The role of microglia in sepsis-associated encephalopathy: a narrative review

Introduction

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection (1). As a severe and common complication of sepsis, sepsis-associated encephalopathy (SAE) refers to diffuse brain dysfunction without overt infection or structural abnormalities of the central nervous system (CNS) (1,2). Clinically, SAE is characterized by acute disturbances of consciousness (e.g., delirium), cognitive impairment (including attention deficits and memory decline), and long-term neurocognitive sequelae in survivors, which significantly increases mortality and impairs quality of life (2,3). Notably, SAE must be distinguished from primary CNS infections (e.g., meningitis or encephalitis), as it arises secondary to systemic sepsis rather than direct microbial invasion of the brain parenchyma (4).

Despite its high prevalence (affecting up to 70% of sepsis patients) and profound impact on prognosis, the pathophysiological mechanisms underlying SAE remain incompletely understood, and specific therapeutic interventions are lacking (4). Microglia, the resident immune cells of the CNS, are recognized as a central feature in the pathogenesis of SAE (5). Under physiological conditions, microglia maintain brain homeostasis by monitoring the microenvironment, clearing cellular debris, and supporting synaptic plasticity. However, during sepsis, systemic inflammatory signals (e.g., pro-inflammatory cytokines, pathogen-associated molecular patterns) trigger robust microglial activation, which in turn drives a cascade of harmful processes: excessive release of pro-inflammatory mediators [e.g., interleukin-1β, tumor necrosis factor-α (TNF-α)], disruption of the blood-brain barrier (BBB), synaptic damage, and mitochondrial dysfunction in neurons (6,7). These events collectively exacerbate brain injury and cognitive decline in SAE.

While several reviews have summarized the role of microglia in SAE (6,7), recent advances in experimental models [e.g., cecal ligation and puncture, lipopolysaccharide (LPS)-induced sepsis] and molecular techniques (e.g., single-cell RNA sequencing, spatial transcriptomics) have shed new light on their dynamic phenotypic changes and regulatory networks. This review focuses on the emerging domains of SAE pathogenesis, including microglial phenotypic polarization, their interactions with the neurovascular unit, and crosstalk with systemic pathways such as the gut-brain axis and circadian rhythm system. By synthesizing these latest findings, we aim to clarify the complex role of microglia in SAE and explore potential therapeutic targets for mitigating neuroinflammation and preserving neurological function. We present this article in accordance with the Narrative Review reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-496/rc).

Methods

A systematic search of PubMed (January 1985–April 2025) was conducted using fuzzy-matching mode with terms including “microglia”, “sepsis-associated encephalopathy”, “blood-brain barrier (BBB)”, “microglia polarization”, “M1/M2 polarization”, “NLRP3 inflammasome”, “inflammation”, “quercetin”, and related Medical Subject Headings (MeSH) terms. The search initially identified 182 records, of which 19 studies met the inclusion criteria after duplicate removal, title/abstract screening, and full-text review. Details of the search strategy, inclusion and exclusion criteria are summarized in Table 1. To provide a clear and systematic overview of the search and selection process, the following details the initial search results, screening procedures, as well as explicit inclusion and exclusion criteria: (I) initial search results: A systematic search was conducted in the PubMed database using the terms “Microglia” and “sepsis-associated encephalopathy” for the period from 1985 to April 2025, initially yielding 182 relevant articles; (II) screening process: first stage (title and abstract screening): after removing duplicate articles, the titles and abstracts of the remaining articles were preliminarily screened to exclude those that were obviously irrelevant. Second stage (full-text screening): full texts of the articles that passed the initial screening were obtained for detailed evaluation, and finally, articles that met all the inclusion criteria were identified; (III) explicit inclusion criteria: studies must meet all the following conditions to be included: study type: basic experimental studies on the mechanism of SAE, studies on the association between microglia and SAE, studies on the pathogenesis of SAE, etc. Publication type: published, peer-reviewed full-text English papers; (IV) explicit exclusion criteria: articles where the research object is inconsistent with the topic. Studies where the full text cannot be obtained or the data reporting is incomplete and cannot be used for analysis. Duplicate publications.

