Age-related chronic inflammatory activation of microglia and their dysfunction are observed in many neurodegenerative diseases, and the potential contributions of these dysfunctional cells to ...neurodegeneration have been demonstrated recently. The housekeeping and defensive functions of microglia, such as surveying brain parenchyma and phagocytosis of neuronal debris after injury, are important for brain homeostasis and immunity. During neurodegenerative diseases, loss of these functions can promote disease pathology by producing proinflammatory cytokines and increasing oxidative stress, which can exaggerate ongoing neuroinflammation. A recent surge in microglial research has unraveled myriads of microglial phenotypes associated with aging and neurodegenerative diseases, in addition to conventional M1/M2 paradigm. Each of these phenotypes can be characterized by distinct transcriptional profiles as well as altered metabolism, migration, and phagocytosis characteristics. Mutations in Trem2 and Grn are associated with various neurodegenerative diseases, and these genes are dysregulated in majority of recently identified microglial phenotypes. These genes act as checkpoint regulators and maintain microglial inflammatory fitness, principally through metabolic modulation. Dysfunctional microglia typically show mitochondrial deficits, glycolysis elevation, and lipid droplet accumulation, which results in reduced migration and phagocytosis and increased proinflammatory cytokine secretion and reactive oxygen species release. In this mini-review, we discuss the existing data regarding metabolic perturbations in dysfunctional microglia and their documented associations with neurodegeneration, highlighting how aging-induced chronic microglial activation alters microglial bioenergetics, leading to impaired homeostatic and housekeeping functions. Dysfunctional microglia initiate or exacerbate neurodegeneration, and key pathways involved in the dysfunctional processes, including metabolism, may represent potential intervention targets for correcting imbalances.
RNA sequencing-based gene expression analysis revealed significant differences between the transcriptional signatures of microglia derived from in vitro cultures and acutely isolated adult microglia. ...Pyroptosis is a form of programmed cell death triggered by the activation of caspases, which leads to the degradation of the cell's structural components and the release of pro-inflammatory molecules (Yu et al., 2021). ...it is not clear how to categorize these microglia, and there is no clear consensus about whether the term “dysfunctional microglia” refers to a specific subtype or is a general term that includes all of the aforementioned microglia. ...it is crucial to define microglial subpopulations and identify their precise functions to better understand various neurological diseases. While RNA serves as a template for protein synthesis, the final protein product can be altered post-translationally, generating diverse proteoforms and altering its function. ...changes in RNA levels do not always correlate with changes in protein levels or activity as shown by Mercurio et al..
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Lipocalin-2 (LCN2), also known as 24p3 and neutrophil gelatinase-associated lipocalin (NGAL), is a 25-kDa secreted protein implicated in various metabolic and inflammatory diseases. ...Early studies suggest the protective function of LCN2 in which it acts as a bacteriostatic agent that competes with bacteria for iron-bound siderophores. However, both detrimental and beneficial roles of LCN2 have recently been documented in metabolic and neuroinflammatory diseases. Metabolic inflammation, as observed in diabetes and obesity, has been closely associated with the upregulation of LCN2 in blood plasma and several tissues in both humans and rodents, suggesting its pro-diabetic and pro-obesogenic role. On the contrary, other studies imply an anti-diabetic and anti-obesogenic role of LCN2 whereby a deficiency in the Lcn2 gene results in the impairment of insulin sensitivity and enhances the high-fat-diet-induced expansion of fat. A similar dual role of LCN2 has also been reported in various animal models for neurological disorders. In the midst of these mixed findings, there is no experimental evidence to explain why LCN2 shows such a contrasting role in the various studies. This debate needs to be resolved (or reconciled) and an integrated view on the topic is desirable. Herein, we attempt to address this issue by reviewing the recent findings on LCN2 in metabolic disorders and assess the potential cellular or molecular mechanisms underlying the dual role of LCN2. We further discuss the possibilities and challenges of targeting LCN2 as a potential therapeutic strategy for metabolic disorders and neurological complications.
Lipocalin-2 (LCN2) is an acute phase protein with multiple functions that has garnered a great deal of interest over the last decade. However, its precise role in the pathophysiology of the central ...nervous system (CNS) remains to be outlined. Emerging evidence indicates that LCN2 is synthesized and secreted as an inducible factor from activated microglia, reactive astrocytes, neurons, and endothelial cells in response to inflammatory, infectious, or injurious insults. More recently, it has been recognized as a modulatory factor for diverse cellular phenotypes in the CNS, such as cell death, survival, morphology, migration, invasion, differentiation, and functional polarization. LCN2 induces chemokine production in the CNS in response to inflammatory challenges, and actively participates in the innate immune response, cellular influx of iron, and regulation of neuroinflammation and neurodegeneration. LCN2 also modulates several biobehavioral responses including pain hypersensitivity, cognitive functions, emotional behaviors, depression, neuronal excitability, and anxiety. This review covers recent advances in our knowledge regarding functional roles of LCN2 in the CNS, and discusses how LCN2 acts as an autocrine mediator of astrocytosis, a chemokine inducer, and a modulator of various cellular phenotypes in the CNS. We finally explore the possibilities and challenges of employing LCN2 as a signature of several CNS anomalies.
