title: Traumatic brain injury enhances neuroinflammation and lesion volume in caveolin deficient mice.
abstract: BACKGROUND
  Traumatic brain injury (TBI) enhances pro-inflammatory responses, neuronal loss and long-term behavioral deficits. Caveolins (Cavs) are regulators of neuronal and glial survival signaling. Previously we showed that astrocyte and microglial activation is increased in Cav-1 knock-out (KO) mice and that Cav-1 and Cav-3 modulate microglial morphology. We hypothesized that Cavs may regulate cytokine production after TBI.
  
  
  METHODS
  Controlled cortical impact (CCI) model of TBI (3 m/second; 1.0 mm depth; parietal cortex) was performed on wild-type (WT; C57Bl/6), Cav-1 KO, and Cav-3 KO mice. Histology and immunofluorescence microscopy (lesion volume, glia activation), behavioral tests (open field, balance beam, wire grip, T-maze), electrophysiology, electron paramagnetic resonance, membrane fractionation, and multiplex assays were performed. Data were analyzed by unpaired t tests or analysis of variance (ANOVA) with post-hoc Bonferroni's multiple comparison.
  
  
  RESULTS
  CCI increased cortical and hippocampal injury and decreased expression of MLR-localized synaptic proteins (24 hours), enhanced NADPH oxidase (Nox) activity (24 hours and 1 week), enhanced polysynaptic responses (1 week), and caused hippocampal-dependent learning deficits (3 months). CCI increased brain lesion volume in both Cav-3 and Cav-1 KO mice after 24 hours (P < 0.0001, n = 4; one-way ANOVA). Multiplex array revealed a significant increase in expression of IL-1β, IL-9, IL-10, KC (keratinocyte chemoattractant), and monocyte chemoattractant protein 1 (MCP-1) in ipsilateral hemisphere and IL-9, IL-10, IL-17, and macrophage inflammatory protein 1 alpha (MIP-1α) in contralateral hemisphere of WT mice after 4 hours. CCI increased IL-2, IL-6, KC and MCP-1 in ipsilateral and IL-6, IL-9, IL-17 and KC in contralateral hemispheres in Cav-1 KO and increased all 10 cytokines/chemokines in both hemispheres except for IL-17 (ipsilateral) and MIP-1α (contralateral) in Cav-3 KO (versus WT CCI). Cav-3 KO CCI showed increased IL-1β, IL-9, KC, MCP-1, MIP-1α, and granulocyte-macrophage colony-stimulating factor in ipsilateral and IL-1β, IL-2, IL-9, IL-10, and IL-17 in contralateral hemispheres (P = 0.0005, n = 6; two-way ANOVA) compared to Cav-1 KO CCI.
  
  
  CONCLUSIONS
  CCI caused astrocyte and microglial activation and hippocampal neuronal injury. Cav-1 and Cav-3 KO exhibited enhanced lesion volume and cytokine/chemokine production after CCI. These findings suggest that Cav isoforms may regulate neuroinflammatory responses and neuroprotection following TBI.
authors.forename: Ingrid R
authors.initials: IR
authors.lastname: Niesman
authors.forename: Jan M
authors.initials: JM
authors.lastname: Schilling
authors.forename: Lee A
authors.initials: LA
authors.lastname: Shapiro
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Kellerhals
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Bonds
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Kleschevnikov
authors.forename: Weihua
authors.initials: W
authors.lastname: Cui
authors.forename: April
authors.initials: A
authors.lastname: Voong
authors.forename: Stan
authors.initials: S
authors.lastname: Krajewski
authors.forename: Sameh S
authors.initials: SS
authors.lastname: Ali
authors.forename: David M
authors.initials: DM
authors.lastname: Roth
authors.forename: Hemal H
authors.initials: HH
authors.lastname: Patel
authors.forename: Piyush M
authors.initials: PM
authors.lastname: Patel
authors.affiliation: Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA. bhead@ucsd.edu.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Head
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology*; D001930:Brain Injuries / Q000150:complications* / Q000473:pathology*; D051242:Caveolin 1 / Q000172:deficiency* / Q000235:genetics; D051244:Caveolin 3 / Q000172:deficiency* / Q000235:genetics; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000209:etiology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000150:complications* / Q000235:genetics; D007839:Functional Laterality; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009069:Movement Disorders / Q000209:etiology; D019255:NADPH Oxidases / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D013574:Synaptosomes / Q000378:metabolism / Q000473:pathology
chemical_list: C495548:Cav3 protein, mouse; D051242:Caveolin 1; D051244:Caveolin 3; D016207:Cytokines; D019255:NADPH Oxidases