Sepsis is one of the leading causes of death worldwide and is characterized by multiple organ injuries resulting from dysregulated host response to infections (Liu et al., 2014; Singer et al., 2016). In addition to its high mortality rate, sepsis can also cause to long-lasting, even permanent, organ damages in septic survivors. It has been estimated that up to 40% of sepsis patients experience neurological and/or cognitive complications even after being discharged (Rudd et al., 2020; Fleischmann-Struzek et al., 2021; Sonneville et al., 2023). Some researchers prefer these prolonged and disabling forms of cognitive impairment in sepsis survivors as sepsis-associated encephalopathy (SAE) (Catarina et al., 2021). Although the exact underlying mechanism is not yet fully understood, it is widely accepted that neuroinflammation plays a significant role (Annane and Sharshar, 2015; Rengel et al., 2019; Pan et al., 2022; Sekino et al., 2022). During the initial systemic inflammation of sepsis, a large amount of cytokines are released, which could enter the central nervous system (CNS) via circumventricular organ and choroid plexus devoid of a blood–brain barrier (Shimada and Hasegawa-Ishii, 2017). Additional, systemic inflammation can also disrupt the blood–brain barriers (Gao and Hernandes, 2021; Sekino et al., 2022; Zou et al., 2022). Once inside the CNS, these cytokines activate microglia, the innate immune cells in the brain, to produce more pro-inflammatory cytokines such as IL-1β, tumor necrosis factor-α (TNF-α), and interferon-γ (INF-γ) (Hoogland et al., 2015; Zrzavy et al., 2019; Hu et al., 2023), ultimately resulting in long-lasting neuroinflammation that leads to neuron loss and cognitive impairment (Sekino et al., 2022; Hu et al., 2023). Among these pro-inflammatory cytokines, IL-1β is particularly important within the CNS after sepsis (Wang et al., 2012; Pozzi et al., 2018). Previous studies have shown that IL-1β, but not TNF-α or IL-6, is the exclusive cytokine within the CNS that has been verified to remain elevated for up to 70 days in rats survived neonatal sepsis but subsequently developed cognitive impairment (Lan et al., 2015; Liao et al., 2023). Furthermore, neurodevelopment of neonatal septic rats could be improved by directly antagonizing IL-1β (Zhang et al., 2022). This review summarizes recent advances in microglia activation-induced excessive IL-1β release and the molecular signaling pathways involved in IL-1β-induced cognitive dysfunction among sepsis survivors.

As the primary immune cell within the CNS, microglia are activated by the recognition of danger signals such as invading pathogens and cytokines during systemic inflammation. For instance, inflammatory cytokines like TNF-α, IL-1β and IL-6 activate microglia through their specific receptors (van Gool et al., 2010).

The nuclear factor kappa B (NF-κB) signaling pathway is a key signal pathway that modulates inflammatory responses. Studies have shown that the NF-κB signaling pathway is involved in the activation of microglia during sepsis (Mulero et al., 2019; Zhao et al., 2019; Nguyen et al., 2021; Wang H. et al., 2022). The NF-κB family consists of subunits p105/p50, p100/p52, p65/RelA, RelB, and c-Rel. These subunits reside in cytoplasm and bind with inhibitory IκB proteins to form an inactive complex (Mitchell et al., 2016; Mulero et al., 2019). The NF-κB signal can be activated through the canonical pathway or the noncanonical pathway. In the canonical pathway, inflammatory stimulation activates a complex containing NF-κB essential modulator (NEMO) and IκB kinases (IKK1/2). This complex phosphorylates IκB proteins that are bound to NF-κB in the cytoplasm, leading to the proteasomal degradation of IκBs. With the rapid degradation of IκBs, the p65:p50 heterodimer is released and translocates into nucleus, where it binds to κB site-containing DNA to enhance the transcription of target genes (Mitchell et al., 2016; Mulero et al., 2019). In the noncanonical pathway, signals such as the activation of TNF receptors by TNF-α or CD40 ligand, activate the NF-κB-inducing kinase (NIK) complex, which is identified as a mitogen-activated protein kinase (MAPK) kinase (Coope et al., 2002; Razani et al., 2011). NIK activates IKK1 through phosphorylation at Ser and Thr residues (Ling et al., 1998; Razani et al., 2011). The activated NIK/IKK1 complex phosphorylates inhibitor IκB and leads to the processing of precursor forms of NF-κB family members, particularly p100. p100 triggers IκB degradation and the release of the active p52 subunit, which forms active RelB:p52 heterodimers. These heterodimers then translocate into the nucleus and regulate specific gene transcription for immune responses (Ling et al., 1998; Coope et al., 2002; Mulero et al., 2019) (Figure 1).