Lipocalin-2 (LCN2) is a 25 kDa secreted protein that belongs to the family of lipocalins, a group of transporters of small hydrophobic molecules such as iron, fatty acids, steroids, and ...lipopolysaccharide in circulation. LCN2 was previously found to be involved in iron delivery, pointing toward a potential role for LCN2 in immunity. This idea was further validated when LCN2 was found to limit bacterial growth during infections in mice by sequestering iron-laden siderophores. Recently, LCN2 was also identified as a critical regulator of energy metabolism, glucose and lipid homeostasis, and insulin function. Furthermore, studies using
knockout mice suggest an important role for LCN2 in several biobehavioral responses, including cognition, emotion, anxiety, and feeding behavior. Owing to its expression and influence on multiple metabolic and neurological functions, there has emerged a great deal of interest in the study of relationships between LCN2 and neurometabolic complications. Thorough investigation has demonstrated that LCN2 is involved in several neurodegenerative diseases, while more recent studies have shown that LCN2 is also instrumental for the progression of diabetic complications like encephalopathy and peripheral neuropathy. Preliminary findings have shown that LCN2 is also a promising drug target and diagnostic marker for the treatment of neuropathic complications from diabetes. In particular, future translational research related to LCN2, such as the development of small-molecule inhibitors or neutralizing antibodies against LCN2, appears essential for exploring its potential as a therapeutic target.
Lipocalin‐2 (LCN2) has diverse functions in multiple pathophysiological conditions; however, its pathogenic role in vascular dementia (VaD) is unknown. Here, we investigated the role of LCN2 in VaD ...using rodent models of global cerebral ischemia and hypoperfusion with cognitive impairment and neuroinflammation. Mice subjected to transient bilateral common carotid artery occlusion (tBCCAo) for 50 min showed neuronal death and gliosis in the hippocampus at 7 days post‐tBCCAo. LCN2 expression was observed predominantly in the hippocampal astrocytes, whereas its receptor was mainly detected in neurons, microglia, and astrocytes. Furthermore, Lcn2‐deficient mice, compared with wild‐type animals, showed significantly weaker CA1 neuronal loss, cognitive decline, white matter damage, blood–brain barrier permeability, glial activation, and proinflammatory cytokine production in the hippocampus after tBCCAo. Lcn2 deficiency also attenuated hippocampal neuronal death and cognitive decline at 30 days after unilateral common carotid artery occlusion (UCCAo). Furthermore, intracerebroventricular (i.c.v) injection of recombinant LCN2 protein elicited CA1‐neuronal death and a cognitive deficit. Our studies using cultured glia and hippocampal neurons supported the decisive role of LCN2 in hippocampal neurotoxicity and microglial activation, and the role of the HIF‐1α–LCN2–VEGFA axis of astrocytes in vascular injury. Additionally, plasma levels of LCN2 were significantly higher in patients with VaD than in the healthy control subjects. These results indicate that hippocampal damage and cognitive impairment are mediated by LCN2 secreted from reactive astrocytes in VaD.
Main Points
Astrocyte‐derived LCN2 mediates hippocampal damage in rodent models of vascular dementia, with higher plasma levels of LCN2 protein in patients with vascular dementia, suggesting the possibility of effective glia‐based treatment for vascular dementia.
Cathelicidin‐related antimicrobial peptide (CRAMP) is an effector molecule of the innate immune system with direct antimicrobial and immunomodulatory activities; however, its role in ...neuroinflammatory responses and related diseases is not clearly understood. In particular, the expression of CRAMP and its functional role has not been previously studied in experimental autoimmune encephalomyelitis (EAE) or multiple sclerosis (MS). Here, we investigated the role of CRAMP in neuroinflammation, using an EAE mouse model of MS and postmortem patient tissues. We found that the CRAMP expression was increased in the spinal cords of EAE‐induced mice. Immunofluorescence analysis revealed that CRAMP is mainly induced in reactive astrocytes in the inflamed spinal cord of EAE mice. A similar pattern of the LL‐37 (human CRAMP) expression was observed in the brain and spinal cord tissues of patients with MS. An intrathecal injection of the CRAMP peptide in EAE mice accelerated the onset of symptoms and increased disease severity with augmented expression of inflammatory mediators, glial activation, infiltration of inflammatory cells, and demyelination. In addition, shRNA‐mediated knockdown of Cramp in the spinal cord resulted in a milder disease course with less inflammation in EAE mice. We identified FPR2 on microglia as a CRAMP receptor and demonstrated that CRAMP potentiates IFN‐γ‐induced microglial activation via the STAT3 pathway. Taken together, our findings suggest that CRAMP is a novel mediator of astrocyte–microglia interactions in neuroinflammatory conditions such as EAE. Thus, CRAMP could be exploited as a biomarker or therapeutic target for the diagnosis or treatment of MS.
Main Points
We report that CRAMP is primarily induced in astrocytes in the spinal cords of EAE mice and MS patients.
CRAMP enhances neuroinflammation by potentiating IFN‐γ‐induced activation of microglial cells via CRAMP‐FPR2‐STAT3 signaling in EAE.