Mechanisms of microglia in SAE

Neuroinflammation

SAE is characterized by a maladaptive neuroimmune response wherein systemic inflammation induces multifactorial brain dysfunction. Peripheral inflammatory mediators, including interleukin (IL)-1β, IL-6, and TNF-α, breach the compromised BBB, triggering microglial activation. These resident immune cells subsequently initiate a neurotoxic cascade through excessive release of reactive oxygen species (ROS), nitric oxide (NO), and pro-inflammatory cytokines, establishing a self-perpetuating cycle of neuroinflammation that exacerbates cognitive impairment (8).

BBB disruption

The BBB acts like a filter, protecting the brain from harmful substances. In SAE, overactive microglia release enzymes [e.g., matrix metalloproteinase (MMP)] and toxic molecules (e.g., ROS) that break down the BBB’s “glue” (proteins such as claudin-5 and occludin). This allows more harmful substances to enter the brain, worsening inflammation. A study has highlighted the dual role of microglia, which initially promote BBB repair but later exacerbate its breakdown under persistent inflammatory conditions (9).

Dysregulated synaptic pruning

Microglia play a crucial role in synaptic pruning through the complement system (10). In SAE, hyperactivated microglia excessively tag synapses with complement proteins (e.g., C1q), leading to pathological synapse elimination and neural circuit disruption (11). This excessive pruning disrupts communication between brain cells, leading to confusion and memory loss.

Mitochondrial dysfunction

Microglia rely on mitochondria (cell powerhouses) for energy. In SAE, these mitochondria malfunction, producing toxic molecules (ROS/RNS) that damage the microglia themselves and nearby brain cells. This dysfunction also releases debris (e.g., mitochondrial DNA) that triggers more inflammation. Treatments targeting mitochondrial health could help calm this process. Therapeutic approaches targeting mitochondrial function have shown promise in mitigating microglia-mediated neurotoxicity (12).

Dysregulated neurotransmitter systems

Dysregulated neurotransmitter systems, particularly glutamate and dopamine, contribute to neuronal damage in SAE (13,14). Microglia influence these pathways by releasing inflammatory mediators that impair neurotransmitter receptor signaling and promote excitotoxicity (15). The activation of hippocampal astrocyte α2A-adrenergic receptors reduces glutamate excitotoxicity and astrocyte reactivity, preventing synaptic damage and providing neuroprotection in SAE via the cAMP/PKA pathway (16). Additionally, microglia are involved in the clearance of neurotransmitter byproducts, and their dysfunction can lead to an accumulation of toxic metabolites, further exacerbating cognitive decline (17).

Gut-brain axis and microglial activation

The gut-brain axis has gained attention as a key regulator of microglial activation in SAE (18). Dysbiosis of gut microbiota alters the production of metabolites, such as short-chain fatty acids (e.g., butyrate), which modulate microglial function (19). For example, butyrate can activate antioxidant responses via the GPR109A/Nrf2/HO-1) signaling pathway, reducing microglial activation and neuroinflammation (19). Restoring gut health could be a new treatment strategy to cure SAE by rebalancing microglial activity.

Impaired cerebral blood flow regulation

Impaired cerebral autoregulation during sepsis leads to hypoxia and ischemia (20), which activate microglia, and exacerbate oxidative stress and inflammation in the brain. Microglial activation in response to hypoxic conditions has been linked to the release of vascular endothelial growth factor and other factors that further disrupt vascular integrity (21).

Dynamic polarization states

Microglia exhibit phenotypic plasticity, shifting between pro-inflammatory (M1) and anti-inflammatory (M2) states based on environmental cues (22). In SAE, prolonged activation favors the M1 phenotype, which is characterized by high levels of pro-inflammatory mediators and neurotoxic effects, while M2-associated repair mechanisms are insufficiently activated (23). This imbalance keeps inflammation active and slows recovery.

Microglia play a key role in SAE by triggering brain inflammation, damaging the BBB (a protective brain filter), disrupting the brain’s cleanup process for unnecessary connections, and interfering with energy use and communication between brain cells. Recent studies have also shown that SAE can also lead to other issues like damaged cell powerhouses (mitochondria), poor communication between the gut and brain, and reduced blood flow in the brain (6,7). Understanding the many roles of microglia—and how they interact—is vital for developing treatments to reduce the severe brain damage caused by SAE.

