Tamara Rodrigues
Gabriel Salles Beltrão
Aguinaldo R. Pinto- Laboratory of Applied Immunology, Department of Microbiology, Immunology and Parasitology, Center for Biological Sciences, Federal University of Santa Catarina, Florianópolis, Brazil
Considerable attention has been recently devoted to the involvement of immune cells in the central nervous system (CNS) during infections with neurotropic viruses, such as SARS-CoV-2, HIV-1, and ZIKV. These viruses are capable of infecting astrocytes and microglia, the main glial cells in the CNS, responsible for regulating neuronal activity. Here, we discuss how viral infections lead to metabolic reprogramming toward aerobic glycolysis in these cells, enhancing pro-inflammatory pathways, such as inflammasome activation, resulting in the secretion of inflammatory cytokines that favor the development of neuroinflammation. In this mini review, we discuss the pivotal interplay between metabolism and immunity towards viral pathogenesis in the CNS, pointing out the relevance of therapeutic strategies targeting both metabolic and immunological pathways to enhance antiviral and neuroprotective responses.
Introduction
The role of immune cells in the central nervous system (CNS) in response to infection, injury or illness has recently been the focus of significant debate, as modulating the signaling and function of these cells has a high potential as a viable target for therapeutic interventions. Microglia are the resident macrophages of the CNS and serve as the first line of defense against foreign agents. Under normal physiological conditions, microglia perform essential support functions for the neural tissue. These functions include synaptic pruning during development and maintaining brain homeostasis through phagocytosis of parenchymal debris. They also continuously monitor the neural environment for signs of cellular damage or infections. When activated, microglia change their morphology to an ameboid state and secrete inflammatory cytokines (1–3). Astrocytes, the most abundant glial cells in the CNS, play a crucial role in maintaining neuronal health. In addition to their basic support functions, astrocytes are involved in a variety of essential processes. These include providing structural and metabolic support, regulating synaptic activity, controlling blood flow and water transport, and preserving the integrity of the blood-brain barrier (BBB). Furthermore, these cells secrete neurotrophic factors like the Brain Derived Neurotrophic Factor (BDNF) and the Glial cell line-Derived Neurotrophic Factor (GDNF), which are vital for the survival of dopaminergic neurons (3–5).
In recent years, it has become clear that metabolism and immune function are closely linked. Notably, each population of immune cells possess a particular metabolic program and pattern of nutrient utilization (6). Microglia and astrocytes can adapt their metabolic profile in response to changes in their microenvironment or disease conditions (5, 7, 8). Among pathological stimuli, viral infections induce significant metabolic reprogramming that is central to effective antiviral immune responses (9). These changes involve shifts in glucose, lipid, and amino acid metabolism, supporting energy-intensive functions such as cytokine production, clonal expansion, and viral clearance (10). Thus, the interplay between metabolism and immunity is critical in viral pathogenesis, underscoring the importance of therapeutic strategies that target both metabolic and immune pathways to enhance antiviral protection. This review explores how viral infections modulate the metabolism of glial cells, with a special focus on microglia and astrocytes, highlighting their metabolic adaptations that contribute to neuroinflammation.
Glial immunometabolism in health and disease
Under physiological conditions, microglia and astrocytes utilize distinct yet complementary metabolic pathways to sustain their specialized roles. Through oxidative phosphorylation (OXPHOS), microglia maintain a metabolic profile that supports their homeostatic and immunoregulatory functions in the healthy brain (11). In this process, electrons derived from the oxidation of metabolic substrates are transferred through a series of protein complexes embedded in the inner mitochondrial membrane. The energy released drives the translocation of protons into the intermembrane space, creating an electrochemical gradient that is then utilized by adenosine triphosphate (ATP) synthase to phosphorylate adenosine diphosphate into ATP (12). This metabolic state is associated with low production of pro-inflammatory mediators and favors the expression of anti-inflammatory cytokines like interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β), which contribute to immune tolerance within the CNS (13). Additionally, OXPHOS enables microglia to preserve redox homeostasis by fueling antioxidant systems, including glutathione synthesis (14). Thus, OXPHOS not only sustains the energetic needs of homeostatic microglia but also underpins their neuroprotective and immunoregulatory functions in the healthy brain.
In pathological conditions, microglia undergo metabolic reprogramming that shifts their primary energy production from OXPHOS to aerobic glycolysis driven by inflammatory stimuli (15) (Figure 1). This shift involves the inhibition of tricarboxylic acid (TCA) cycle enzymes, notably isocitrate dehydrogenase and succinate dehydrogenase. Blocking these enzymatic steps leads to the accumulation of citrate and succinate. Succinate acts as an immunometabolic signal by stabilizing hypoxia-inducible factor 1-alpha (HIF-1α), promoting the transcription of glycolytic enzymes such as hexokinase 2 (HK2), phosphofructokinase (PFK), and the glucose transporter GLUT1, as well as pro-inflammatory mediators including IL-1β, Tumor Necrosis Factor (TNF-α), and nitric oxide (NO). Additionally, inflammatory signaling pathways such as AKT-mTOR contribute to this response by enhancing the translation and stabilization of HIF-1α, thereby intensifying aerobic glycolytic flux and the sustained production of these inflammatory mediators (16, 17). Concurrently, mitochondrial fragmentation is exacerbated, and the expression of OXPHOS components is reduced, impairing cellular respiration. Although glycolysis is less efficient in generating ATP, it is activated for its rapid ATP production and its ability to supply biosynthetic intermediates essential for the synthesis of inflammatory mediators, including IL-1β, TNF-α, and NO. However, this reprogramming also results in elevated production of reactive oxygen species (ROS) and a decline in phagocytic capacity, consolidating a persistently pro-inflammatory, metabolically impaired phenotype that exacerbates oxidative stress, disrupts tissue homeostasis, and perpetuates CNS inflammation (18).
Figure 1. Viral infection-induced metabolic alterations in microglia and astrocytes drive neuroinflammation. Homeostatic microglia and astrocytes undergo metabolic and inflammatory reprogramming during viral infection with Zika virus (ZIKV), SARS-CoV-2, or Human Immunodeficiency Virus (HIV), characterized by decreased oxidative phosphorylation (OXPHOS), increased glycolysis, and production of nitric oxide (NO), reactive oxygen species (ROS), and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). Created in BioRender. Beltrao, G. S. (2025) https://BioRender.com.
Astrocytes are metabolically specialized to support both neuronal activity and local immune responses. Under physiological conditions, they primarily rely on aerobic glycolysis, converting glucose into lactate, which is exported to neurons as an energy substrate through the astrocyte-neuron lactate shuttle (5). This metabolic strategy enables rapid ATP generation and the production of biosynthetic intermediates necessary for neurotransmitter recycling, ion homeostasis, and maintenance of synaptic function (19). In addition to glucose metabolism, astrocytes exhibit remarkable metabolic flexibility, engaging in fatty acid oxidation and glutaminolysis, particularly under conditions of increased energy demand or oxidative stress (20).
