Absence of TLR4 Reduces Neurovascular Unit and Secondary Inflammatory Process after Traumatic Brain Injury in Mice

Abstract

BackgroundTraumatic brain injury (TBI) initiates a neuroinflammatory cascade that contributes to neuronal damage and behavioral impairment. Toll-like receptors (TLRs) are signaling receptors in the innate immune system, although emerging evidence indicates their role in brain injury. We have therefore investigated the role played by TLR4 signaling pathway in the development of mechanisms of secondary inflammatory process in traumatic brain injury (TBI) differ in mice that lack a functional TLR4 signaling pathway.Methods/Principal FindingsControlled cortical impact injury was performed on TLR4 knockout (KO) mice (C57BL/10ScNJ) and wild-type (WT) mice (C57BL/10ScNJ). TBI outcome was evaluated by determination of infarct volume and assessment of neurological scores. Brains were collected at 24 h after TBI. When compared to WT mice, TLR4 KO mice had lower infarct volumes and better outcomes in neurological and behavioral tests (evaluated by EBST and rotarod test). Mice that lacked TLR4 had minor expression of TBI-induced GFAP, Chymase, Tryptase, IL-1β, iNOS, PARP and Nitrotyrosine mediators implicated in brain damage. The translocation of expression of p-JNK, IκB-α and NF-κB pathway were also lower in brains from TLR4 KO mice. When compared to WT mice, resulted in significant augmentation of all the above described parameters. In addition, apoptosis levels in TLR4 KO mice had minor expression of Bax while on the contrary with Bcl-2.Conclusions/SignificanceOur results clearly demonstrated that absence of TLR4 reduces the development of neuroinflammation, tissues injury events associated with brain trauma and may play a neuroprotective role in TBI in mice.

The Possible Role of Toll-Like Receptor 4 in the Pathology of Stroke

“…Furthermore, they showed that TLR4 deficiency led to decreased parenchymal stress responses and, so, enhanced neuronal survival. These findings were also confirmed by Ahmad et al [50 ]who demonstrated that TLR4 plays a neuroprotective role in traumatic brain injury by reducing neuroinflammation and brain trauma. In accordance, Hua et al [51 ]also showed that TLR4-knockout mice had a smaller brain infarct size in comparison with TLR4-bearing mice in the middle cerebral artery occlusion (MCAO) animal model.…”

Depletion of macrophages in CD11b diphtheria toxin receptor mice induces brain inflammation and enhances inflammatory signaling during traumatic brain injury

“…Consistent with these findings, genetic deletion or inhibition of many proinflammatory mediators like IL-1β, NOX, and TLRs are protective during brain injury (Ahmad et al, 2013; Clausen et al, 2011; Dohi et al, 2010; Tehranian et al, 2002). In contrast, deletion or inhibition of other proinflammatory cytokines like TNF-α and IL-6 have been shown to exacerbate injury and impair neurological function (Clausen et al, 2011; Quintana et al, 2007; Scherbel et al, 1999).…”

Neuroimmunology of Traumatic Brain Injury: Time for a Paradigm Shift

“…The functional role of TLR4 in this process was examined using controlled cortical impact (CCI), a model of cerebral contusion TBI. In this study, TLR4-deficient mice had smaller brain lesions and a reduced expression of inflammatory markers after CCI when compared to wild type controls (Ahmad et al, 2013). Similarly, a highly selective TLR4 blocker, VGX1027, lessened cerebral edema after TBI in mice, presumably by blocking HMGB1-induced IL-6 release from microglia and subsequent upregulation of the water channel, aquaporin 4 (AQP4), on astrocytes (Laird et al, 2014).…”