Neuroinflammation is characterized by glial cell activation and is mediated via pro-inflammatory signals (Ji et al., 2014; Rivest, 2009). In general, acute inflammation is the initial response of the immune system and is characterized by activation of immune cells, rapid production of various cytokines and chemokines, and phagocytic mechanisms. Although these processes are important to combat pathogens, persistent inflammation can lead to a pathophysiological state that results in tissue damage and loss of function. It is well known that during inflammation, pro- and anti-inflammatory cytokines interact and influence the outcome. Examples of pro-inflammatory cytokines include interleukin (IL)–1β and tumor necrosis factor α (TNF-α), both of which elicit a strong acute inflammatory response (Dinarello, 1996; Leal et al., 2013). In contrast, anti-inflammatory cytokines such as IL-4, IL-10 (De Beaux et al., 1996; Marie et al., 1996), or IL-37 (Nold et al., 2010) inhibit the action of pro-inflammatory cytokines and hence limit inflammation (Cavaillon, 2001). In the CNS, long-term activation of glial cells leads to neuroinflammation, which is an important hallmark of many neurological disorders, including Alzheimer’s disease (AD), Parkinson’s disease or multiple sclerosis (Ji et al., 2014). In particular, AD is the most common form of dementia characterized by amyloid-β plaques and neurofibrillary tangles in the brain tissue. Patients with AD suffer from memory loss, speech disorders, confusion, problems with attention, and spatial orientation. Currently, there are no effective treatment strategies to combat AD despite the considerable clinical need.

Innate immune responses and neuroinflammation are thought to contribute significantly to the progression of AD (Tan et al., 2007). Therefore, regulatory cytokines that can reduce inflammation in the CNS are of therapeutic value (Banchereau et al., 2012; Cavalli et al., 2016). Nevertheless, it remains unclear which of the regulatory mediators act adversely or beneficially at each stage of the neuroinflammatory process (Ji et al., 2014; Grace et al., 2014; Kigerl et al., 2009).

For example, the release of IL-1β under pathological conditions can lead to deficits in learning and memory processes as well as in long-term potentiation (LTP) (Avital et al., 2003; Hein et al., 2010; Tong et al., 2012). In addition, pro-inflammatory cytokines such as TNF-α and interferon-γ (IFN-γ) have been associated with impairments in hippocampal neuron structure and function during viral infection (Hosseini et al., 2018). It is important to note that in chronic inflammation, the homeostasis of pro- and anti-inflammatory mediators is completely disturbed and must be therapeutically directed at attenuating persistent inflammatory processes. Among the important pro-inflammatory mediators, both IL-1α and IL-1β play a role in autoinflammatory, autoimmune, infectious, and degenerative diseases (Dinarello, 2009; Dinarello, 2010; Dinarello et al., 2012; Gabay et al., 2010; Sims and Smith, 2010). Although IL-1α and IL-1β are encoded by different genes, both cytokines are structurally related proteins that bind to the type I interleukin 1 receptor (IL-1R1) and elicit similar innate responses. However, IL-1α is constitutively present in healthy cells but is only released under cell stress conditions, as is the case during inflammation. Moreover, because it is constitutively present, IL-1α acts rapidly to trigger local inflammation. In contrast, IL-1β is not present in the healthy state; the IL-1β precursor is not active but requires processing by caspase-1, an intracellular protease, resulting in conversion to an active cytokine that is secreted (Garlanda et al., 2013).