In pathological contexts, astrocytes undergo metabolic remodeling that transforms their functional profile. In chronic neuroinflammatory conditions, they shift into a reactive state marked by hypertrophy, altered transcriptional programs, and loss of homeostatic roles (21) (Figure 1). This transformation is often driven by microglial-derived proteins, including IL-1α, TNF-α, and complement component C1q, which collectively induce a reactive pro-inflammatory astrocyte (A1) (22). A1 astrocytes lose their neuroprotective capacities and begin secreting pro-inflammatory and neurotoxic molecules, such as complement C3, that exacerbate neuronal injury. Metabolically, these cells exhibit impaired OXPHOS and reduced fatty acid oxidation, accompanied by a compensatory increase in glycolytic flux and glutaminolysis. This shift compromises mitochondrial efficiency and antioxidant defenses, leading to elevated oxidative stress and impaired regulation of glutamate uptake, similar to the reactive pro-inflammatory microglia (23). As a result, neuronal excitotoxicity, synaptic dysfunction, and BBB disruption are intensified. Reactive astrocytes also contribute to glial scar formation, limiting tissue repair and facilitating chronic immune cell infiltration. Collectively, these changes are active contributors to disease progression, sustaining CNS inflammation and neurodegeneration (24).
Therefore, glial cells play an essential role in CNS homeostasis and are rapidly responsive to pathological stimuli, undergoing metabolic changes that lead to their activation. The microglial activation reflects their immune-sensing and inflammatory cytokine production, while astrocytic activation corresponds to their transition into reactive phenotypes (A1/A2) involving metabolic and functional reprogramming (25–27).
Viral modulation of glial metabolism
Neurotropic viruses such as Zika virus (ZIKV), Severe Acute Respiratory Syndrome Virus 2 (SARS-CoV-2), and Human Immunodeficiency virus 1 (HIV-1) modulate the metabolism of the host cell to invade, persist, and replicate within the CNS (10, 28, 29). When infecting glial cells, such as microglia and astrocytes, neurotropic viruses modulate the intracellular metabolism of host cells, changing the energy production pathway from OXPHOS to glycolysis, decreasing the Pentose Phosphate Pathway (PPP), and increasing the TCA cycle (10, 28).
SARS-CoV-2 infects astrocytes via the Neuropilin 1 receptor (NRP1) and modulates the glycolysis pathway, reducing pyruvate and lactate levels, in addition to affecting the production of essential intermediates of the PPP. The glutaminolysis and TCA pathways also change in glial cells, leading to a decrease in glutamine and its metabolites, such as GABA, glutamate and alpha-ketoglutarate. These changes suggest a compromise in energy metabolism, mainly in the glycolysis and glutaminolysis pathways, which are crucial for neuronal support and cerebral homeostasis, as demonstrated in postmortem human brain slice cultures (30, 31). In the human microglial cell line HMC3, the SARS-CoV-2 S protein increases the oxygen consumption rate (OCR), indicating mitochondrial dysfunction (32). Such metabolic changes might be triggering the observed pro-inflammatory phenotype in these cells, characterized by the release of IL-1β, IL-6 and TNF-α (29).
The neuronal cells are the main target of ZIKV infection in the CNS. The excessive inflammatory response caused by this infection is responsible for neuroinflammation and neuronal damage, which can lead to complications such as congenital microcephaly, Guillain-Barré Syndrome, transverse myelitis, and meningoencephalitis (33). Infection of astrocytes by ZIKV activates MAPK and leads to the degradation of NMNAT2, and, therefore, a reduction in nicotinamide adenine dinucleotide (NAD+), favoring metabolic dysfunctions. Such a response is explained by nicotinamide adenine dinucleotide (NAD+) metabolism, which is highly dependent on the degradation of MAPK-mediated nicotinamide adenylyltransferase 2 (NMNAT2) (34). The described metabolic dysfunctions trigger axon degeneration, indicating a critical impact on the pathogenesis of ZIKV-induced microcephaly. In addition, they interrupt the glycolytic flow in the TCA cycle in human primary astrocyte and microglia in vitro models, leading to mitochondrial dysfunction, which triggers inflammation, with the release of pro-inflammatory cytokines, such as IL-6, IL-1α, IL-4, IL-10, IL-8, and TNF-α, and resulting in neuronal cell death (35–37).
HIV is strongly associated with neurological complications and cognitive impairment. The HIV Tat protein accelerates cell damage in the CNS, in addition to activating astrocytes and damaging surrounding neurons in transgenic mouse models (38). Astrocytes’ metabolic response to the Tat protein is the alteration of aerobic glycolysis for mitochondrial respiration, mediated by the mitochondrial Ca2+ uniporter (MCU), which regulates the uptake of Ca2+; however, the direction of the MCU rescues glycolysis and normalizes the levels of extracellular lactate in the astrocyte. The Tat protein is also involved in the energy metabolism of glial cells, decreasing the activity of lactate dehydrogenase in activated astrocytes, which has led to a reduction in extracellular lactate levels (39, 40). HIV carriers have an imbalance in the levels of glutamate, a more abundant excitatory neurotransmitter, and GABA, an inhibitory neurotransmitter in the CNS, which can generate complications in brain functions, including alterations in synaptic signaling, cognition, motor stimuli and pain (28). Although robust data on metabolic reprogramming in glia are available mainly for ZIKV, HIV-1 and SARS-CoV-2, we have compiled a comprehensive summary in Table 1, including other neurotropic viruses (HSV-1, EBV, CMV, RABV), in order to also highlight knowledge gaps. For this reason, we will focus our discussion on ZIKV, HIV-1, and SARS-CoV-2, the viruses with the most consistent and well-documented evidence of glial metabolic reprogramming.
Table 1. Metabolic signatures and neurological manifestations induced by neurotropic viruses.
Inflammasomes at the interface between metabolism and viral neuroinflammation
Inflammasomes are cytosolic multiprotein complexes that play a crucial role in orchestrating inflammatory responses in multiple organs, including the CNS (62–64). Within the CNS, inflammasomes are expressed by a subset of glial cells, such as microglia and astrocytes, and, interestingly, have also been detected in neurons (65, 66).
Among the inflammasome complexes, NLRP3 is the most abundant and extensively investigated in the CNS, given its relevance to neuroinflammation and neurological disorders (64). The activation of NLRP3 recruits the adaptor molecule ASC and triggers the release of the pro-inflammatory cytokines IL-1β and IL-18, processed by caspase (casp-1), which compromises brain homeostasis and is associated with cognitive deficits and depressive-like behavior (64, 67, 68). Inflammasome activation can also induce pyroptosis, an inflammatory cell death mediated by gasdermin D (GSDMD), a pore-forming molecule, further aggravating neuronal damage (65, 69–71).
The activation of inflammasomes in glial cells remains controversial. In microglial BV2 cells, intrinsic NLRP3 activation can occur in response to diverse stimuli (72, 73). Astrocytes, in contrast, are traditionally viewed as being activated indirectly by microglia, which sense danger signals, activate NLRP3, and release IL-1β and IL-18, thereby promoting the A1 reactive astrocyte phenotype (27, 74). However, more recent evidence shows that astrocytes can also intrinsically activate inflammasomes. In Alzheimer’s disease, microglia activate pyroptosis via the canonical NLRP3 pathway, while astrocytes utilize alternative caspase-8 or caspase-4 dependent pathways, a process associated with neuronal loss (65). In rodent models of prion disease, GFAP+ astrocytes express NLRP3 and exhibit GSDMD cleavage, contributing to inflammation and neuronal death (75).
