Traumatic brain injury enhances neuroinflammation and lesion volume in caveolin deficient mice

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.conclusion: 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. © 2014 niesman et al.; licensee biomed central ltd.