Unlike most members of the IL-1 family that induce inflammation, this important cytokine family also includes two members (IL-37 and IL-38) that act as anti-inflammatory signalling agents and are thought to dampen an ongoing innate immune response (Nold et al., 2010; Dinarello, 2018). In particularly, IL-37 serves as a potent mediator to limit the inflammatory responses (Cavalli and Dinarello, 2018; Caraffa et al., 2018). Therefore, a transgenic mouse model expressing the human splice variant IL-37b (hIL-37tg) was developed (Nold et al., 2010; Cavalli and Dinarello, 2018) and showed potent anti-inflammatory and beneficial effects in a wide variety of different pathological conditions in different organs (Nold et al., 2010; Ballak et al., 2014; Coll-Miró et al., 2016; McNamee et al., 2011; Yousif et al., 2011). The transgenic mouse was generated to allow continuous expression of IL-37 in almost all cells. This was achieved by using the full-length cDNA of IL-37b through the CMV promoter (Nold et al., 2010). It is important to note that these IL-37tg mice did not exhibit an abnormal phenotype and reproduced normally (Nold et al., 2010; Dinarello et al., 2016). IL-37 has been described as a protein that binds to the IL-18 receptor (IL-18R) and, unlike IL-18, does not elicit a pro-inflammatory immune response but prevents it and is even involved in an anti-inflammatory response (Cavalli and Dinarello, 2018). IL-37 binds the alpha chain of the IL-18R and additionally interacts with IL-1R8 (also known as TIR8 or SIGIRR) rather than recruiting the beta chain of the IL-18R (as is the case with IL-18 binding) (Nold-Petry et al., 2015). This co-localization was also demonstrated in mouse cells (Nold-Petry et al., 2015). Other studies showed the mRNA of IL-18Rα and SIGIRR receptors on astrocytes and microglia (Andre et al., 2005). Notably, IL-18Rα has been shown to be expressed on astrocytes and microglia, and IL-18 is produced only by microglial cells, suggesting a signalling cascade running mainly through microglia with respect to IL-18 and IL-37 (Andre et al., 2005; Tsilioni et al., 2019). In addition, two recent studies focusing on the central and peripheral nervous systems have demonstrated the therapeutic potential of IL-37 in autism spectrum disorders (ASD) and multiple sclerosis (MS) (Tsilioni et al., 2019; Cavalli et al., 2019). Tsilioni et al., 2019 have demonstrated a reducing effect of inflammation on IL-37 expression in cultured human microglia.

An important factor for the expression of IL-37 related to the instability sequence was also discovered in a mouse cell line. Bufler et al., 2004 showed that despite strong activation of the CMV promoter, expression of IL-37 could not be detected (Bufler et al., 2004). It was also shown that the specific mRNA was rapidly degraded. However, a significant and rapid increase in IL-37 mRNA could be achieved by an LPS stimulus (Bufler et al., 2004). Similarly, administration of recombinant IL-37 frequently exhibited beneficial effects on the outcome of various animal models of human diseases (Cavalli et al., 2016; Coll-Miró et al., 2016; Moretti et al., 2014; Wu et al., 2014). In addition, IL-37 has been shown to regulate cellular metabolism after an inflammatory stimulus (Su and Tao, 2021). In the last decade, metabolic changes have been described as an important determinant of immunological processes, as shown in macrophages after LPS stimulation (Su and Tao, 2021; O’Neill and Hardie, 2013). The LPS-induced increase in mTOR phosphorylation and decreased AMP-activated protein kinase activity were reversed by expression of IL-37 (Nold et al., 2010; Ballak et al., 2014; Nold-Petry et al., 2015; Su and Tao, 2021).

In the present study, we used hIL-37tg mice to investigate the effect of IL-37 expression on the acute inflammatory processes induced by LPS or IL-1β administration. In addition, we crossed the APP/PS1 mouse model of AD with hIL-37tg mice to investigate the role of IL-37 expression during the chronic state of neuroinflammation and the consequences for the progression of AD pathology.

The regulation of inflammation is an extremely complex and tightly controlled signaling event in which cytokines crucially modulate the process (Shaikh, 2011). The interplay and balance between pro- and anti-inflammatory components are crucial for the delicate balance of inflammatory responses. Anti-inflammatory cytokines are known to limit persistent or excessive inflammation, but they may also be insufficient or overcompensated (Shaikh, 2011; Kasai et al., 1997; Munoz et al., 1991). IL-37 is expressed in many human tissues and cells, especially in monocytes, tissue macrophages or dendritic cells (Cavalli and Dinarello, 2018; Su and Tao, 2021; Rudloff et al., 2017), where it is produced in response to inflammatory stimuli and may act as a self-protective mechanism against escalating inflammatory processes (Su and Tao, 2021). In this study, we showed that IL-37, an anti-inflammatory cytokine, is able to reduce both acute and chronic neuroinflammation and that the IL-37tg mouse model is a valuable animal model to study the details of neurodegenerative diseases caused by chronic inflammation.