Other studies show that AIM2 inflammasome could also be activated in astrocytes. In the experimental autoimmune encephalomyelitis model, inflammasome activation occurs mainly in resident astrocytes, depends on AIM2, and does not involve cell death and a robust IL-1β secretion, indicating a less inflammatory function (76). Interestingly, evidence also points to homeostatic roles for inflammasomes in the CNS. Hippocampal ASC clusters disassemble during cognitive tasks, and the deletion of astrocytes casp-1 alters neuronal excitability and memory, supporting a regulatory role in brain physiology (77).
Oxidative stress plays a central role in NLRP3 inflammasome activation, with ROS acting as a major upstream signal, including in neuronal cells (78–83). Metabolic shifts, such as increased glycolysis, accumulation of succinate, and compromised mitochondrial function, promote NLRP3 inflammasome activation, positioning it as a central mediator between bioenergetic stress and inflammation (84–86). For instance, the M2 isoform of muscle pyruvate kinase (PKM2), which catalyzes the final reaction of the glycolytic pathway, induces NLRP3 and AIM2 inflammasome activation (87). Furthermore, succinate accumulation acts as an inflammatory signal, inducing IL-1β production through HIF-1α (86) and ROS generation (88). In addition to these upstream effects, there is growing evidence that inflammasome activation also remodels glial metabolism, establishing a bidirectional axis between metabolism and inflammation. In microglia, NLRP3 activation reinforces a pro-inflammatory bioenergetic state, reducing mitochondrial flexibility, while its inhibition increases OXPHOS and reprograms glial metabolism (89). The NLRP3 inflammasome can induce glycolysis via 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), leading to microglial polarization towards the M1 phenotype (85, 90). In addition, casp-1 cleavage in astrocytes regulates metabolic pathways by modulating pyruvate flow into mitochondria, directly influencing glycolysis, TCA, and mTORC activity (46).
Viral infection in the CNS is a potent inducer of inflammasome-mediated neuroinflammation. For example, ZIKV can infect and replicate in glial cells, including microglia, inducing NLRP3 activation, resulting in the release of mature IL-1β (44, 67). This inflammatory response has deleterious consequences for neurodevelopment, as ZIKV infection can lead to severe birth defects, such as microcephaly, by affecting neural progenitors and impairing brain development (67, 91). In addition, the P2X7 receptor, a key upstream activator of the NLRP3 inflammasome, is highly expressed in the brains of infected mice, contributing to neuronal loss, neuroinflammation, and brain anomalies by inhibiting the neuroprotective AKT/mTOR pathway (67). However, a recent study showed that ZIKV activates casp-1 in primary astrocytes even in the absence of other inflammasome signals, and astrocytes deficient for casp-1 and caspase-11 (Casp1/11-/-) become more permissive to ZIKV replication due to glycolytic hyperactivation, indicating that inflammasomes also participate in antiviral control in these cells (46). Therefore, although inflammasomes can trigger potentially deleterious inflammatory responses, their components also perform non-canonical functions, such as modulating cellular metabolism and controlling viral replication.
Regarding SARS-CoV-2, the S1 protein can cross the BBB (80) and induce neuroinflammation, even in the absence of productive infection, with S1 binding to microglial TLR4 receptors (81, 92). It is well established that SARS-CoV-2 activates the NLRP3 inflammasome and contributes to disease severity (93–95). SARS-CoV-2 infection in transgenic animal models results in microglial activation and upregulation of the NLRP3 inflammasome in the brain, accompanied by an increase in casp-1 activity and IL-1β production (96, 97). Similarly, NLRP3 was active in the brains of COVID-19 cases, associated with microglial dysfunction, significant morphological changes, and microglial degeneration (41, 42, 98). Metabolic failure and mitochondrial damage, associated with the efflux of Cytochrome c (Cytc), are also observed in areas of the brain affected by vascular inflammation related to viral antigens (42). The consequences of NLRP3 activation include cognitive impairment, neuronal loss, and neuroinflammation (96). This inflammatory cycle can become chronic, leading to persistent microglial dysfunction and neurodegeneration, as observed in SARS-CoV-2 and HIV-1 infections (99–103). Thus, inflammasomes can act as sensors of cellular metabolism and also modulate it: when acutely activated, they can contribute to the control of viral infections; however, their persistent activation can promote neuroinflammation, lasting neural damage, and compromise brain function.
Therapeutic implications and future directions
As glial cells alter their metabolic programs during inflammation, especially changing from OXPHOS to glycolysis (104), these metabolic changes offer actionable targets for therapeutic intervention in CNS infections. To modulate the OXPHOS pathway, therapeutic targets have focused on promoting an anti-inflammatory phenotype of microglia and restoring mitochondrial function, aiming to enhance the use of the OXPHOS pathway and consequently contribute to neuroprotection and brain recovery. On the other hand, the main therapeutic targets of glycolysis focus on inhibiting specific enzymes, such as PFKFB3 and PKM2, thereby decreasing microglial pro-inflammatory activation by restraining hyperactive glycolysis (105–107). The modulation of these two pathways has been presented as a potential therapeutic strategy in neurodegenerative diseases, such as Alzheimer’s Disease (AD) and Multiple Sclerosis (MS) (108).
Pharmacological agents have been used as metabolic interventions to limit viral replication and preserve neuronal function. Glycolysis inhibitors, such as 2-DG, a drug that structurally mimics glucose, are promising against excessive inflammation, in addition to metabolic modulators that transform immune metabolism towards OXPHOS, such as metformin and AMPK activators. Additionally, ketogenic diets have shown promising responses in neuroprotection in viral infections in the CNS (10, 109). A clinical trial using 2-DG along with standard medications for concomitant treatment of moderate to severe COVID-19 resulted in faster recovery of patients as measured by oxygen levels, time to discharge and normalization of vital signs, as well as by increment on tolerance to treatment as revealed by the presence of moderate side effects (110). However, CNS viral disease pathogenesis requires therapeutic strategies that integrate glial cell activation and metabolic control. The decrease or remission of neuroinflammation caused by viral invasion can help relieve symptoms and reduce severe neurological sequelae. The currently available antiviral drugs are not effective for CNS infections, demanding a deeper understanding of viral neuropathogenesis, improvement of strategies for the treatment and diagnosis of these infections (10, 28).
