 was performed in the sera and brain obtained from Reeler mice, an experimental model of autism.
  
  
  METHODS
  Serum IL-18 levels were measured by ELISA. IL-18 was localized by immunohistochemical analysis in brain sections obtained from tuberous sclerosis and encephalitis patients, as well as from gender- and age-matched controls, and in the brain sections of both Reeler and wild-type mice. IL-18 was also quantified by Western blots in homogenates of Reeler and wild-type mice brains. IL-18 binding protein (IL-18BP) was evaluated in Reeler and wild-type mice plasma as well as in their brains (sections and homogenates).
  
  
  RESULTS
  IL-18 content decreased in the sera of patients with autism compared to healthy subjects and in Reeler sera compared to wild-type controls. IL-18 was detected within glial cells and neurons in the brain of subjects affected by tuberous sclerosis and encephalitis whereas in healthy subjects, only a weak IL-18 positivity was detected at the level of glial cells. Western blot identified higher amounts of IL-18 in Reeler brain homogenates compared to wild-type littermates. IL-18BP was expressed in higher amounts in Reeler brain compared to the brain of wild-type mice, whereas no significant difference was detected comparing IL-18BP plasma levels.
  
  
  CONCLUSIONS
  IL-18 is dysregulated in ASD patients. Further studies seemed necessary to clarify the molecular details behind IL-18 increase in the brain and IL-18 decrease in the sera of patients. An increase in the size of the patient cohort seems necessary to ascertain whether decreased IL-18 content in the sera can become a predictive biomarker of ASD and whether its measure, in combination with other markers (e.g., increased levels of brain-derived neurotrophic factor (BDNF)), may be included in a diagnostic panel.
authors.affiliation: Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, 04100, Latina, Italy. rita.businaro@uniroma1.it.
authors.forename: Rita
authors.initials: R
authors.lastname: Businaro
authors.affiliation: Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, 04100, Latina, Italy. mariangela.corsi@uniroma1.it.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Corsi
authors.affiliation: Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, 04100, Latina, Italy. gabriella.azzara@uniroma1.it.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Azzara
authors.affiliation: Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, 04100, Latina, Italy. tania.diraimo@uniroma1.it.
authors.forename: Tania
authors.initials: T
authors.lastname: Di Raimo
authors.affiliation: Section of Department of Cell Biology & Neuroscience, Section Behavioural Neuroscience, Istituto Superiore di Sanità, Roma, Italy. gianni.laviola@iss.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Laviola
authors.affiliation: Section of Department of Cell Biology & Neuroscience, Section Behavioural Neuroscience, Istituto Superiore di Sanità, Roma, Italy. emilia.romano@iss.it.
authors.forename: Emilia
authors.initials: E
authors.lastname: Romano
authors.affiliation: Department of Anatomical, Histological, Legal Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy. lidiaricci@hotmail.it.
authors.forename: Lidia
authors.initials: L
authors.lastname: Ricci
authors.affiliation: European Center for Brain Research (CERC)/IRCCS Santa Lucia Foundation, Via del Fosso di Fiorano 64-65, 00143, Rome, Italy. m.maccarrone@unicampus.it.|School of Medicine and Center of Integrated Research, Campus Bio-Medico University of Rome, via Alvaro del Portillo 21, 00128, Rome, Italy. m.maccarrone@unicampus.it.
authors.forename: Mauro
authors.initials: M
authors.lastname: Maccarrone
authors.affiliation: Department of (Neuro)Pathology, Academic Medical Center and Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands. e.aronica@amc.uva.nl.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
authors.affiliation: European Center for Brain Research (CERC)/IRCCS Santa Lucia Foundation, Via del Fosso di Fiorano 64-65, 00143, Rome, Italy. andrea.fuso@uniroma1.it.|Department of Psychology, Sapienza University of Rome, Rome, Italy. andrea.fuso@uniroma1.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Fuso
authors.affiliation: Department of Anatomical, Histological, Legal Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy. serafino.ricci@uniroma1.it.
authors.forename: Serafino
authors.initials: S
authors.lastname: Ricci
mesh_terms: D000293:Adolescent; D000818:Animals; D000067877:Autism Spectrum Disorder / Q000473:pathology*; D001921:Brain / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D011795:Surveys and Questionnaires; D055815:Young Adult
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; C118370:interleukin-18 binding protein