The acute inflammatory response was analyzed in a mouse model of septic shock in which increased levels of IL-6, TNF-α, and IL-1β produced by activated microglia were detected (Lemstra et al., 2007; Widmann and Heneka, 2014). The ability of IL-37 to suppress pro-inflammatory cytokines induced by Toll-like receptors (TLR) was first demonstrated in mouse macrophages transfected with human IL-37 (Nold et al., 2010) and recently described for TLR-induced activation of microglial cells (Conti et al., 2020). Because there is no homologous gene for IL-37 in mice, transgenic mice expressing the human IL-37 gene were generated (IL-37tg) (Nold et al., 2010; Cavalli and Dinarello, 2018). Here we showed the effect of IL-37 on CNS tissue resident macrophages (microglia) in terms of reducing inflammatory markers similar to those in the periphery. In contrast, no reduction was detected in primary astrocytes from IL-37tg mice, suggesting a specific modulatory role of microglia in this scenario. The timing of LPS stimulation is important because prolonged treatment of 24 hr results in higher cytokine release compared to 6 hr (Liu et al., 2018; Wu et al., 2009).

Remarkably, the Warburg effect describes the change in metabolism toward the production of ATP from anaerobic glycolysis to oxidative phosphorylation observed in macrophages by increased mTOR levels and decreased AMPK activity after LPS stimulation (Su and Tao, 2021; O’Neill and Hardie, 2013). It was shown that IL-37 can reverse the Warburg effect (Nold et al., 2010; Ballak et al., 2014; Nold-Petry et al., 2015; Su and Tao, 2021) and, moreover, the metabolic cost of inflammation in plasma and muscle cells by reducing the concentration of succinate, a potent mediator in inflammatory states (Tannahill et al., 2013; Cavalli et al., 2017; Fedotcheva et al., 2006; Mills and O’Neill, 2014). In addition, macrophage activation has been found to increase the production of itaconate, which in turn inhibits succinate dehydrogenase (SDH), leading to an increase in succinate levels (He et al., 2021; O’Neill and Artyomov, 2019). Therefore, we focused here on two metabolites associated with inflammation in tissue macrophages. Our results showed that levels of itaconate and succinate decreased after LPS stimulation in primary microglia from IL-37tg animals. In conclusion, we demonstrated that the anti-inflammatory property of IL-37 is able to reduce inflammation in microglial cells in vitro. In addition, the restoration of metabolic cost plays a role in reversing cognitive decline in old age, as has been shown previously (Minhas et al., 2021).