Considering the crucial role of the NF-κB signaling pathway in microglia activation, numerous studies have indeed explored the potential of attenuating microglia activation by targeting the NF-κB signaling pathway. Zhao et al. demonstrated in mice that lipopolysaccharide (LPS) induced cognitive impairment and neuroinflammation occurred due to microglia activation via activation of the NF-kB signaling pathway. By pharmacological suppressing TLR-4/MyD88, they were able to abolish LPS-induced NF-κB activation and the release of pro-inflammatory cytokines, which in turn mitigated cognitive impairment (Zhao et al., 2019).

The nuclear erythroid 2-related factor 2 (Nrf2) is a transcription factor, which, under normal homeostatic conditions, is expressed with Kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm. When stimulated by hazardous signals like oxidative or inflammatory stress, Nrf2 is released from Keap1 and translocates into the nucleus, where it binds to antioxidant response elements (AREs). This leads to the transcription of ARE genes involved in cellular defense and antioxidant responses, ultimately promoting cellular adaptation and survival under stress conditions (Saha et al., 2020). NF-κB is one of the downstream targets of Nrf2 that has been extensively studied. Nrf2 restricts the degradation of IκBα, thereby indirectly inhibiting the nuclear translocation of NF-κB and blocking the activation of the NF-κB signaling pathway (Yerra et al., 2013; Chen et al., 2018; Saha et al., 2020; Yu et al., 2020). Previous studies have highlighted the neuroprotective role of Nrf2 in various conditions, such as traumatic and ischemic brain injury (Dong A. et al., 2018; Dong W. et al., 2018; Yang et al., 2018). Chen et al. further demonstrated thathydrogen gas improved neuronal injury or cognitive dysfunction in mice with SAE through the activation of the Nrf2 pathway (Chen et al., 2021).

Forkhead box C1 (Foxc1) is another transcription factor implicated in the defense processes against oxidative damage, inflammation, and apoptosis (Xia et al., 2019; Zhao et al., 2020). Wang et al. showed with a cecal ligation perforation (CLP) sepsis model that overexpression of Foxc1 suppressed microglia activation related to the NF-κB pathway by enhancing IκBα expression, stabilizing the IκBα/p65 complex and reducing transcription driven by p65. This ultimately resulted in improved cognitive function in mice with SAE (Wang H. et al., 2022).

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling system is an essential cascade involved in cell proliferation, differentiation, and immune modulation (Xin et al., 2020). Therefore, it is not surprising that JAK/STAT signaling pathway interacts with the NF-κB pathway, and these interactions regulate immune responses during sepsis (Cai et al., 2015). Persistently activated JAK/STAT signaling is associated with prolonged inflammation and organ damage observed in sepsis (Cai et al., 2015; Wu et al., 2020; Xin et al., 2020). The complex interactions with other signaling pathways make the biological effects of JAK/STAT signaling more intricate. Septic cytokine-mediated activation of JAK/STAT3 signaling enhances STAT3 binding to the telomerase reverse transcriptase (TERT) promoter and leads to increased TERT protein expression (Cai et al., 2015; Wu et al., 2020). TERT, the telomerase protein, provides neuroprotection against LPS-induced brain injury by converting microglial polarization from M1 to M2 phenotype (Xin et al., 2020; Zhou et al., 2021). Furthermore, JAK2/STAT3 also modulates inflammatory responses through the α7 nicotinic receptor (α7nAChR), suppressing NF-κB and cytokine production and improving survival in sepsis (Peña et al., 2010; Zhang et al., 2017).

The chemokine C-X-C motif ligand 13 (CXCL13) and its receptor CXCR5 also play important roles in various immune and inflammatory processes (Kazanietz et al., 2019). Activation of the CXCL13/CXCR5 axis in microglia results in p38MAPK/NF-κB signal activation and promotes microglial polarization into the M1 phenotype. Conversely, down-regulation of CXCR5 suppresses neuroinflammation caused by microglial activation and alleviates cognitive dysfunction in a mouse model of sepsis (Li et al., 2017; Shen et al., 2021).