Diabetic peripheral neuropathy (DPN) is a common complication of uncontrolled diabetes. The pathogenesis of DPN is associated with chronic inflammation in dorsal root ganglion (DRG), eventually ...causing structural and functional changes. Studies on DPN have primarily focused on neuronal component, and there is limited knowledge about the role of satellite glial cells (SGCs), although they completely enclose neuronal soma in DRG. Lipocalin‐2 (LCN2) is a pro‐inflammatory acute‐phase protein found in high levels in diverse neuroinflammatory and metabolic disorders. In diabetic DRG, the expression of LCN2 was increased exclusively in the SGCs. This upregulation of LCN2 in SGCs correlated with increased inflammatory responses in DRG and sciatic nerve. Furthermore, diabetes‐induced inflammation and morphological changes in DRG, as well as sciatic nerve, were attenuated in Lcn2 knockout (KO) mice. Lcn2 gene ablation also ameliorated neuropathy phenotype as determined by nerve conduction velocity and intraepidermal nerve fiber density. Mechanistically, studies using specific gene KO mice, adenovirus‐mediated gene overexpression strategy, and primary cultures of DRG SGCs and neurons have demonstrated that LCN2 enhances the expression of mitochondrial gate‐keeping regulator pyruvate dehydrogenase kinase‐2 (PDK2) through PPARβ/δ, thereby inhibiting pyruvate dehydrogenase activity and increasing production of glycolytic end product lactic acid in DRG SGCs and neurons of diabetic mice. Collectively, our findings reveal a crucial role of glial LCN2‐PPARβ/δ‐PDK2‐lactic acid axis in progression of DPN. Our results establish a link between pro‐inflammatory LCN2 and glycolytic PDK2 in DRG SGCs and neurons and propose a novel glia‐based mechanism and drug target for therapy of DPN.
Main Points
Diabetes upregulates LCN2 in satellite glia, which in turn increases pyruvate dehydrogenase kinase‐2 (PDK2) expression and lactic acid production in dorsal root ganglia (DRG).
Glial LCN2‐PDK2‐lactic acid axis in DRG plays a crucial role in the pathogenesis of diabetic neuropathy.
Main Points
Diabetes upregulates LCN2 in satellite glia, which in turn increases pyruvate dehydrogenase kinase‐2 (PDK2) expression and lactic acid production in dorsal root ganglia (DRG).
Glial LCN2‐PDK2‐lactic acid axis in DRG plays a crucial role in the pathogenesis of diabetic neuropathy.
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Preclinical studies have suggested that chronic inflammation in the brain might be associated with multiple metabolic disorders, including obesity and diabetes. In particular, ...hypothalamic inflammation interferes with the endocrine system and modulates nutritional homeostasis, leading to metabolic alterations and consequent pathologies. With regard to the mechanisms underlying molecular and cellular pathogenesis, neurons, non-neuronal cells, and the crosstalk between them have gained particular attention. Specifically, malfunctioning glia have recently been implicated as an important component of pathological hypothalamic inflammation. Hypothalamic inflammation modulates food intake, energy expenditure, insulin secretion, hepatic glucose production, and glucose and fatty acid metabolism. Moreover, growing evidence suggests that hypothalamic inflammation is intrinsically associated with the pathogenesis of obesity, diabetes, and their dysfunctional consequences. However, the translational significance of hypothalamic inflammation has not yet been fully explored. In this review, we cover recent advances suggesting that hypothalamic inflammation and glia play a central role in the ontology of obesity, diabetes, and their complications. Finally, we explore the possibilities and challenges of targeting hypothalamic inflammation as a potential therapeutic strategy.
Astrocytes provide structural and functional support for neurons, as well as display neurotoxic or neuroprotective phenotypes depending upon the presence of an immune or inflammatory ...microenvironment. This study was undertaken to characterize multiple phenotypes of activated astrocytes and to investigate the regulatory mechanisms involved. We report that activated astrocytes in culture exhibit two functional phenotypes with respect to pro- or anti-inflammatory gene expression, glial fibrillary acidic protein expression, and neurotoxic or neuroprotective activities. The two distinct functional phenotypes of astrocytes were also demonstrated in a mouse neuroinflammation model, which showed pro- or anti-inflammatory gene expression in astrocytes following challenge with classical or alternative activation stimuli; similar results were obtained in the absence of microglia. Subsequent studies involving recombinant lipocalin-2 (LCN2) protein treatment or Lcn2-deficient mice indicated that the pro- or anti-inflammatory functionally polarized phenotypes of astrocytes and their intracellular signaling pathway were critically regulated by LCN2 under in vitro and in vivo conditions. Astrocyte-derived LCN2 promoted classical proinflammatory activation of astrocytes but inhibited IL-4-STAT6 signaling, a canonical pathway involved in alternative anti-inflammatory activation. Our results suggest that the secreted protein LCN2 is an autocrine modulator of the functional polarization of astrocytes in the presence of immune or inflammatory stimuli and that LCN2 could be targeted therapeutically to dampen proinflammatory astrocytic activation and related pathologies in the CNS.
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