In neurodegenerative diseases, modulation of microglial metabolism has become a possible therapeutic strategy to restore cellular homeostasis and reduce neuroinflammation. For instance, metformin and rapamycin are pharmacological agents that inhibit the AKT-mTOR-HIF-1α and AMPK-mTOR-HIF-1α pathways, contributing to a decrease in energy production by glycolysis while increasing production by the OXPHOS pathway, consequently reducing the production of pro-inflammatory cytokines. Metformin acts on the mTOR pathway by targeting AMPK, while rapamycin directly inhibits mTOR activity by binding to mTORC1 (17, 109). The Triggering Receptor Expressed in Myeloid Cells 2 (TREM2) could be another target to modulate the mTOR pathway in microglia, in the absence of which, it may result in defective glycolysis. However, there are still not enough studies on pharmacological agents that modulate TREM2 directly, making it difficult to understand the functionality of TREM2 and its precise association with neurological disorders (17, 111). In addition, modulating glucose microglial metabolism remains incompletely understood regarding its efficacy in changing microglial phenotype, immunological tolerance and the neuropathogenesis of neurodegenerative diseases (17). Therefore, current data highlight the need for further studies aimed at therapeutic development in neuroinflammation caused by viral infections.
Final remarks
This review points out that viral infections caused by neurotropic viruses, such as HIV, SARS-CoV-2, and ZIKV, modulate the metabolism of glial cells, especially microglia and astrocytes, causing metabolic adaptations that contribute to neuroinflammation through inflammatory mechanisms, such as the activation of inflammasomes. Under physiological conditions, microglia and astrocytes utilize distinct metabolic pathways, with the former utilizing OXPHOS while astrocytes are predominantly glycolytic, however, under pathological conditions such as viral infections, microglia shift their primary energy production to aerobic glycolysis and adopt a more glycolytic metabolism, similar to astrocytes. Aerobic glycolysis favors the activation of inflammasomes, which are often associated with the pathogenesis of these diseases, inducing an exacerbated inflammatory response. This inflammatory cycle can lead to the dysfunction of glial cells, inducing neurodegeneration in viral infections.
Despite substantial advances, important limitations remain in the study of glial cells. Differences between human and mouse glia, the restricted access to primary human CNS tissue, and the heterogeneity of glial states across brain regions limit the generalizability of many mechanistic findings (112–114). In addition, although in vitro models using isolated glial populations are essential for dissecting cell-intrinsic pathways with experimental precision, they only partially capture the dynamic interactions that occur between microglia and astrocytes in vivo. Microglia and astrocytes are known to communicate through various molecular signals, such as the release of metabolites and cytokines, and their reciprocal signaling significantly influences neuroinflammation (115, 116). For instance, the metabolic state and cytokine profile of microglia can determine whether astrocytes adopt protective or neurotoxic reactive phenotypes (27). Thus, complementary approaches, including iPSC-derived glia, co-cultures, and 3D organoids, are therefore valuable to contextualize how inflammasome signaling and metabolic reprogramming emerge in more physiologically integrated environments.
Although there is a limitation in selectively modulating the metabolism of specific cells, the similar metabolic changes in astrocytes and microglia lead us to believe that targeting cellular metabolism may be a promising neuroprotective therapeutic strategy and may be important for the development of biomarkers. Further mechanistic and translational research is warranted to clarify these functions and explore these metabolic pathways as therapeutic targets in neuroinflammation.
Author contributions
TR: Conceptualization, Investigation, Project administration, Supervision, Visualization, Writing – original draft, Writing – review & editing, Data curation, Methodology. GB: Conceptualization, Data curation, Investigation, Methodology, Software, Visualization, Writing – original draft, Writing – review & editing. HG: Conceptualization, Data curation, Investigation, Methodology, Software, Visualization, Writing – original draft, Writing – review & editing. AP: Conceptualization, Data curation, Investigation, Visualization, Writing – original draft, Writing – review & editing, Funding acquisition, Project administration, Resources, Supervision.
Funding
The author(s) declared financial support was received for this work and/or its publication. This work was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and the Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina (FAPESC).
Acknowledgments
We thank Dr. Edmundo Grisard for his critical review and valuable contributions to improving the manuscript’s quality and clarity.
Conflict of interest
The authors declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
1. Lehnardt S. Innate immunity and neuroinflammation in the CNS: the role of microglia in Toll-like receptor-mediated neuronal injury. Glia. (2010) 58:253–63. doi: 10.1002/glia.20928
2. Jin X and Yamashita T. Microglia in central nervous system repair after injury. J Biochem. (2016) 159:491–6. doi: 10.1093/jb/mvw009
3. Kwon HS and Koh SH. Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Transl Neurodegener. (2020) 9:42. doi: 10.1186/s40035-020-00221-2
4. Booth HDE, Hirst WD, and Wade-Martins R. The role of astrocyte dysfunction in parkinson’s disease pathogenesis. Trends Neurosci. (2017) 40:358–70. doi: 10.1016/j.tins.2017.04.001
5. Zhang YM, Qi YB, Gao YN, Chen WG, Zhou T, Zang Y, et al. Astrocyte metabolism and signaling pathways in the CNS. Front Neurosci. (2023) 17:1217451. doi: 10.3389/fnins.2023.1217451
6. Makowski L, Chaib M, and Rathmell JC. Immunometabolism: From basic mechanisms to translation. Immunol Rev. (2020) 295:5–14. doi: 10.1111/imr.12858
7. Lonkar N, Latz E, and McManus RM. Neuroinflammation and immunometabolism in neurodegenerative diseases. Curr Opin Neurol. (2025) 38:163–71. doi: 10.1097/WCO.0000000000001356
8. Traetta ME, Vecchiarelli HA, and Tremblay MÈ. Fundamental Neurochemistry Review: Lipids across microglial states. J Neurochem. (2025) 169:16259. doi: 10.1111/jnc.16259
9. Palmer CS. Innate metabolic responses against viral infections. Nat Metab. (2022) 4:1245–59. doi: 10.1038/s42255-022-00652-3
10. Darweesh M, Mohammadi S, Rahmati M, Al-Hamadani M, and Al-Harrasi A. Metabolic reprogramming in viral infections: the interplay of glucose metabolism and immune responses. Front Immunol. (2025) 16:1578202. doi: 10.3389/fimmu.2025.1578202
11. Hasel P, Aisenberg WH, Bennett FC, and Liddelow SA. Molecular and metabolic heterogeneity of astrocytes and microglia. Cell Metab. (2023) 35:555–70. doi: 10.1016/j.cmet.2023.03.006
12. Lehninger AL, Wadkins CL, Cooper C, Devlin TM, and Gamble JL Jr. Oxidative phosphorylation. Science. (1958) 128:450–6. doi: 10.1126/science.128.3322.450
13. Borst K, Schwabenland M, and Prinz M. Microglia metabolism in health and disease. Neurochem Int. (2019) 130:104331. doi: 10.1016/j.neuint.2018.11.006
14. Rojo AI, McBean G, Cindric M, Egea J, López MG, Rada P, et al. Redox control of microglial function: molecular mechanisms and functional significance. Antioxid Redox Signal. (2014) 21:1766–801. doi: 10.1089/ars.2013.5745
15. Lauro C and Limatola C. Metabolic reprograming of microglia in the regulation of the innate inflammatory response. Front Immunol. (2020) 11:493. doi: 10.3389/fimmu.2020.00493
16. Bai J, Geng B, Wang X, Wang S, Yi Q, Tang Y, et al. Exercise facilitates the M1-to-M2 polarization of microglia by enhancing autophagy via the BDNF/AKT/mTOR pathway in neuropathic pain. Pain Physician. (2022) 25:1137–51.