Silent information regulator 1 (SIRT1), a deacetylase-dependent nicotinamide adenine dinucleotide (NAD), is a key regulator in energy metabolism and tissue survival (Houtkooper et al., 2012; Jiao and Gong, 2020). The SIRT1 protein, which mediates oxidative respiration and anti-inflammatory responses, directly inhibits NF-κB signaling and mitigates SAE (Kauppinen et al., 2013). Specifically, SIRT1 deacetylates the RelA/p65 complex at Lys310, inhibits the nuclear translocation of NF-κB, and leads to IκBα-dependent nuclear export of NF-κB (Yeung et al., 2004; Han et al., 2019; Tian et al., 2019; Yang et al., 2020).

These studies have revealed the critical role of the NF-κB signaling pathway in microglial activation, neuroinflammation and cognitive impairment following sepsis. Moreover, they suggest that targeting the NF-κB signaling may be a potential intervention for improving cognitive dysfunction induced by sepsis (Figure 1).

In summary, the activation of NF-κB plays a pivotal role in initiating the transcription of pro-inflammatory cytokines, such as IL-1β. This NF-κB pathway is a component of a larger inflammatory response encompassing the activation of other signaling pathways and the release of inflammatory mediators. It is imperative to comprehend the molecular events that connect NF-κB activation and to the release of IL-1β in order to understand the mechanisms that drive inflammation and to devise therapeutic strategies to manipulating these processes in diverse diseases.

Microglia, the main type of resident macrophages in the CNS, play a crucial role in immunological surveillance. Equipped with an array of pattern recognition receptors (PRRs), they detect changes in cytokine and chemokine levels as well as identify infections and damages (Ransohoff and Perry, 2009; Cherry et al., 2014; Roh and Sohn, 2018; Wesselingh et al., 2019). Therefore, it is not surprising that microglia can be activated by septic cytokine storms reaching the brain, utilizing the aforementioned pathways and receptors (Yan et al., 2022). Activation of microglia has been observed as early as 6 h following sepsis induced by CLP (Ye et al., 2019). Prolonged activation of microglia following sepsis has been associated with SAE. Wang et al. and Lan KM et al. discovered that following exposure to LPS in newborn rats resulted in sustained activation of microglia until postnatal day 71, leading to severe cognitive dysfunction (Wang et al., 2013; Lan et al., 2015). Numerous studies have indicated that inflammation caused by activated microglia is the main contributor to cognitive impairment following sepsis (Goshen et al., 2007; Ye et al., 2019; Zrzavy et al., 2019; Yan et al., 2022; Hu et al., 2023; Mordelt and de Witte, 2023). Neuroprotective benefits and reduced cognitive impairment induced by sepsis or surgery have been observed when microglia activation is prevented using the antibiotic minocycline (Michels et al., 2015; Tan et al., 2023). Unfortunately, minocycline failed to prevent postoperative cognitive dysfunction in a recent clinical trial, suggesting that the mechanisms underlying neuroinflammation-related brain dysfunction extend well beyond microglial activation (Takazawa et al., 2023).

Even in the context of microglial activation, there are two distinct phenotypes that can occur. Microglia can be activated and polarized into the M1 phenotype through the pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs), which occurs via PRRs such as membrane Toll-like receptors (TLRs), Scavenger receptors (RAGE) and cytoplasmic Nod-like receptors (NLRs) and RIG-like receptors (RLRs) (Boche et al., 2013; Roh and Sohn, 2018; Hu et al., 2023). The M1 phenotype of microglia releases large amount of pro-inflammatory cytokines, including IL-1β, which induces inflammation to combat invading pathogens (Cherry et al., 2014; Wang et al., 2023). Morphologically, M1 phenotype microglia is characterized by larger amoeboid-like somata, with expression of Iba-1, CD68 and CD11b as the surface markers (Hoogland et al., 2015; Orihuela et al., 2016). Another activated phenotype of microglia is the M2 phenotype, which releases anti-inflammatory mediators and contributes to the resolution of inflammatory responses and tissue repair. The M2 phenotype microglia have a rod-like shape and express CD206 as a surface marker (Orihuela et al., 2016; Zhuang et al., 2020). Microglia play a crucial role in maintaining brain homeostasis through the balanced regulation of M1 and M2 phenotypes, as well as regulating immune response within the CNS. An imbalance in the M1/M2 ratio can have significant implications for neuroinflammation following sepsis (Orihuela et al., 2016; Hu et al., 2023; Wang et al., 2023). As demonstrated in previous studies, excessive production of IL-1β following M1 activation may lead to sustained neuroinflammation, contributing to the progression of cognitive dysfunction in neonatal sepsis. Conversely, an overactive M2 response may suppress necessary immune responses, impairing the ability to eliminate pathogens or clear cellular debris.