Regulation of BBB function by microglia

A key feature of sepsis-associated brain injury (e.g., SAE) is damage to the BBB, a protective shield made up of specialized cells and structures that keep the brain’s environment stable. In SAE, microglial activation contributes significantly to BBB breakdown by releasing MMPs, ROS, and pro-inflammatory cytokines (24). These factors compromise the structural integrity of the BBB, allowing peripheral inflammatory mediators and toxic substances to enter the brain, further exacerbating neuroinflammation and neuronal damage (25). Essentially, the breakdown of the BBB creates a vicious cycle, whereby more harmful substances enter the brain, leading to greater damage.

Mechanisms of microglia-induced BBB damage

Overactive brain immune cells (microglia) play a major role in damaging the BBB during sepsis-related brain injury (e.g., SAE). Peripheral inflammatory cytokines such as TNF-α, IL-1β, and IL-6 stimulate microglia, triggering the release of MMPs (26). These enzymes degrade tight junction proteins, such as occludin and claudin-5, which are essential for maintaining BBB integrity (27). This allows inflammatory molecules and immune cells to enter the brain, worsening inflammation and damage.

In addition to MMPs, microglia release ROS, which further compromise BBB function. ROS cause oxidative damage to endothelial cells and activate inflammatory pathways such as the nuclear factor kappa B (NF-κB) signaling cascade, accelerating the degradation of tight junction proteins (28). Together, these two processes—enzyme damage and oxidative stress—explain how overactive microglia destroy the BBB in SAE.

Therapeutic strategies targeting microglia to protect BBB integrity

Microglial activity is central to the way in which the BBB fails in SAE; thus, altering their behavior could prove useful in keeping the barrier intact. There is a growing view that shifting how microglia work (e.g., altering their polarization and interfering with certain signaling routes could result in tangible benefits) could be key treatment strategy.

Regulating microglial polarization

Altering microglial polarization could switch microglia from an aggressive M1 state to a more healing, M2 mode, which then generally lowers the output of MMPs and inflammatory signals. For example, hydrogen therapy has been shown to promote M2 polarization through the regulation of the mammalian target of rapamycin (mTOR)-autophagy pathway, alleviating neuroinflammation and protecting BBB integrity in SAE models (29).

Blocking microglial migration

Targeting the CCL2/CCR5 signaling pathway to inhibit microglial migration toward blood vessels has demonstrated efficacy in reducing BBB disruption (30). By preventing microglia from directly damaging the vascular endothelium, this approach shows promise in experimental models of acute brain injury and may hold potential for SAE treatment (30).

The loss of proper BBB function is a major problem in SAE, and microglia contribute significantly by releasing both MMPs and ROS. Strategies that decrease microglial activation, adjust their inflammatory response, or limit their movement offer encouraging paths toward fortifying the BBB. In addition, methods like antioxidant treatments, MMP blockers, and changes in tight junction protein expression may aid in BBB repair. Future work should, in most cases, seek to apply these experimental approaches in clinical practice—a change that could ultimately improve outcomes for SAE patients.

Mechanisms of microglia-driven neuroinflammation and targeted therapeutic strategies

Microglial activation and inflammatory cytokine release

During sepsis, large amounts of peripheral pro-inflammatory cytokines (e.g., IL-1β, IL-6, and TNF-α) enter the brain tissue via the disrupted BBB, leading to microglial activation (31). Activated microglia release ROS, NO, and various pro-inflammatory cytokines (e.g., IL-1β and TNF-α), further exacerbating neuronal damage and dysfunction (32). This activated state perpetuates neuroinflammation through positive feedback loops, resulting in more severe brain injury (33).

To stop this cycle, scientists are exploring ways to “switch” microglia from their aggressive state (M1, which attacks threats) to a calmer, healing state (M2, which repairs damage). For instance, puerarin inhibits the AKT1 signaling pathway, reducing pro-inflammatory cytokine release and improving neuronal function and inflammation (34). TRIM45 exacerbates neuroinflammation and cognitive impairment in SAE by promoting microglial pyroptosis via the Atg5/NLRP3 axis (35). Its knockdown reduces ROS production, stabilizes mitochondrial function, and inhibits NLRP3 activation, making TRIM45 a potential therapeutic target for SAE (35).

