Abstract
BackgroundMicroglia, the mononuclear immune cells of the central nervous system (CNS), are essential for the maintenance of CNS homeostasis. BAP31, a resident and ubiquitously expressed protein of the endoplasmic reticulum, serves as a sorting factor for its client proteins, mediating the subsequent export, retention, and degradation or survival. Recently, BAP31 has been defined as a regulatory molecule in the CNS, but the function of BAP31 in microglia has yet to be determined. In the present study, we investigated whether BAP31 is involved in the inflammatory response of microglia.MethodsThis study used the BV2 cell line and BAP31 conditional knockdown mice generated via the Cre/LoxP system. A BAP31 knockdown experiment was performed to elucidate the role of BAP31 in the endogenous inflammatory cytokine production by microglial BV2 cells. A mouse model of lipopolysaccharide (LPS)-induced cognitive impairment was established to evaluate the neuroprotective effect of BAP31 against neuroinflammation-induced memory deficits. Behavioral alterations were assessed with the open field test (OFT), Y maze, and Morris water maze. The activation of microglia in the hippocampus of mice was observed by immunohistochemistry. Western blot, enzyme-linked immunosorbent assay (ELISA), immunofluorescence staining, and reverse transcription quantitative real-time polymerase chain reaction (RT-PCR) were used to clarify the mechanisms.ResultsBAP31 deficiency upregulates LPS-induced proinflammatory cytokines in BV2 cells and mice by upregulating the protein level of IRAK1, which in turn increases the translocation and transcriptional activity of NF-κB p65 and c-Jun, and moreover, knockdown of IRAK1 or use of an IRAK1 inhibitor reverses these functions. In the cognitive impairment animal model, the BAP31 knockdown mice displayed increased severity in memory deficiency accompanied by an increased expression of proinflammatory factors in the hippocampus.ConclusionsThese findings indicate that BAP31 may modulate inflammatory cytokines and cognitive impairment induced by neuroinflammation through IRAK1, which demonstrates that BAP31 plays an essential role in microglial inflammation and prevention of memory deficits caused by neuroinflammation.
Highlights
Microglia, the mononuclear immune cells of the central nervous system (CNS), are essential for the maintenance of CNS homeostasis
Nitric oxide (NO) production in LPS-treated scramble BV2 cells increased to 10.70 ± 0.08-fold compared to that of scramble BV2 cells, but with B cell receptor-associated protein 31 (BAP31) protein knockdown; NO formation increased to 17.52 ± 0.17-fold, without affecting cell viability (Fig. 1b, c)
BAP31 deficiency exacerbates memory deficits caused by experimental cerebral inflammation Anecdotal evidence suggests that memory deficits caused by neuroinflammation are mediated mostly by the production of proinflammatory cytokines such as tumor necrosis factor α (TNFα), IL-1β, and COX2 in hippocampus, and it was LPS leads to learning and memory deficits
Summary
The mononuclear immune cells of the central nervous system (CNS), are essential for the maintenance of CNS homeostasis. We investigated whether BAP31 is involved in the inflammatory response of microglia. Preclinical and clinical studies have established that neuroinflammation is not merely a response to pathophysiological events, and contributes to and drives pathogenesis [3]. Resident inflammatory cells, play a decisive role in neuroinflammation, Lipopolysaccharide (LPS), a major bacterial Toll-like receptor 4 (TLR4) ligand, can trigger an innate immune response, induce neuroinflammation, and influence the function of neuronal cells, leading to cognitive impairment. Intracerebroventricular administration of LPS is a well-established model of cognitive and behavioral impairment. The level of amyloid-β (Aβ), and the activities of β- or γ-secretases are increased in the hippocampus upon LPS administration [5]. Acute neuroinflammation impairs context discrimination memory and disrupts pattern separation processes in the hippocampus [6]
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