Neuroprotection by Nrf2 via modulating microglial phenotype and phagocytosis after intracerebral hemorrhage
Chuntian LiangLirong LiuShuangjin BaoZhenjia YaoQinqin BaiPengcheng FuXiangyu LiuJohn H. ZhangGaiqing Wang
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Activated microglia are divided into pro-inflammatory and anti-inflammatory functional states. In anti-inflammatory state, activated microglia contribute to phagocytosis, neural repair and anti-inflammation. Nrf2 as a major endogenous regulator in hematoma clearance after intracerebral hemorrhage (ICH) has received much attention. This study aims to investigate the mechanism underlying Nrf2-mediated regulation of microglial phenotype and phagocytosis in hematoma clearance after ICH. In vitro experiments, BV-2 cells were assigned to normal group and administration group (Nrf2-siRNA, Nrf2 agonists Monascin and Xuezhikang). In vivo experiments, mice were divided into 5 groups: sham, ICH + vehicle, ICH + Nrf2−/−, ICH + Monascin and ICH + Xuezhikang. In vitro and in vivo, 72 h after administration of Monascin and Xuezhikang, the expression of Nrf2, inflammatory-associated factors such as Trem1, TNF-α and CD80, anti-inflammatory, neural repair and phagocytic associated factors such as Trem2, CD206 and BDNF were analyzed by the Western blot method. In vitro, fluorescent latex beads or erythrocytes were uptaken by BV-2 cells in order to study microglial phagocytic ability. In vivo, hemoglobin levels reflect the hematoma volume. In this study, Nrf2 agonists (Monascin and Xuezhikang) upregulated the expression of Trem2, CD206 and BDNF while decreased the expression of Trem1, TNF-α and CD80 both in vivo and in vitro. At the same time, after Monascin and Xuezhikang treatment, the phagocytic capacity of microglia increased in vitro, neurological deficits improved and hematoma volume lessened in vivo. These results were reversed in the Nrf2-siRNA or the Nrf2−/− mice. All these results indicated that Nrf2 enhanced hematoma clearance and neural repair, improved neurological outcomes through enhancing microglial phagocytosis and alleviating neuroinflammation.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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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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Macrophages maintain tissue homeostasis by phagocytosing and removing unwanted materials such as dead cells and cell debris. Microglia, the resident macrophages of the central nervous system (CNS), are no exception. In addition, a series of recent studies have shown that microglia phagocytose the neuronal synapses that form the basis of neural circuit function. This discovery has spurred many neuroscientists to study microglia. Importantly, in the CNS parenchyma, not only microglia but also blood-derived monocytes, which essentially differentiate into macrophages after infiltration, exert phagocytic ability, making the study of phagocytosis in the CNS even more interesting and complex. In particular, in the diseased brain, the phagocytosis of tissue-damaging substances, such as myelin debris in multiple sclerosis (MS), has been shown to be carried out by both microglia and blood-derived monocytes. However, it remains largely unclear why blood-derived monocytes need to invade the parenchyma, where microglia are already abundant, to assist in phagocytosis. We will also discuss whether this phagocytosis can affect the fate of the phagocytosing cell itself as well as the substance being phagocytosed and the surrounding environment in addition to future research directions. In this review, we will introduce recent studies to answer a question that often arises when studying microglial phagocytosis: under what circumstances and to what extent blood-derived monocytes infiltrate the CNS and contribute to phagocytosis. In addition, the readers will learn how recent studies have experimentally distinguished between microglia and infiltrating monocytes. Finally, we aim to contribute to the progress of phagocytosis research by discussing the effects of phagocytosis on phagocytic cells.
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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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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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