Polarization imbalance

Microglial polarization imbalance is a hallmark of SAE, characterized by sustained M1 activation and impaired M2 anti-inflammatory function (22). This imbalance not only exacerbates the inflammatory response but also hinders tissue repair and neural recovery, further worsening SAE pathology (36).

Restoring microglial polarization balance through pharmacological interventions is a feasible therapeutic strategy (37). For example, quercetin inhibits the CXCL2/CXCR2 signaling pathway, reducing pro-inflammatory cytokine release and improving neuronal function by disrupting neuro-glial crosstalk (38).

Metabolic reprogramming

Microglial metabolism shifts from oxidative phosphorylation to glycolysis on activation to meet the energy demands of inflammation (39). However, this metabolic reprogramming is accompanied by excessive ROS production and mitochondrial dysfunction, further activating the NLRP3 inflammasome and amplifying neuroinflammation (40).

Targeting this energy shift in microglia could treat sepsis-related brain injury (e.g., SAE). For instance, dichloroacetate inhibits the PDK4/NLRP3 axis, reducing ROS generation and pyroptosis, thereby improving neuronal survival and cognitive function (41).

Dysregulated signaling pathways

Microglia-mediated inflammation is significantly influenced by aberrant signaling pathway activation. For example, the overactivation of the NF-κB pathway and complement systems (e.g., C1q signaling) leads to the excessive release of pro-inflammatory cytokines and synaptic overtrimmed, disrupting neural network integrity and impairing cognitive function (42). By inhibiting the NF-κB pathway, ketamine lessens neuroinflammation and cognitive decline by decreasing the pro-inflammatory polarization of microglia. Moreover, ketamine activates the brain-derived neurotrophic factor pathway, promoting neuronal survival (43). By blocking the RhoA/ROCK2-NF-κB signaling pathway, TIPE2 has been found to be a crucial regulator of neuroinflammation in SAE. Its expression in microglia attenuates neuroinflammatory responses and protects against sepsis-induced brain injury, providing a potential therapeutic target for the management of SAE (44).

Paeonol modulates the HIF1A pathway to mitigate neuroinflammation

Paeonol, a natural compound found in the Moutan plant, fights inflammation and protects the brain during infections. It modulates the hypoxia-inducible factor 1α (HIF1A) pathway in microglia to exert neuroprotective effects (45). Specifically, paeonol reduces the expression of pro-inflammatory factors such as IL-6, TNF-α, and PFKFB3, thereby alleviating hippocampal inflammation and neuronal damage (45). The anti-inflammatory effects of paeonol are reversed by HIF1A agonists (e.g., CoCl2), confirming the critical role of the HIF1A pathway in its therapeutic effects (45).

By focusing on HIF1A, researchers believe they can reduce harmful microglia activity, offering hope for treating brain damage caused by severe infections (e.g., SAE). This strategy could treat dangerous inflammation without harming healthy brain functions.

PLX5622 prevents synaptic phagocytosis and chronic inflammation

PLX5622, a CSF1R inhibitor, reduces microglial activation and synaptic phagocytosis, thereby improving long-term cognitive deficits in SAE models (46). Low-dose PLX5622 (300 ppm) inhibits pathological microglial activation while preserving host immune defenses, making it a promising therapeutic candidate (46).

At low doses, PLX5622 targets only on the problem-causing microglia, leaving the rest of the immune system intact. This balance makes it both safe and effective. The drug also soothes ongoing brain inflammation and protects vital communication networks between brain cells, helping the brain function normally again. Targeting PLX5622 reduces microglia-induced synaptic phagocytosis and chronic inflammation, protecting neural network integrity and enhancing cognitive function (46).