To confirm the anti-inflammatory effect of IL-37 in acute inflammatory conditions in vivo, further studies were performed by systemic LPS injection in control and IL-37tg animals. Inflammation and activation of microglia are crucial hallmarks of various neurological diseases (Qin et al., 2007). On the one hand, activation of microglia is essential for homeostasis in the brain for an appropriate inflammatory response. On the other hand, overactivation of these processes can lead to neuronal damage (Qin et al., 2007; McGeer et al., 2005; Polazzi and Contestabile, 2002). In acute inflammation, little LPS is likely to enter the brain because the blood-brain barrier (BBB) is intact (Nadeau and Rivest, 1999). It is more likely that peripherally-induced neuroinflammation is an indirect effect (Qin et al., 2007), in which LPS activates the inflammatory cascade that signals to the CNS via TLR and/or TNF-α receptors on the BBB (Qin et al., 2007; Block and Hong, 2005; Chakravarty and Herkenham, 2005; Ji et al., 2008; Kim et al., 2000; Laflamme et al., 2003; Wu et al., 2011; Yang et al., 2013). Systemic inflammation induces increased density and reactivity of microglial cells characterized by increased secretion of pro-inflammatory cytokines such as IL-1 (Widmann and Heneka, 2014), changes in the morphological shape (retraction of the processes) (Yang et al., 2013; Kettenmann et al., 2011), greatly increased levels of surface proteins such as CD68 (Jurga et al., 2020; Yang et al., 2013; Kettenmann et al., 2011), and increased density of IBA-1-positive cells (Yang et al., 2013). In this study, we demonstrated that peripheral induced inflammation resulted in significantly increased numbers of IBA-1-positive cells and increased levels of CD68 and IL-1β in the CNS of control animals. In contrast, IL-37tg mice showed anti-inflammatory effects and did not exhibit an activated microglial phenotype in these features. However, the typical morphological changes described as retraction of processes (Yang et al., 2013) were not observed in either genotype. IL-37 was originally described as a basic inhibitor of innate immunity with reduced pro-inflammatory cytokine levels in plasma (Nold et al., 2010) and particularly in peripheral organs and in diseases such as endotoxemia, spinal cord injury, colitis, myocardial ischemia, obesity, and metabolic syndrome (Nold et al., 2010; Cavalli and Dinarello, 2018; Ballak et al., 2014; Coll-Miró et al., 2016; McNamee et al., 2011; Yousif et al., 2011; Nold-Petry et al., 2015). Our results clearly show that in vivo neuroinflammatory processes are reduced in acutely inflammatory challenged mice after transgenic IL-37 expression. IL-37 is a dual-function protein that has both intracellular and extracellular properties (Cavalli and Dinarello, 2018). Intracellularly, IL-37 interacts with SMAD3, translocates to the nucleus and induces anti-inflammatory effects (Amo-Aparicio et al., 2021; Sharma et al., 2008). Extracellularly, IL-37 binds to the IL-18Rα and the co-receptor IL-1R8 (SIGGIR), resulting in a signaling cascade with anti-inflammatory effects (Nold-Petry et al., 2015; Amo-Aparicio et al., 2021). The differences between these two signaling pathways were demonstrated by Amo-Aparicio et al., 2021 in a spinal cord injury model (Amo-Aparicio et al., 2021).

The resulting neuroinflammation and activation of microglial cells after peripheral LPS challenge also lead to functional and structural changes in the neuronal network, particularly affecting long-term potentiation (LTP) (Beyer et al., 2020; Commins et al., 2001; Di Filippo et al., 2013; Hennigan et al., 2007; Strehl et al., 2014) and spine morphology with implications for dendritic spine density (Beattie et al., 2002; Boulanger, 2009; Ikegaya et al., 2003; Kondo et al., 2011; Lucin and Wyss-Coray, 2009). Here, we showed that LTP was impaired in control animals after immunostimulation with LPS, whereas IL-37tg animals showed no defects in LTP. Loss of dendritic spines after LPS challenge was also restored in IL-37tg stimulated with LPS. These data indicate that deleterious neuronal changes known to be associated with acute inflammatory processes in the CNS are reduced in IL-37tg mice.

