Neuroinflammation in Response to Intracerebral Injections of Different HMGB1 Redox Isoforms
Hannah AucottJohan LundbergHenna SaloLena KlevenvallPeter DambergLars OttossonJan AnderssonStaffan HolminHelena Erlandsson Harris
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<b><i>Background:</i></b> Neuroinflammation triggered by infection or trauma is the cause of central nervous system dysfunction. High-mobility group box 1 protein (HMGB1), released from stressed and dying brain cells, is a potent neuroinflammatory mediator. The proinflammatory functions of HMGB1 are tightly regulated by post-translational redox modifications, and we here investigated detailed neuroinflammatory responses induced by the individual redox isoforms. <b><i>Methods:</i></b> Male Dark Agouti rats received a stereotactic injection of saline, lipopolysaccharide, disulfide HMGB1, or fully reduced HMGB1, and were accessed for blood-brain barrier modifications using magnetic resonance imaging (MRI) and inflammatory responses by immunohistochemistry. <b><i>Results and Conclusions:</i></b> Significant blood-brain barrier disruption appeared 24 h after injection of lipopolysaccharide, disulfide HMGB1, or fully reduced HMGB1 compared to controls, as assessed in post-gadolinium T1-weighted MRI images and confirmed by increased uptake of FITC-conjugated dextran. Immunohistochemistry revealed that both HMGB1 isoforms also induced a local production of IL-1β. Additionally, disulfide HMGB1 increased major histocompatibility complex class II expression and apoptosis. Together, the results demonstrate that extracellular, cerebral HMGB1 causes significant blood-brain barrier disruption in a redox-independent manner and activates several components of neuroinflammation. Blocking HMGB1 might potentially improve clinical outcome in conditions such as stroke and traumatic brain injury.Keywords:
HMGB1
Proinflammatory cytokine
Abstract Neuroinflammation is associated with neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Microglia and astrocytes are key regulators of inflammatory responses in the central nervous system. The activation of microglia and astrocytes is heterogeneous and traditionally categorized as neurotoxic (M1-phenotype microglia and A1-phenotype astrocytes) or neuroprotective (M2-phenotype microglia and A2-phenotype astrocytes). However, this dichotomized classification may not reflect the various phenotypes of microglia and astrocytes. The relationship between these activated glial cells is also very complicated, and the phenotypic distribution can change, based on the progression of neurodegenerative diseases. A better understanding of the roles of microglia and astrocytes in neurodegenerative diseases is essential for developing effective therapies. In this review, we discuss the roles of inflammatory response in neurodegenerative diseases, focusing on the contributions of microglia and astrocytes and their relationship. In addition, we discuss biomarkers to measure neuroinflammation and studies on therapeutic drugs that can modulate neuroinflammation.
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Objective To investigate the effect of Xuebijing injection on release of high mobility group box 1 (HMGB1) in endotoxin-induced cells. Methods HMGB1 concentration and mRNA expression were analyzed by enzyme-linked immunosorbent assay (ELISA) and RT-PCR, respectively. The effects of Xuebijing injection with 2, 10 and 50 mg/ml on HMGB 1 concentration in the culture medium of 200 ng/ml lipopolysaccharide-induced macrophage-like RAW 264.7 cells and BRL-3A hepatocytes, and HMGB1 mRNA expression in lipopolysaccharide-induced macrophages were observed. Results 50 mg/ml Xuebijing injection significantly decreased HMGB1 concentration in the culture medium of lipopolysaccharide-induced macrophages and hepatocytes(P< 0.01), and inhibited HMGB1 mRNA expression in macrophages. Conclusion Xuebijing injection inhibits endotoxin-induced release of HMGB1.
Key words:
HMGB1 protein; XueBiJing; Macrophages; Hepatocytes; Endotoxins
HMGB1
High-mobility group
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Microglia, the mononuclear phagocytes of the central nervous system (CNS), are important for the maintenance of CNS homeostasis, but also critically contribute to CNS pathology. Here we demonstrate that the nuclear factor kappa B (NF-κB) regulatory protein A20 is crucial in regulating microglia activation during CNS homeostasis and pathology. In mice, deletion of A20 in microglia increases microglial cell number and affects microglial regulation of neuronal synaptic function. Administration of a sublethal dose of lipopolysaccharide induces massive microglia activation, neuroinflammation, and lethality in mice with microglia-confined A20 deficiency. Microglia A20 deficiency also exacerbates multiple sclerosis (MS)-like disease, due to hyperactivation of the Nlrp3 inflammasome leading to enhanced interleukin-1β secretion and CNS inflammation. Finally, we confirm a Nlrp3 inflammasome signature and IL-1β expression in brain and cerebrospinal fluid from MS patients. Collectively, these data reveal a critical role for A20 in the control of microglia activation and neuroinflammation.