Adenosine triggers astrocytic reactivity and drives microglial activation

Peripheral LPS-induced systemic inflammation triggers an early astrocytic response via elevated adenosine levels, which activate A1 adenosine receptors (A1ARs) (47). This leads to the release of inflammatory cytokines (e.g., CCL2, CCL5, CXCL1), which subsequently activate microglia, resulting in increased cytokine release, BBB disruption, and immune cell infiltration (48). This mechanism highlights the critical role of astrocytes in initiating SAE-associated inflammation (47). Targeting A1ARs effectively blocks the astrocyte-to-microglia inflammatory cascade, improving neural function and cognitive deficits (47).

NLRP3 inflammasome activation and its role

The NLRP3 inflammasome is a key regulatory node in microglia-mediated neuroinflammation (49). Its activation, triggered by danger signals such as ROS and mitochondrial dysfunction, leads to pyroptosis, neuronal apoptosis, and tau pathology (50). Further, the activation of the NLRP3 inflammasome exacerbates BBB permeability, creating a “vicious cycle” that promotes further microglial activation and CNS damage (51). Inhibiting the NLRP3 inflammasome and its downstream effectors (e.g., IL-1β and Gasdermin-D) disrupts the inflammatory cascade, mitigating microglia-mediated neuroinflammation and cognitive deficits (52).

Regulation of microglial activation by autophagy and microRNAs

Microglia normally acts like the brain’s janitors, keeping things tidy and balanced. However, during sepsis-related brain damage (e.g., SAE), microglia become overdrive, worsening inflammation and accelerating harm. Autophagy and microRNAs have been identified as key regulatory mechanisms of microglial activation (53). Autophagy suppresses inflammation by clearing intracellular harmful substances such as ROS, damaged mitochondria, and intracellular pathogens (54). Additionally, microRNAs play a pivotal role in modulating neuroinflammation by regulating microglial phenotypic transition and inflammatory cytokine expression (54). For example, microRNA-124 has been shown to inhibit the polarization of microglia toward the pro-inflammatory M1 phenotype while promoting their transition to the anti-inflammatory M2 phenotype, thereby alleviating inflammation (55).

MicroRNAs can be thought of as tiny genetic “switches” that control microglia behavior. For example, microRNA-124 can flip the behavior of microglia from causing damage (“attack mode”) to promoting healing (“repair mode”). By boosting autophagy or using tools like microRNA-124, researchers believe they could reduce overactive microglia and treat SAE. However, microglia also harm the brain in other ways (e.g., by releasing toxic signals, disrupting energy production in cells, and triggering harmful inflammation pathways like HIF1A and NLRP3). Blocking these pathways or rebalancing microglia activity offers hope for new treatments. The next step is to test these ideas in real patients and tailor therapies to individual needs (e.g., personalized medicine for the brain).

Synaptic pruning and cognitive dysfunction

Recent research has shown that microglia, the resident immune cells of the brain, play a major role in the pathogenesis of SAE (10,11). In both murine models of sepsis and hippocampal autopsy tissues from sepsis patients, the activation of microglia and upregulation of the complement system (specifically C1q) have been identified as key contributors to synapse elimination and cognitive deficits (56). Studies of mice and brain tissue from sepsis patients have shown that overactive microglia, along with high levels of a protein called C1q (an immune system marker), drive this destructive pruning (10,56). This leads to memory issues and damaged brain cells. For instance, research showed that the intrahippocampal injection of C1q-blocking antibodies significantly reduced microglia-mediated synaptic pruning and preserved synaptic density, leading to improved cognitive performance in behavioral assays (56).

Similarly, a drug called PLX5622, which temporarily removes microglia, was also shown to lower C1q levels and protect brain connections. PLX5622 not only depletes microglia but also reduces C1q expression and synaptic tagging, preventing excessive synaptic pruning and cognitive decline (56,57). These findings suggest that targeting microglia or C1q could help treat SAE.

In Alzheimer’s disease, C1q-driven microglial phagocytosis has been linked to synaptic and cognitive impairments (58). Similarly, the targeted deletion of C1q from microglia has been shown to alleviate cognitive dysfunction and protect synaptic integrity in both experimental models of neuroinflammation and aging (59). These findings suggest that targeting C1q or microglia (with drugs like PLX5622) could be a promising way to stop brain damage in SAE and other conditions like Alzheimer’s disease. Overall, reducing the overactive immune response in the brain might help preserve memory and prevent cognitive decline.

