Abstract
Objective We have previously demonstrated that inflammation induced by toll-like receptors (TLRs) 2/4 exert cerebral deleterious effects after diffuse axonal injury (DAI); however, the underlying mechanisms are not fully understood. Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine involved in inflammatory responses. The purpose of this study was to investigate the role of MIF in inflammation induced by TLRs in the cortices of DAI rats. Methods The rat DAI model was established by head rotational acceleration and confirmed by β-APP, HE, and silver staining. MIF protein expression at 3 h, 6 h, 12 h, 1 d, and 3 d after DAI was measured by western blot. The localization of MIF was measured by immunofluorescence. MIF antagonist ISO-1 was intracerebroventricularly injected to inhibit MIF. Neuronal and axonal injury and glial responses were assessed by TUNEL, immunohistochemistry, and TEM. Expression of TLR2, TLR4, ERK, phospho-ERK, NF-κB, and phospho-NF-κB was examined by western blot. The level of IL-1β, IL-6, and TNF-α was measured by ELISA. Results MIF expression was significantly increased, peaking at 1 day after DAI, and MIF was mainly localized in microglial cells and neurons. ISO-1 suppressed neuronal apoptosis, axonal injury, and glial responses and decreased the expression of downstream signaling molecules related to TLR2/4, including ERK, phospho-ERK, NF-κB, phospho-NF-κB, IL-1β, IL-6, and TNF-α. Conclusion MIF was involved in the neuronal and axonal damage through a TLR-related pathway following DAI.
Highlights
Diffuse axonal injury (DAI), caused by shearing forces leading to widespread tearing of axons, is considered an important pathologic features of traumatic brain injury
We previously found that toll-like receptors (TLRs) 2 and 4, localized primarily in microglia, might be involved in mediating secondary injury after DAI by inducing inflammation via MAPK or NF-κB pathways [2, 3]
In Hematoxylin and Eosin (H&E) stained sections, vacuoles, nuclear fragmentation, and pyknosis were observed in the DAI 1 d group
Summary
Diffuse axonal injury (DAI), caused by shearing forces leading to widespread tearing of axons, is considered an important pathologic features of traumatic brain injury. Dysregulated neuroinflammation exacerbates secondary injury following DAI [1]. We previously found that toll-like receptors (TLRs) 2 and 4, localized primarily in microglia, might be involved in mediating secondary injury after DAI by inducing inflammation via MAPK or NF-κB pathways [2, 3]. High-mobility group box 1 (HMGB1), considered as stress-released alarmins, are chromatin-associated protein that can initiate a noninfectious inflammatory response through TLR2/4 pathway [4]. Our previous study found that HMGB1 may be involved in the inflammatory response after DAI [5]. Whether there are other factors that could initiate inflammatory response through TLR2/4 pathway after DAI is still not clear
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