17. Huang Q, Wang Y, Chen S, and Liang F. Glycometabolic reprogramming of microglia in neurodegenerative diseases: insights from neuroinflammation. Aging Dis. (2024) 15:1155–75. doi: 10.14336/AD.2023.0807
18. Muzio L, Viotti A, and Martino G. Microglia in neuroinflammation and neurodegeneration: from understanding to therapy. Front Neurosci. (2021) 15:742065. doi: 10.3389/fnins.2021.742065
19. Siracusa R, Fusco R, and Cuzzocrea S. Astrocytes: role and functions in brain pathologies. Front Pharmacol. (2019) 10:1114. doi: 10.3389/fphar.2019.01114
20. Calì C, Cantando I, Veloz Castillo MF, Gonzalez L, and Bezzi P. Metabolic reprogramming of astrocytes in pathological conditions: implications for neurodegenerative diseases. Int J Mol Sci. (2024) 25:8922. doi: 10.3390/ijms25168922
21. Xiong XY, Tang Y, and Yang QW. Metabolic changes favor the activity and heterogeneity of reactive astrocytes. Trends Endocrinol Metab. (2022) 33:390–400. doi: 10.1016/j.tem.2022.03.001
22. Patani R, Hardingham GE, and Liddelow SA. Functional roles of reactive astrocytes in neuroinflammation and neurodegeneration. Nat Rev Neurol. (2023) 19:395–409. doi: 10.1038/s41582-023-00822-1
23. Singh D. Astrocytic and microglial cells as the modulators of neuroinflammation in Alzheimer’s disease. J Neuroinflammation. (2022) 19:206. doi: 10.1186/s12974-022-02565-0
24. Brandebura AN, Paumier A, Onur TS, and Allen NJ. Astrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders. Nat Rev Neurosci. (2023) 24:23–39. doi: 10.1038/s41583-022-00641-1
25. Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. Neuro-toxic reactive astrocytes are induced by activated microglia. Nature. (2017) 541:481–7. doi: 10.1038/nature21029
26. Liu D, Wei Y, Liu Y, Wu T, Hu J, and Lu H. The long non-coding RNA NEAT1/miR-224-5p/IL-33 axis modulates macrophage M2a polarization and A1 astrocyte activation. Mol Neurobiol. (2021) 58:4506–19. doi: 10.1007/s12035-021-02405-x
27. Lawrence JM, Schardien K, Wigdahl B, and Nonnemacher MR. Roles of neuropathology-associated reactive astrocytes: a systematic review. Acta Neuropathol Commun. (2023) 11:42. doi: 10.1186/s40478-023-01526-9
28. Wongchitrat P, Chanmee T, and Govitrapong P. Molecular mechanisms associated with neurodegeneration of neurotropic viral infection. Mol Neurobiol. (2024) 61:2881–903. doi: 10.1007/s12035-023-03761-6
29. Jeong GU, Lyu J, Kim K, Chung YC, Yoon GY, Lee S, et al. SARS-coV-2 infection of microglia elicits proinflammatory activation and apoptotic cell death. Microbiol Spectr. (2022) 10:e0109122. doi: 10.1128/spectrum.01091-22
30. Crunfli F, Carregari VC, Veras FP, Silva LS, Nogueira MH, Antunes ASLM, et al. Morphological, cellular, and molecular basis of brain infection in COVID-19 patients. Proc Natl Acad Sci U S A. (2022) 119:e2200960119. doi: 10.1073/pnas.2200960119
31. Kong W, Montano M, Corley MJ, Helmy E, Kobayashi H, Kinisu M, et al. Neuropilin-1 mediates SARS-coV-2 infection of astrocytes in brain organoids, inducing inflammation leading to dysfunction and death of neurons. mBio. (2022) 13:e0230822. doi: 10.1128/mbio.02308-22
32. Clough E, Inigo J, Chandra D, Chaves L, Reynolds JL, Aalinkeel R, et al. Mitochondrial dynamics in SARS-COV2 spike protein treated human microglia: implications for neuro-COVID. J Neuroimmune Pharmacol. (2021) 16:770–84. doi: 10.1007/s11481-021-10015-6
33. Carod-Artal FJ. Neurological complications of Zika virus infection. Expert Rev Anti Infect Ther. (2018) 16:399–410. doi: 10.1080/14787210.2018.1466702
34. Pang H, Jiang Y, Li J, Wang Y, Nie M, Xiao N, et al. Aberrant NAD+ metabolism underlies Zika virus-induced microcephaly. Nat Metab. (2021) 3:1109–24. doi: 10.1038/s42255-021-00437-0
35. Ojha CR, Rodriguez M, Karuppan MKM, Lapierre J, Kashanchi F, and El-Hage N. Toll-like receptor 3 regulates Zika virus infection and associated host inflammatory response in primary human astrocytes. PloS One. (2019) 14:e0208543. doi: 10.1371/journal.pone.0208543
36. Lum F, Low DKS, Fan Y, Tan JJL, Lee B, Chan JKY, et al. Zika virus infects human fetal brain microglia and induces inflammation. Clin Infect Dis. (2017) 64:914–20. doi: 10.1093/cid/ciw878
37. Yau C, Low JZH, Gan ES, Kwek SS, Cui L, Tan HC, et al. Dysregulated metabolism underpins Zika-virus-infection-associated impairment in fetal development. Cell Rep. (2021) 37:110118. doi: 10.1016/j.celrep.2021.110118
38. Zhao X, Fan Y, Vann PH, Wong JM, Sumien N, and He JJ. Long-term HIV-1 tat expression in the brain led to neurobehavioral, pathological, and epigenetic changes reminiscent of accelerated aging. Aging Dis. (2020) 11:93–107. doi: 10.14336/AD.2019.0323
39. Sivalingam K, Cirino TJ, McLaughlin JP, and Samikkannu T. HIV-tat and cocaine impact brain energy metabolism: redox modification and mitochondrial biogenesis influence NRF transcription-mediated neurodegeneration. Mol Neurobiol. (2021) 58:490–504. doi: 10.1007/s12035-020-02131-w
40. Campbell GR, Rawat P, To RK, and Spector SA. HIV-1 tat upregulates TREM1 expression in human microglia. J Immunol. (2023) 11:429–42. doi: 10.4049/jimmunol.2300152
41. Cama VF, Marín-Prida J, Acosta-Rivero N, Acosta EF, Díaz LO, Casadesús AV, et al. The microglial NLRP3 inflammasome is involved in human SARS-CoV-2 cerebral pathogenicity: A report of three post-mortem cases. J Neuroimmuno. (2021) 361:577728. doi: 10.1016/j.jneuroim.2021.577728
42. Fekete R, Simats A, Bíró E, Pósfai B, Cserép C, Schwarcz AD, et al. Microglia dysfunction, neurovascular inflammation and focal neuropathologies are linked to IL-1- and IL-6-related systemic inflammation in COVID-19. Nat Neurosci. (2025) 28:558–76. doi: 10.1038/s41593-025-01871-z