Our results suggest decreased neuroinflammation induced by systemic immune stimulation in the presence of IL-37. However, the anti-inflammatory effect of IL-37 in the CNS may be a secondary effect due to the reduction of the inflammatory response in the periphery. To identify the direct possibility of IL-37 expression in the CNS without peripheral influence, further electrophysiological experiments were performed with acute hippocampal slices from control and IL-37tg mice. Administration of LPS to the acute slices of IL-37tg mice suggests that IL-37 expression directly in the CNS may also be responsible for the reversal of neuronal impairments after peripheral LPS challenge. In addition, we confirmed the mechanisms of anti-inflammatory action in IL-37tg mice by using the recombinant IL-37 in WT mice. Recombinant human IL-37 has protective effects against endotoxemia, acute lung and spinal cord injury, asthma, and myocardial infarction (Cavalli et al., 2016; Cavalli and Dinarello, 2018; Coll-Miró et al., 2016; Moretti et al., 2014; Wu et al., 2014; Li et al., 2015; Lunding et al., 2015; Ye et al., 2014). Next, we investigated whether recombinant IL-37 has a similar effect on inflammatory processes in the CNS. Our results showed a reduction in pro-inflammatory cytokine levels in the brain. The consequences of acute peripheral immune stimulation by either LPS or IL-1β as a key cytokine triggering innate immune responses are the induction of pro-inflammatory cytokines leading to impaired learning and memory (Arai et al., 2001; Gonzalez et al., 2013; Rachal Pugh et al., 2001; Shaw et al., 2001; Sparkman et al., 2005; Yirmiya and Goshen, 2011). The effect of reduced neuroinflammation was analyzed on cognition and demonstrated by behavioral improvements in the Y-Maze test in animals pretreated with rIL-37. Spontaneous alternation behavior (SAB) in a symmetrical Y-shaped maze was used previously for pharmacological studies of short-term memory performance (Drew et al., 1973; Hughes, 2004; Kokkinidis and Anisman, 1976; Swonger and Rech, 1972). Systemic inflammation primarily affects attention and cognitive flexibility, including working memory, rather than associative learning. Low-dose injection of LPS, which elicits a very mild immune response and small changes (<1 °C) in core body temperature, has been shown to severely impair working memory (Murray et al., 2012). We therefore show that systemic injection of rIL-1β completely abolishes working memory. Consequently, rIL-37 was used as a preventive strategy by generating a certain level of IL-37 in the WT mice. Other studies using rIL-37 as a therapeutic intervention were performed, for example, after spinal cord injury by local administration of rIL-37 (Coll-Miró et al., 2016; Amo-Aparicio et al., 2021).

In this study, we specifically analyzed the activation status of microglial cells as a neuroinflammatory feature leading to structural changes in the neuronal network. Although our data suggest that IL-37 most likely transmits its signals via microglia, astrocytes also play an important role in maintaining neuronal circuits (Nizami et al., 2019; Schafer et al., 2012). Activated astrocytes express many complement factors that lead to synapse formation and elimination (Nizami et al., 2019; Stephan et al., 2012; Stevens et al., 2007). Therefore, it would be of interest in future experiments to dissect the underlying mechanism of synapse elimination with respect to IL-37 expression including microglia and astrocytes.

To better predict the role of microglia in IL-37 signal transduction after immunostimulation, single-cell type RNA sequencing was performed. Analysis of mRNA gene expression profiles revealed that approximately 11014 genes were differentially expressed in microglia after systemic LPS administration, clearly confirming the close communication between the peripheral immune system and the CNS. Although no significant differences were found between the microglial gene profile of WT and IL-37tg mice, however, these data indicated the specific gene profile in the both genotypes after the LPS challenge. For example, some genes were up- or down-regulated in the WT mice, which was the case to a lesser extent in the IL-37tg mice. Among them were some important genes such as Saa2 (Ye and Sun, 2015), Vgf (Busse et al., 2014), Bcl6b (Koyasu and Moro, 2011), Il23a (Ando et al., 2012), Icam1 (van de Stolpe and van der Saag, 1996), and Tk2 (Zhou et al., 2013), which contribute to inflammatory responses and are involved in many inflammation-related diseases. Interestingly, peripheral LPS exposure led to downregulation of some genes such as Kcnj9 (Liu et al., 2019) and Kif21b (Asselin et al., 2020), the deficiency of which has been associated with the occurrence of neurological and neurodevelopmental disorders, again highlighting the importance of the immune system-brain axis. Moreover, peripheral LPS challenge induced the upregulation of some genes equally in both genotypes, such as Gpr84 (Bouchard et al., 2007), Mmp3 (Kim et al., 2005) which are associated with neuroinflammation and neurodegeneration. Or Acod1, which produces the immune metabolite itaconate that has been shown to be upregulated after LPS administration and to inhibit inflammatory signaling in monocytes (Wu et al., 2020). Our mRNA gene expression analysis showed upregulation of Acod1, suggesting a link between the in vitro model (primary microglia) and the in vivo model here, because primary microglia showed upregulation of itaconate upon LPS treatment. Finally, RNA sequencing data showed upregulated gene expression of the IL-18 receptor, suggesting that expression of the IL-18 receptor on microglial cells may be responsible for IL-37 signal transduction by microglia in IL-37tg mice. It is worth noting that the lack of large differences in microglial gene expression profiles between WT and IL-37tg mice may be due to the timing of microglial isolation, because we isolated microglia 3 hr after the last LPS injection, which was also the case for the other experiments. However, the timing of gene regulation is different from that of protein synthesis. Therefore, it can be assumed that 3 hr after the last LPS injection, when we detected the deleterious effects, the transcripts of the responsible genes have already been degraded.

