S100A8 Promotes Inflammation via Toll-Like Receptor 4 After Experimental Traumatic Brain Injury

Abstract

Background: S100A8 is involved in the pathological processes of a variety of central nervous system(CNS) diseases related to inflammation including traumatic brain injury (TBI). However, the underlying mechanism for the induction of inflammation in the brain by S100A8 after TBI remains unclear, which was investigated in the present study.Methods: The weight-drop TBI model was used in this study. The mice were randomly assigned into 5 groups: the Sham, S100A8, S100A8 + TAK-242, TBI, and TBI + TAK-242 groups. In the S100A8 + TAK-242 and TBI + TAK-242 groups, mice were treated with TAK-242, an inhibitor of Toll-like receptor (TLR) 4, intraperitoneally at half an hour before TBI. In the S100A8 and S100A8 + TAK-242 groups, S100A8 recombinant protein was injected into the lateral ventricle of the brain. To explore the relationship between S100A8 and TLR4, Western Blot (WB), immunofluorescence, enzyme-linked immunosorbent assay (ELISA) and Nissl staining were employed. Neurological score and the brain water content were also assessed. Additionally, BV-2 microglial cells were stimulated with lipopolysaccharide (LPS) or S100A8 recombinant protein with/without TAK-242 in vitro. The expressions of the related proteins were subsequently detected with WB or ELISA.Results: The levels of S100A8 protein and pro-inflammatory cytokines were significantly increased after TBI. After intracerebroventricular administration of S100A8, the neurological scores of non-TBI animals were decreased remarkably with severe brain edema. Furthermore, the levels of TLR4, p-p65 and myeloid differentiation factor 88(MyD88) were all increased after S100A8 administration or TBI, which could be restored by TAK-242. Meanwhile, p-p65 and MyD88 were upregulated after S100A8 or LPS stimulation in vitro, which also could be suppressed by TAK-242.Conclusions: The present study demonstrated that TLR4-MyD88 pathway was activated by S100A8, which was essential to the development of inflammation in the brain after TBI.

Toll-like receptor-mediated neuroinflammation: relevance for cognitive dysfunctions

“…Targeting TLR4 signaling with the selective inhibitor TAK-242 (resatorvid) within hours of the injury reduces neuronal apoptosis and improves neurobehavioral impairments in rodents [64][65][66].…”

Fra‐1 induces apoptosis and neuroinflammation by targeting S100A8 to modulate TLR4 pathways in spinal cord ischemia/reperfusion injury

“…TAK‐242 can disrupt the interaction between TLR4 and the ligand, thereby inhibiting TLR4 signal transduction and its downstream signal activation [53, 54]. A previous study reported that TAK‐242 treatment alleviated S100A8‐induced neurological deficits and brain edema [20] also NF‐κB phosphorylation and proinflammatory cytokine production [29]. In the study about hypoxic–ischemic brain injury, NF‐κB signaling can regulate microglia‐mediated neuroinflammation [55].…”

“…Sham rats were injected with 10 μl of normal saline. The process was performed following a previously reported method [20,29]. TAK-242 was intraperitoneally injected (3 mg/kg) 30 min before the injection of rS100A8 [20,29,30].…”

“…The process was performed following a previously reported method [20,29]. TAK-242 was intraperitoneally injected (3 mg/kg) 30 min before the injection of rS100A8 [20,29,30]. The rS100A8 and TAK-242 can permeate the bloodbrain barrier [20,29,30].…”

“…In the previous study, S100A8 has been found to be expressed in microglia and neurons in the central nervous system and is secreted by neuronal cells under hypoxic conditions, which promotes activation of the Toll-like receptor 4(TLR4)/ nuclear factor-κB (NF-κB) pathway and production of interleukin-1β (IL-1β), resulting in neuroinflammation and apoptosis [17]. Multiple lines of evidence support the idea that S100A8, a known ligand of TLR4, can induce downstream TLR4 genes [18][19][20]. Besides, phosphorylated extracellular regulated protein kinases (p-ERK) and phosphorylated NF-κB (p-NB-κB) in TLR4 downstream pathways, act as important factors contributing to inflammation and apoptosis [17,21,22], especially after SCII [23,24].…”