43. Sánchez KE and Rosenberg GA. Shared inflammatory pathology of stroke and COVID-19. Int J Mol Sci. (2022) 23:5150. doi: 10.3390/ijms23095150
44. Tricarico PM, Caracciolo I, Crovella S, and D’Agaro P. Zika virus induces inflammasome activation in the glial cell line U87-MG. Biochem Biophys Res Commun. (2017) 492:597–602. doi: 10.1016/j.bbrc.2017.01.158
45. Gim E, Shim D, Hwang I, Shin OS, and Yu J. Zika virus impairs host NLRP3-mediated inflammasome activation in an NS3-dependent manner. Immune Netw. (2019) 19:e40. doi: 10.4110/in.2019.19.e40
46. de Farias IS, Ribeiro G, Noronha IH, Lucena VWL, Peron JP, Moraes-Vieira PM, et al. Caspase-1/11 controls Zika virus replication in astrocytes by inhibiting glycolytic metabolism. FEBS J. (2025) 292:3113–28. doi: 10.1111/febs.70061
47. Walsh JG, Reinke SN, Mamik MK, McKenzie BA, Maingat F, Branton WG, et al. Rapid inflammasome activation in microglia contributes to brain disease in HIV/AIDS. Retrovirology. (2014) 11:35. doi: 10.1186/1742-4690-11-35
48. Fattakhov N, Ngo A, Torices S, Joseph J, Okoro A, Moore C, et al. Cenicriviroc prevents dysregulation of astrocyte/endothelial cross talk induced by ischemia and HIV-1 via inhibiting the NLRP3 inflammasome and pyroptosis. Am J Physiol Cell Physiol. (2024) 326:C487–C504. doi: 10.1152/ajpcell.00600.2023
49. Xu XQ, Xu T, Ji W, Wang C, Ren Y, Xiong X, et al. Herpes simplex virus 1-induced ferroptosis contributes to viral encephalitis. ASM J. (2023) 14:e0237022. doi: 10.1128/mbio.02370-22
50. Gonzalez-Dosal R, Horan KA, Rahbek SH, Ichijo H, Chen ZJ, Mieyal JJ, et al. HSV infection induces production of ROS, which potentiate signaling from pattern recognition receptors: role for S-glutathionylation of TRAF3 and 6. PloS Pathog. (2011) 7:e1002250. doi: 10.1371/journal.ppat.1002250
51. Schachtele SJ, Hu S, Little WR, and Lokensgard JR. Research Herpes simplex virus induces neural oxidative damage via microglial cell Toll-like receptor-2. J Neuroinflammation. (2010) 7:35. doi: 10.1186/1742-2094-7-35
52. Feige L, Zaeck LM, Sehl-Ewert J, Finke S, and Bourhy H. Innate immune signaling and role of glial cells in herpes simplex virus- and rabies virus-induced encephalitis. Viruses. (2021) 13:2364. doi: 10.3390/v13122364
53. Wang Z, Liu J, Han J, Zhang T, Li S, Hou Y, et al. Herpes simplex virus 1 accelerates the progression of Alzheimer’s disease by modulating microglial phagocytosis and activating NLRP3 pathway. J Neuroinflamm. (2024) 21:176. doi: 10.1186/s12974-024-03166-9
54. Hensel N, Raker V, Förthmann B, Buch A, Sodeik B, Pich A, et al. The proteome and secretome of cortical brain cells infected with herpes simplex virus. Front Neurol. (2020) 11:844. doi: 10.3389/fneur.2020.00844
55. Zhang N, Zou Y, Jiang L, Peng Y, Huang X, and Zou L. Epstein-barr virus and neurological diseases. Front Mol Biosci. (2022) 8:816098. doi: 10.3389/fmolb.2021.816098
56. Cao Y, Xie L, Shi F, Tang M, Li Y, Hu J, et al. Targeting the signaling in Epstein–Barr virus-associated diseases: mechanism, regulation, and clinical study. Signal Transduct Target Ther. (2021) 6:15. doi: 10.1038/s41392-020-00376-4
57. Ballerini C, Amoriello R, Maghrebi O, Belluci G, Addazio I, Betti M, et al. Exploring the role of EBV in multiple sclerosis pathogenesis through EBV interactome. Front Immunol. (2025) 16:1557483. doi: 10.3389/fimmu.2025.1557483
58. Yu M, Zhang X, Wang Z, Wang S, Li J, Huang H, et al. Brain-specific expression of cytomegalovirus immediate early protein 1 disrupts neurodevelopment in mice by inducing neuroinflammation and altering astrocytic metabolism. Virol J. (2025) 22:258. doi: 10.1186/s12985-025-02874-9
59. Kvestak D, Lisnic VJ, Lisnic B, Tomac J, Golemac M, Brizic I, et al. NK/ILC1 cells mediate neuroinflammation and brain pathology following congenital CMV infection. J Exp Med. (2021) 218:e20201503. doi: 10.1084/jem.20201503
60. Pei J, Yuan Y, Tian D, Huang F, Zhang C, Wang C, et al. Comprehensive analysis of protein acetylation and glucose metabolism in mouse brains infected with rabies virus. J Virol. (2022) 96:e0194221. doi: 10.1128/JVI.01942-21
61. Kiflu A. The immune escape strategy of rabies virus and its pathogenicity mechanisms. Viruses. (2024) 16:1774. doi: 10.3390/v16111774
62. Gustin A, Kirchmeyer M, Koncina E, Felten P, Losciuto S, Heurtaux T, et al. NLRP3 inflammasome is expressed and functional in mouse brain microglia but not in astrocytes. PloS One. (2015) 10:e0130624. doi: 10.1371/journal.pone.0130624
63. Kim H, Seo JS, Lee SY, Ha KT, Choi BT, Shin Y, et al. AIM2 inflammasome contributes to brain injury and chronic post-stroke cognitive impairment in mice. Brain Behav Immun. (2020) 87:765–76. doi: 10.1016/j.bbi.2020.03.011
64. Martinon F, Burns K, and Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. (2002) 10:417–26. doi: 10.1016/s1097-2765(02)00599-3
65. Moonen S, Koper MJ, Van Schoor E, Schaeverbeke JM, Vandenberghe R, von Arnim CAF, et al. Pyroptosis in Alzheimer’s disease: cell type-specific activation in microglia, astrocytes and neurons. Acta Neuropathol. (2023) 145:175–95. doi: 10.1007/s00401-022-02528-y
66. Wong LJ, Lee BWL, Sng YJ, Poh L, Rajeev V, Selvaraji S, et al. Inflammasome activation mediates apoptotic and pyroptotic death in astrocytes under ischemic conditions. NeuroMol Med. (2023) 25:533–44. doi: 10.1007/s12017-023-08753-2
67. Leite-Aguiar R, Cristina-Rodrigues F, Ciarlini-Magalhães R, Dantas DP, Alves VS, Gavino-Leopoldino D, et al. ATP-P2X7 signaling mediates brain pathology while contributing to viral control in perinatal Zika virus infection. Brain Behav Immun. (2024) 118:318–33. doi: 10.1016/j.bbi.2024.02.035