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Experimental studies of neuroinflammation in Alzheimer’s disease (AD) have mostly investigated microglia, the brain-resident macrophages. This review focused on human microglia obtained at rapid autopsies. Studies employing methods to isolate and culture human brain microglia in high purity for experimental studies were discussed. These methods were employed to isolate human microglia for investigation of a number of features of neuroinflammation, including activation phenotypes, neurotoxicity, responses to abnormal aggregated proteins such as amyloid beta, phagocytosis, and the effects of aging and disease on microglia cellular properties. In recent years, interest in human microglia and neuroinflammation has been renewed due to the identification of inflammation-related AD genetic risk factors, in particular the triggering receptor expressed on myeloid cells (TREM)-2. Because of the difficulties in developing effective treatments for AD, there has been a general need for greater understanding of the functions of microglia in normal and AD brains. While most experimental studies on neuroinflammation have employed rodent microglia, this review considered the role of human microglia in experimental studies. This review focused on the development of in vitro methodology for the culture of postmortem human microglia and the key findings obtained from experimental studies with these cells.
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Human brain
Neurotoxicity
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Background: Peripheral inflammation-triggered mild neuroinflammation impacts the brain and behavior through microglial activation. In this study, we performed an unbiased analysis of the vulnerability of different brain areas to neuroinflammation induced by systemic inflammation. Methods: We injected mice with a single low dose of LPS to induce mild inflammation and then analyzed microglial activation in 34 brain regions by immunohistochemical methods and whole-brain imaging using multi-slide scanning microscopy. We also conducted quantitative RT-PCR to measure the levels of inflammatory cytokines in selected brain regions of interest. Results: We found that microglia in different brain regions are differentially activated by mild, LPS-induced inflammation relative to the increase in microglia numbers or increased CD68 expression. The increased number of microglia induced by mild inflammation was not attributable to infiltration of peripheral immune cells. In addition, microglia residing in brain regions, in which a single low-dose injection of LPS produced microglial changes, preferentially generated pro-inflammatory cytokines. Conclusion: Our results suggest that mild neuroinflammation induces regionally different microglia activation, producing pro-inflammatory cytokines. Our observations provide insight into induction of possible region-specific neuroinflammation-associated brain pathologies through microglial activation. Keywords: neuroinflammation, microglia, inflammatory cytokines, lipopolysaccharide, regional vulnerability
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High mobility group box-1 (HMGB1) is an evolutionarily conserved protein, which widely exists in mammals. HMGB1 contains the nucleus localization sequences. Intracellular and extracellular HMGB1 shows different biological functions. Extracellular HMGB1 is closely related to sepsis, cancer, rheumatoid immune, atherosclerosis, ischemia-reperfusion injury and so on. The mobilization of HMGB1 from the nucleus to the cytoplasm and subsequent release involves the processes of post-translation modification, active secretion and nuclear localization.高迁移率族蛋白B1(high mobility group box-1，HMGB1)是一种在哺乳动物中广泛存在、进化中高度保守的蛋白质。细胞核定位序列的存在使得生理状态下的HMGB1主要存在于细胞核内，但其在细胞内外的不同位置具有不同的生物学功能。细胞外的HMGB1与脓毒症、肿瘤、风湿免疫、动脉粥样硬化及缺血再灌注损伤等多种疾病密切相关。HMGB1由细胞核内迁移至细胞质再释放到细胞外的过程，涉及核定位序列的翻译后修饰、主动分泌或被动释放等机制。.
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High-mobility group
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Homeostasis
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Neuroinflammation is a pathological mechanism contributing to neurodegenerative diseases. For in-depth studies of neuroinflammation, several animal models reported reproducing behavioral dysfunctions and cellular pathological mechanisms induced by brain inflammation. One of the most popular models of neuroinflammation is the one generated by lipopolysaccharide exposure. Despite its importance, the reported results using this model show high heterogeneity, making it difficult to analyze and compare the outcomes between studies. Therefore, the current review aims to summarize the different experimental paradigms used to reproduce neuroinflammation by lipopolysaccharide exposure and its respective outcomes, helping to choose the model that better suits each specific research aim.
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