Deficiency in interleukin-18 ameliorated glial activation and neuroinflammation after traumatic brain injury in mice

Abstract

Background: Neuroinflammation is recognized as one of the main pathological mechanisms of secondary injury caused by traumatic brain injury (TBI). It has been reported that interleukin (IL)-18 is expressed in glial cells and involved in the regulation of neuroinflammation. Further studies have revealed that IL-18 expression is upregulated and may contribute to pathogenesis in the later phases of TBI; however, the mechanism underlying the effect of IL-18 on TBI remains unclear. Our present study assessed the roles of IL-18 in inflammatory and neurodegenerative pathology in mice subjected to TBI.Methods: A controlled cortical impact (CCI) injury model was conducted to mimic TBI, and brains were collected at 3 and 7 days post TBI (dpi). The levels of IL-18 were detected by qRT-PCR and immunofluorescence staining. In addition, neurological severity score (NSS) was used to assess neurological deficits after TBI. Furthermore, neuronal cell death, glial activation, and inflammatory cytokine and chemokine secretion were evaluated in wild-type ( WT ) and Il18-knockout ( Il18 -KO) mice to explore the role of IL-18 in TBI.Results: IL-18 levels were upregulated post TBI, accompanied by reactive glial activation. Il-18 deficiency significantly ameliorated glial activation and improved neuronal cell death and neurological deficits. In addition, Il-18 deficiency reduced the TBI-induced M1-like microglia frequency. Interestingly, the levels of all pro- and anti-inflammatory cytokines, including IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12p40, IL-12p70, IL-13, IL17A, G-CSF, GM-CSF, IFN-γ, and TNF-α, were downregulated in Il18 -KO mice. The deletion of Il-18 attenuated the levels of most chemokines induced by TBI, including CCL2, CCL3, CCL4, CCL5, CCL7, CCL12, CCL20, CXCL1, CXCL2, CXCL10, CXCL12, CXCL13, and CXCL16.Conclusions: These data demonstrated that IL-18 is involved in TBI induced neuroinflammation, which suggests that IL-18 is important for the development of secondary injury induced by TBI.

The Role of Neuroinflammatory Mediators in the Pathogenesis of Traumatic Brain Injury: A Narrative Review

“…59 The findings from this study suggested that suppression of the NRLP-mediated IL-18 response may reduce neuronal death via neuroinflammation. Similarly, the relationship between glia and IL-18 levels was studied in a mice TBI model of cortical injury, where mice that were genetically unable to produce IL-18 showed a significant increase in glial recovery and activation, as well as reduced levels of TBI-induced chemokines 60 (Table 1). These data suggested that IL-18 may enhance neuroinflammation and may attenuate glial healing post injury.…”