68. Xia CY, Guo YX, Lian WW, Yan Y, Ma BZ, Cheng YC, et al. The NLRP3 inflammasome in depression: Potential mechanisms and therapies. Pharmacol Res. (2023) 187:106625. doi: 10.1016/j.phrs.2022.106625
69. Aglietti RA, Estevez A, Gupta A, Ramirez MG, Liu PS, Kayagaki N, et al. GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes. Proc Natl Acad Sci U S A. (2016) 113:7858–63. doi: 10.1073/pnas.1607769113
70. Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. (2015) 526:660–5. doi: 10.1038/nature15514
71. Van Schoor E, Ospitalieri S, Moonen S, Tomé SO, Ronisz A, Ok O, et al. Increased pyroptosis activation in white matter microglia is associated with neuronal loss in ALS motor cortex. Acta Neuropathol. (2022) 144:393–411. doi: 10.1007/s00401-022-02466-9
72. Xu X, Zhang L, Ye X, Hao Q, Zhang T, Cui G, et al. Nrf2/ARE pathway inhibits ROS-induced NLRP3 inflammasome activation in BV2 cells after cerebral ischemia reperfusion. Inflam Res. (2018) 67:57–65. doi: 10.1007/s00011-017-1095-6
73. Sun Y, Gao S-Q, Wang X, Li T, Han Y-L, Miao S-H, et al. Galectin-3 activates microglia and promotes neurological impairment via NLRP3/pyroptosis pathway following traumatic brain injury. Brain Res. (2025) 1855:149560. doi: 10.1016/j.brainres.2025.149560
74. Li X, Chen Y, Liu L, Zhu L, Zheng Y, Zhang J, et al. Galectin-3 induces microglial A1-like reactive phenotype through TLR4-NF-κB/NLRP3 signaling. J Neuroinflammation. (2022) 19:1–17. doi: 10.1016/j.expneurol.2024.114777
75. Zhou DH, Jia XX, Wu YZ, Zhang WW, Wang Y, Liang DL, et al. Aberrant enhanced NLRP3 inflammasomes and cell pyroptosis in brains of prion-infected rodent models are largely associated with proliferative astrocytes. Mol Neurobiol. (2024) 61:9582–94. doi: 10.1007/s12035-024-04169-6
76. Barclay WE, Aggarwal N, Deerhake ME, Inoue M, Nonaka T, Nozaki K, et al. The AIM2 inflammasome is activated in astrocytes during the late phase of EAE. JCI Insight. (2022) 7:e155563. doi: 10.1172/jci.insight.155563
77. Zengeler KE, Hollis A, Deutsch TCJ, Samuels JD, Ennerfelt H, Moore KA, et al. Inflammasome signaling in astrocytes modulates hippocampal plasticity. Immunity. (2025) 58:1519–153. doi: 10.1016/j.immuni.2025.04.007
78. Liu Q, Tan Y, Zhang ZW, Tang W, Han L, Peng KP, et al. The role of NLRP3 inflammasome-mediated pyroptosis in astrocytes during hyperoxia-induced brain injury. Inflammation Res. (2025) 74:25. doi: 10.1007/s00011-024-01984-4
79. Minutoli L, Puzzolo D, Rinaldi M, Irrera N, Marini H, Arcoraci V, et al. ROS-mediated NLRP3 inflammasome activation in brain, heart, kidney, and testis ischemia/reperfusion injury. Oxid Med Cell Longev. (2016) 2016:2183026. doi: 10.1155/2016/2183026
80. Rhea EM, Logsdon AF, Hansen KM, Williams LM, Reed MJ, Baumann KK, et al. The S1 protein of SARS-CoV-2 crosses the blood-brain barrier in mice. Nat Neurosci. (2021) 24:368–78. doi: 10.1038/s41593-020-00771-8
81. Zhao Y, Kuang M, Li J, Zhu L, Jia Z, Guo X, et al. SARS-CoV-2 spike protein interacts with and activates TLR41. Cell Res. (2021) 31:818–20. doi: 10.1038/s41422-021-00495-9
82. Peruzzotti-Jametti L, Willis CM, Krzak G, Hamel R, Pirvan L, Ionescu RB, et al. Mitochondrial complex I activity in microglia sustains neuroinflammation. Nature. (2024) 628:195–203. doi: 10.1038/s41586-024-07167-9
83. Tschopp J and Schroder K. NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production? Nat Rev Immunol. (2010) 10:210–5. doi: 10.1038/nri2725
84. Billingham LK, Stoolman JS, Vasan K, Rodriguez AE, Poor TA, Szibor M, et al. Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation. Nat Immunol. (2022) 23:692–704. doi: 10.1038/s41590-022-01185-3
85. Finucane OM, Sugrue J, Rubio-Araiz A, Guillot-Sestier MV, and Lynch MA. The NLRP3 inflammasome modulates glycolysis by increasing PFKFB3 in an IL-1β-dependent manner in macrophages. Sci Rep. (2019) 9:4034. doi: 10.1038/s41598-019-40619-1
86. Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G, et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature. (2013) 496:238–42. doi: 10.1038/nature11986
87. Xie M, Yu Y, Kang R, Zhu S, Yang L, Zeng L, et al. PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation. Nat Commun. (2016) 7:13280. doi: 10.1038/ncomms13280
88. Kamarauskaite J, Baniene R, Trumbeckas D, Strazdauskas A, and Trumbeckaite S. Increased succinate accumulation induces ROS generation in in vivo ischemia/reperfusion-affected rat kidney mitochondria. BioMed Res Int. (2020) 2020:8855585. doi: 10.1155/2020/8855585
89. McManus RM, Komes MP, Griep A, Santarelli F, Schwartz S, Perea JR, et al. NLRP3-mediated glutaminolysis controls microglial phagocytosis to promote Alzheimer’s disease progression. Immunity. (2025) 58:326–43. doi: 10.1016/j.immuni.2025.01.007
90. Yu H, Chang Q, Sun T, He X, Wen L, An J, et al. Metabolic reprogramming and polarization of microglia in Parkinson’s disease: Role of inflammasome and iron. Ageing Res Rev. (2023) 90:102032. doi: 10.1016/j.arr.2023.102032
91. Costello A, Dua T, Duran P, Gülmezoglu M, Oladapo OT, Perea W, et al. Defining the syndrome associated with congenital Zika virus infection. Bull World Health Organ. (2016) 94:406–6. doi: 10.2471/BLT.16.176990
92. Fontes-Dantas FL, Fernandes GG, Gutman EG, De Lima EV, Antonio LS, Hammerle MB, et al. SARS-CoV-2 Spike protein induces TLR4-mediated long-term cognitive dysfunction recapitulating post-COVID-19 syndrome in mice. Cell Rep. (2023) 42:112189. doi: 10.1016/j.celrep.2023.112189
93. Rodrigues TS, de Sá KS, Ishimoto AY, Becerra A, Oliveira S, Almeida L, et al. Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with COVID-19 severity in patients. J Exp Med. (2020) 218:e20201707. doi: 10.1084/jem.20201707