In the first part of this study, we showed that acute neuroinflammation, microglial activation, deficits in functional and structural plasticity, and impaired cognition induced by peripheral immune stimulation were attenuated or rescued in the presence of IL-37 (either transgene or recombinant). Moreover, these results suggest that rIL-37 may play an important future role as a therapeutic intervention in many neurological diseases associated with inflammatory responses. However, further experiments with recombinant IL-37 need to be performed to obtain a detailed picture of the mechanism underlying rIL-37 signaling. A recent study has shown that the efficacy of IL-37 is limited when administered systemically, suggesting a beneficial effect on local CNS cells rather than cells in the periphery (Amo-Aparicio et al., 2021). Further experiments need to analyze therapeutic approaches for acute neuroinflammation, as it is not clear whether treating the peripheral immune response is sufficient to produce beneficial effects in brain tissue. Here, we show that local expression of IL-37 in the brain is sufficient to rescue LPS-induced LTP impairments. However, translation to brain impairments in acute systemic inflammation remains to be investigated with respect to systemic rIL-37 administration.

To analyze chronic neuroinflammation, we used APP/PS1 mice as a model for Alzheimer’s disease (AD). AD is the most common form of dementia, and in 2015, an estimated 46.8 million people worldwide were living with the dementia (Prince, 2015). Research on AD has mainly focused on the long-lasting known pathological hallmarks namely beta-amyloid plaques and neurofibrillary tangles (Ardura-Fabregat et al., 2017; Glabe, 2005; Hardy and Selkoe, 2002; Wang et al., 2015). Recently, reports linking neuroinflammation to the pathogenic process of AD have been accumulating, showing that the brain can no longer be considered as an absolutely immune-privileged organ in disease progression (Ardura-Fabregat et al., 2017; Wang et al., 2015; Heneka et al., 2015; Heneka et al., 2014). In addition to the accumulation of amyloid-β (Aβ) during the progression of neuroinflammatory processes, pro-inflammatory cytokines such as TNF-α, IL-1β, or IL-6 have been shown to promote phosphorylation of tau (Bhaskar et al., 2010; Kitazawa et al., 2011; Quintanilla et al., 2004; Xu et al., 2021). In the present study, we focused on reducing the chronic neuroinflammatory response by decreasing microglial cell activation and proinflammatory mediators release and the subsequent effect on Aβ accumulation. For this purpose, we used the IL-37tg mouse line described above. To investigate the role of the anti-inflammatory cytokine IL-37 in chronic inflammation, we crossed the IL-37tg mouse with the APP/PS1 mouse. The APP/PS1 mouse line represents a reliable model that exhibits Aβ deposition as early as 6 months of age and has been reported to exhibit cognitive deficits starting at 8 months of age (Jankowsky et al., 2004; O’Leary and Brown, 2009; Garcia-Alloza et al., 2006). Microglial cells, the resident immune cells of the brain, are described (along with astrocytes) as a major source of cytokines that have a significant and distinct impact on the neuroinflammation aspects in AD (Heneka et al., 2015; Prinz et al., 2011). It has been previously described that microglia respond to Aβ peptides, which might be able to trigger the inflammatory process in AD that contributes to microglial activation, release of pro-inflammatory cytokines and memory deficits (Wang et al., 2015; Heneka et al., 2015; Zilka et al., 2012). Here, we show reduced pro-inflammatory cytokine levels for IL-1 and IL-6 in brain lysates from 9- to 12-month-old APP/PS1-IL37tg mice compared to APP/PS1 animals. In addition, microglial activation was significantly higher in APP/PS1 mice compared to control mice, whereas APP/PS1-IL37tg mice did not show a significant increase in microglial activation due to CD68 expression. Furthermore, we analyzed Aβ deposition in the brain tissue of APP/PS1 animals compared with APP/PS1-IL37tg mice. Overexpression of the anti-inflammatory cytokine IL-37 in APP/PS1 animals used in this study resulted in significantly higher plaque phagocytosis capacity, lower plaque burden, and smaller plaque size compared to APP/PS1 control mice. In conclusion, reduction of pro-inflammatory response or inhibition of excessive inflammation by IL-37 expression may lead to better Aβ uptake and may be involved in higher clearance of Aβ plaques.