Inflammasomes are multiprotein complex modulating the inflammatory response and host defense against pathogens (Broz and Dixit, 2016). The inflammasome comprises several subunits, including nucleotide-binding oligomerization domain leucine-rich-repeat-containing pyrin 3 (NLRP3), the adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and the effector molecule pro-caspase-1 (Paerewijck and Lamkanfi, 2022). Inflammasomes are assembled when microglia are stimulated by a variety of stimuli, such as PAMPs (viral, bacterial, or fungal pathogens) and DAMPs (extracellular ATP, mtDNA, ROS, etc.) (Broz and Dixit, 2016; Paerewijck and Lamkanfi, 2022). Upon autoproteolytic activation inside the complex, pro-caspase-1 is hydrolyzed into active caspase-1, which then processes pro-IL-1β and pro-IL-18 into their mature, active forms (Broz and Dixit, 2016; Paerewijck and Lamkanfi, 2022) (Figure 1). Active caspase-1 also cleaves gasdermin D (GSDMD) and triggers pyroptosis, resulting in release of mature IL-1β (Shi et al., 2017). It has been found that activated microglia, not astrocytes, are the sole source of NLRP3 inflammasome in CNS of rodents (Gustin et al., 2015; Moraes et al., 2023). Numerous studies have demonstrated that NLRP3-induced IL-1β release is the main cause of the brain dysfunction following sepsis (Sui et al., 2016; Xie et al., 2020; Yan et al., 2022). Pharmacological inhibition of NLRP3 not only reduces the expression of IL-1β, but also alleviates cognition impairment after sepsis (Sui et al., 2016; Xie et al., 2020; Li et al., 2022; Sekino et al., 2022; Moraes et al., 2023).

As a pro-inflammatory cytokine, IL-1β is involved in inflammation and the host’s defensive response. Once it binds with its receptor (IL-1R), IL-1β can increase the expression of adhesion factors and facilitate the chemotaxis of leukocytes to infection sites, intensifying the cascade of immune reaction (Weber et al., 2010). Aside from regulating immune responses, IL-1β in the CNS is also associated with learning and memory. The hippocampus is a critical structure located in the medial temporal lobe of the brain, playing a central role in learning and memory formation. It is particularly involved in the consolidation of short-term memory into long-term memory, as well as spatial memory and navigation. Both IL-1β and IL-1R are expressed in the hippocampus under normal physiological conditions (Huang and Sheng, 2010). Previous studies have demonstrated that a physiological level of IL-1β is necessary for memory formation, especially for hippocampus-dependent memory (Goshen et al., 2007; Yirmiya and Goshen, 2010; Wang et al., 2012). Disruption of IL-1 signaling through either the use of IL-1R antagonist (IL-1ra) or genetic deletion of IL-1R (IL-1rKO) impairs hippocampus-dependent memory (Avital et al., 2003; Goshen et al., 2007). Additionally, a physiological level of IL-1β is also essential for high-frequency stimulation-induced long-term potentiation (LTP) and normal hippocampal development (Goshen et al., 2007). Treatment with IL-1rKO or IL-1ra can impair memory formation and the maintenance of LTP (Schneider et al., 1998; Weber et al., 2010). On the contrary, excessive IL-1β produced detrimental effect on hippocampus-dependent memory formation and LTP maintenance. However, this effect can be reversed by blocking IL-1β signaling with IL-1ra, which improves cognitive function (Goshen et al., 2007; Weber et al., 2010). In summary, current data suggests that the effect of IL-1β on memory follows a U-shaped pattern: physiological level of IL-1β is necessary for memory formation and a slight increase in IL-1β can improve memory function. However, deviations from physiological range of IL-1β levels, whether through inhibition of IL-1β signaling or excessive IL-1β expression, lead to impaired memory formation and consolidation (Goshen et al., 2007; Weber et al., 2010).