94. Rodrigues TS, Caetano CC, de Sá KS, Almeida L, Becerra A, Gonçalves AV, et al. Casp4/11 contributes to Nlrp3 activation and covid-19 exacerbation. J Infect Dis. (2023) 227:1364–1375. doi: 10.1093/infdis/jiad037
95. de Sá KSG, Amaral LA, Rodrigues TS, Caetano CCS, Becerra A, Batah, et al. Pulmonary inflammation and viral replication define distinct clinical outcomes in fatal cases of COVID-19. PloS Pathog. (2024) 20:e1012222. doi: 10.1371/journal.ppat.1012222
96. Kattan D, Barsa C, Mekhijian S, Shakkour Z, Jammoul M, Doumit M, et al. Inflammasomes as biomarkers and therapeutic targets in traumatic brain injury and related-neurodegenerative diseases: A comprehensive overview. Neurosci Biobehav Rev. (2023) 144:104969. doi: 10.1016/j.neubiorev.2022.104969
97. Albornoz EA, Amarilla AA, Modhiran N, Parker S, Li XX, Wijesundara DK, et al. SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein. Mol Psychiatry. (2023) 28:2878–93. doi: 10.1038/s41380-022-01831-0
98. Zhang PP, He ZC, Yao XH, Tang R, Ma J, Luo T, et al. COVID-19-associated monocytic encephalitis (CAME): histological and proteomic evidence from autopsy. Transduct Target Ther. (2023) 8:24. doi: 10.1038/s41392-022-01291-6
99. Argandona Lopez C and Brown AM. Microglial- neuronal crosstalk in chronic viral infection through mTOR, SPP1/OPN and inflammasome pathway signaling. Front Immunol. (2024) 15:1368465. doi: 10.3389/fimmu.2024.1368465
100. Dey R and Bishayi B. Microglial inflammatory responses to SARS-coV-2 infection: A comprehensive review. Cell Mol Neurobiol. (2023) 44:2. doi: 10.1007/s10571-023-01444-3
101. Hou Y, Wei Y, Lautrup S, Yang B, Wang Y, Cordonnier S, et al. NAD+ supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer’s disease via cGAS-STING. Proc Natl Acad Sci U S A. (2021) 118:2011226118. doi: 10.1073/pnas.2011226118
102. Kempuraj D, Thangavel R, Natteru PA, Selvakumar GP, Saeed D, Zahoor H, et al. Neuroinflammation induces neurodegeneration. J Neurol Neurosurg Spine. (2016) 1:1003.
103. Lima MN, Barbosa-Silva MC, and Maron-Gutierrez T. Microglial priming in infections and its risk to neurodegenerative diseases. Front Cell Neurosci. (2022) 16:878987. doi: 10.3389/fncel.2022.878987
104. Vasilopoulou F, Piers TM, Wei J, Hardy J, and Pocock JM. Amelioration of signaling deficits underlying metabolic shortfall in TREM2R47H human iPSC-derived microglia. FEBS J. (2025) 292:1743–62. doi: 10.1111/febs.17353
105. Kim Y, Park TY, Baik E, and Lee SH. Fructose-1,6-bisphosphate attenuates induction of nitric oxide synthase in microglia stimulated with lipopolysaccharide. Life Sci. (2012) 90:365–72. doi: 10.1016/j.lfs.2011.12.011
106. Li M, Lu H, Wang X, Duan C, Zhu X, Zhang Y, et al. Pyruvate kinase M2 (PKM2) interacts with activating transcription factor 2 (ATF2) to bridge glycolysis and pyroptosis in microglia. Mol Immunol. (2021) 140:250–66. doi: 10.1016/j.molimm.2021.10.017
107. Miao J, Chen L, Pan X, Li L, Zhao B, and Lan J. Microglial metabolic reprogramming: emerging insights and therapeutic strategies in neurodegenerative diseases. Cell Mol Neurobiol. (2023) 43:3191–210. doi: 10.1007/s10571-023-01376-y
108. Wang L, Zhang Y, Kiprowska M, Guo Y, Yamamoto K, and Li X. Diethyl succinate modulates microglial polarization and activation by reducing mitochondrial fission and cellular ROS. Metabolites. (2021) 11:854. doi: 10.3390/metabo11120854
109. Sahoo BR, Crook AA, Pattnaik A, Torres-Gerena AD, Khalimonchuk O, Powers R, et al. Redox regulation and metabolic dependency of zika virus replication: inhibition by nrf2-antioxidant response and NAD(H) antimetabolites. J Virol. (2023) 97:e0136322. doi: 10.1128/jvi.01363-22
110. Bhatt AN, Shenoy S, Munjal S, Chinnadurai V, Agarwal A, Kumar AV, et al. 2-deoxy-D-glucose as an adjunct to standard of care in the medical management of COVID-19: a proof-of-concept and dose-ranging randomised phase II clinical trial. BMC Infect Dis. (2022) 22:669. doi: 10.1186/s12879-022-07642-6
111. Lengerich BV, Zhan L, Xia D, Chan D, Joy D, Park JI, et al. A TREM2-activating antibody with a blood–brain barrier transport vehicle enhances microglial metabolism in Alzheimer’s disease models. Nat Neurosci. (2023) 26:416–29. doi: 10.1038/s41593-022-01240-0
112. Pinto L and Götz M. Radial glial cell heterogeneity–the source of diverse progeny in the CNS. Prog Neurobiol. (2007) 83:2–23. doi: 10.1016/j.pneurobio.2007.02.010
113. Thomsen ER, Mich JK, Yao Z, Hodge RD, Doyle AM, Jang S, et al. Fixed single-cell transcriptomic characterization of human radial glial diversity. Nat Methods. (2016) 13:87–93. doi: 10.1038/nmeth.3629
114. Lanjewar SN and Sloan SA. Growing glia: cultivating human stem cell models of gliogenesis in health and disease. Front Immunol. (2021) 9:649538. doi: 10.3389/fcell.2021.649538
115. Liu L, Liu J, Bao J, Bai Q, and Wang G. Interaction of microglia and astrocytes in the neurovascular unit. Front Immunol. (2020) 11:1024. doi: 10.3389/fimmu.2020.01024
Keywords: CNS, glial cells, inflammasome, metabolic reprogramming, neuroinflammation, neurotropic viruses
Citation: Rodrigues T, Beltrão GS, Girardi H and Pinto AR (2025) Viral reprogramming of glial metabolism as a driver of neuroinflammation. Front. Immunol. 16:1686774. doi: 10.3389/fimmu.2025.1686774
Received: 15 August 2025; Accepted: 05 December 2025; Revised: 01 December 2025;
Published: 19 December 2025.
Edited by:
Juliana Escher Toller-Kawahisa, Trinity College Dublin, IrelandReviewed by:
Ingrid Farias, Federal University of São Paulo, BrazilCopyright © 2025 Rodrigues, Beltrão, Girardi and Pinto. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Tamara Rodrigues, dGFtYXJhLnJvZHJpZ3Vlc0B1ZnNjLmJy
†These authors have contributed equally to this work