Experimental models and clinical translation

Development and application of experimental models

Scientists study how brain immune cells (microglia) worsen sepsis-related brain damage (e.g., SAE) using two key methods: mice with infections that mimic human sepsis, and microglia grown in laboratory dishes. These models effectively simulate the neuroinflammatory features of SAE, such as microglial activation, neuronal damage, and cognitive impairment (60). A study has shown that the cecal ligation and puncture model is particularly useful for exploring microglia-induced neuroinflammation and its molecular regulatory mechanisms in SAE (33). For example, a study using TNFRSF6-deficient mice revealed the critical role of this gene in microglia-mediated neuroinflammation and mitochondrial dysfunction (61).

Another area of study is the gut-brain connection. By transferring gut bacteria between mice, researchers discovered that gut-produced chemicals (e.g., butyrate) activate antioxidant defenses through specific pathways. This helps protect the brain during SAE. By transplanting fecal microbiota from mice with varying microbial states, it was shown that short-chain fatty acids like butyrate can activate antioxidant responses via the GPR109A/Nrf2/HO-1 signaling pathway, thereby mitigating microglial activation and cognitive dysfunction (19).

Brain organoids and single-cell omics technologies

Scientists use miniature brain models grown in laboratories, called organoids, to study how the human brain works. These organoids provide a valuable platform for studying interactions between microglia and other brain cells, as well as for testing the safety and efficacy of potential therapeutic drugs on humanized tissues (62).

The application of single-cell omics technologies has significantly enhanced our understanding of microglial heterogeneity (63,64). For example, recent genetic studies have shown that in SAE, microglia switch between causing harmful inflammation (“attack mode”) and promoting healing (“repair mode”), which should help scientists design better treatments (6,8). Recent research has also found that groups of cells, like astrocytes (support cells), microglia, and blood vessel cells, work together in SAE (9). Such findings provide critical insights for the development of targeted therapies.

Using single-nucleus RNA sequencing and spatial transcriptomics, a recent study identified a unique astrocyte-microglia-vascular cell niche (Astro-2, Micro-2, and Vas-1) in a murine SAE model, revealing key ligand-receptor interactions and the critical role of Anxa1 in maintaining this niche and influencing survival outcomes (64). Classical RNA editing, particularly Apobec1 and Apobec3, regulates microglial homeostasis and contributes to SAE, as revealed by single-cell RNA sequencing, which highlights alterations in synaptic and immune-related genes (53).

Challenges and prospects in clinical translation

Despite improvements in laboratory studies and basic research, it is still difficult to use these findings to help patients. For example, the way in which brain immune cells react in animal experiments often does not reflect the actual brain damage observed in human SAE patients. Differences between patients and how inflammation changes over time also make it difficult to establish effective treatments. Future research should focus on establishing improved animal and laboratory-grown human cell models that mimic human SAE more accurately, and using advanced tools (e.g., gene/protein analysis and live monitoring) to design personalized therapies.

Conclusions

SAE is a severe multifactorial brain dysfunction triggered by severe infections. These infections initiate a series of systemic and CNS responses, which in turn contribute to its pathogenesis. It is characterized by persistent neurocognitive deficits, which are the main clinical manifestations affecting patients’ functional outcomes. At the pathological level, SAE involves neuroinflammation, BBB, and a severe imbalance in the phenotypic polarization of microglia—the resident immune cells of the CNS. This imbalance is manifested as microglia being in a sustained pro-inflammatory state with impaired reparative functions, accompanied by the activation of the NLRP3 inflammasome, ultimately forming a deleterious cycle of neuroinflammation and neuronal damage, which serves as the basis for the pathological progression of SAE. Microglia (the brain’s immune cells) are central to SAE, causing harm through brain inflammation, the excessive pruning of brain connections, and disrupting how brain cells use energy. Future studies should seek to: (I) understand how microglia change during SAE; and (II) develop treatments that specifically target these cells, using new tools to turn laboratory findings into real-world therapies.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-496/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-496/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-496/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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(English Language Editor: L. Huleatt)