In addition to serving as pivotal pro-inflammatory cytokine in the innate immune response, IL-1β also plays a critical role in the pathogenesis of a variety of CNS diseases associated with cognitive impairment, such as epilepsy, stroke, schizophrenia, and autism (Iori et al., 2016; Krakowiak et al., 2017; Tsai, 2017). Research has provided evidence demonstrating that elevated expression of IL-1β can impair synaptic formation and function, thereby interfering normal neuronal communication and disrupting cognitive function.

The sustained elevation of IL-1β levels in the CNS after a single dose of LPS treatment raises another important and interesting question: what is the underlying mechanism for prolonged microglia activation and IL-1β release after transient systemic inflammation? In the context of neuroinflammation, researchers have identified a feed-forward loop between neurons and microglia (Terrando et al., 2010; Lan et al., 2015). They have discovered that the IL-1 receptor antagonist (IL-1ra) not only decreases IL-1β-induced long-lasting cognitive impairments but also suppresses microglia activation and IL-1β production (Terrando et al., 2010; Wang et al., 2013; Lan et al., 2015). In the absence of pathogen or PAMPs, microglia are activated by DAMPs, which are only produced by dying cells (Lehnardt, 2010; Ransohoff and Brown, 2012). Together, they have concluded that IL-1β-mediated neuroinflammation caused neuronal death, which then released DAMPs to activate microglia and release more IL-1β, creating a feed-forward loop that leads to chronic neuroinflammation and long-term cognitive dysfunction (Terrando et al., 2010; Wang et al., 2013; Lan et al., 2015).

Endogenous DAMPs are molecules that promote inflammation and passively leak out of dying cells when membranes rupture. Numerous cell death processes, including necrosis/necroptosis, pyroptosis, and ferroptosis, are connected to the release of DAMPs (Murao et al., 2021). All these different types of cell death have been reported in the pathological development of sepsis and cognitive dysfunction associated with sepsis (Fu et al., 2019; Zhou et al., 2019; Chu et al., 2022; Liao et al., 2022; Wang J. et al., 2022; Liao et al., 2023). Our recent research showed that necrostatin-1 and xenon were protective against sepsis-induced brain injury by preventing necroptosis. Necroptosis was activated via receptor interacting protein 1/3 (RIP1/3), which contributed to impaired neurodevelopment in neonatal sepsis survivors (Liao et al., 2022, 2023). The NLRP3/caspase-1 pathway-induced pyroptosis has also been linked to cognitive impairment following sepsis. Inhibiting pyroptosis by inhibiting NLRP3 and caspase-1 expression has shown protective effects on cognitive impairment following sepsis in newborn rats (Fu et al., 2019; Zhou et al., 2019). According to Wang (Wang J. et al., 2022) and Chu (Chu et al., 2022), ferroptosis contributed to cognitive dysfunction following SAE via the Nrf2/ferroptosis-related protein (GPX4) signaling pathway. In conclusion, all these types of cell death that release DAMPs may create a feed-forward loop that eventually results in chronic neuroinflammation and cognitive impairment after sepsis. To break the feed-forward cycle, future research should focus on the molecular mechanisms linking cell death and persistent neuroinflammation. It should also investigate possible therapeutic interventions for sepsis-related cognitive impairment (Figure 3).

Significant advancements have been made in the past two decades regarding our understanding of the correlation between neuroinflammation and post-septic cognitive impairment. This review encompasses an examination of the diverse effects of IL-1β generated following microglial activation on cognitive impairment, as well as delves into the underlying molecular mechanisms behind microglia activation, the influence of IL-1β on synapse development, and the impact of impairment on synaptic function. Furthermore, we explore the feed-forward loop mechanism, which relies on different types of cell death and releases endogenous DAMPs to activate the innate immune system and create persistent neuroinflammation. Researchers have conducted experimented utilizing several approaches based on these mechanisms, yielding encouraging results. Given the intricate interplay among these processes, a multifaceted approach should be employed in future preclinical and clinical trials to target various pathways in order to prevent or treat cognitive impairment following sepsis.

QZ: Writing – original draft, Writing – review & editing. LW: Writing – original draft, Writing – review & editing. HH: Writing – original draft, Writing – review & editing. ZL: Writing – original draft, Writing – review & editing.