It is noteworthy that previous studies have shown that IL-1β and IL-6 play an important role in the progression of AD, as both were released from microglial cells surrounding Aβ plaques in AD patients and animal models (Wang et al., 2015; Boutajangout and Wisniewski, 2013; Hunter et al., 2012; Vukic et al., 2009). Furthermore, IL-1β and IL-6 are described to play complex roles in regulating cognitive function in AD (Yirmiya and Goshen, 2011; Wang et al., 2015; Kitazawa et al., 2011; Dugan et al., 2009; Weaver et al., 2002). The present results showed an impairment of spatial memory in 9- to 12-month-old APP/PS1 mice compared with control animals. However, APP/PS1-IL37tg mice showed partially rescued spatial memory performance compared with APP/PS1 mice. In addition, APP/PS1-IL37tg mice did not exhibit any impairment during the reference memory test. Given the observed impairment in spatial learning in APP/PS1 animals, we further analyzed synaptic plasticity by measuring LTP as a cellular correlate of learning and memory in all groups. The findings demonstrated that the maintenance and induction phases of LTP were impaired in APP/PS1 mice compared to control animals. In contrast, the induction phase of LTP in APP/PS1-IL37tg mice was similar to that in control animals. However, the maintenance phase of LTP was also impaired in APP/PS1-IL37tg animals. These observations suggest that overexpression of IL-37 is sufficient to rescue the early phase of LTP (E-LTP; the first 20 min after stimulation), which is independent of protein synthesis. However, impaired late LTP in APP/PS1 mice, which requires regulation of gene expression at the transcriptional and translational levels (Auffret et al., 2010), was not rescued by IL-37 overexpression. Interestingly, there is evidence that the water maze task can be efficiently solved despite late-LTP impairments in the CA1 or the CA3 hippocampal subregion (Bannerman et al., 2012; Nakazawa et al., 2002). In addition, neuronal morphology was analyzed to investigate whether structural cellular changes were the reason for the decline in LTP and cognitive function. When APP/PS1 mice were compared with control mice, it was found that APP/PS1 mice exhibited decreased spine density in the apical dendrites of CA1 pyramidal neurons. In contrast, APP/PS1-IL37tg did not show decreased numbers of dendritic spines.

In general, the putative mechanism of IL-37 signaling in neurodegenerative diseases is not clear. Translation to humans might suggest IL-37 as a biomarker for inflammatory diseases with changes in IL-37 levels in patients associated with these diseases (Su and Tao, 2021). IL-37 as a dual-acting cytokine during AD progression, we suggest that both intracellular and extracellular IL-37 signaling can reduce neuroinflammation and microglial activation. Because IL-37 is also produced by peripheral cells, this could lead to a reduced inflammatory response and a reduction in activated circulating immune cells, whether or not these peripheral immune cells enter the brain. In addition, it is not clear whether infiltrating immune cells have positive or negative effects on AD progression. There are some studies showing that phagocytic peripheral immune cells can infiltrate the brain and serve as a surrogate for microglial populations (Dionisio-Santos et al., 2019; Fiala et al., 2002; Merlini et al., 2018; Thériault et al., 2015; Town et al., 2005).

In summary, during chronic neuroinflammation associated with Alzheimer’s disease, a significant deficit in synaptic plasticity (functional LTP and structural spine density) was documented, whereas rescue was observed in transgenic AD animals overexpressing the anti-inflammatory cytokine IL-37. In addition, a significant effect on the formation of amyloid-β plaques, a pathological feature of AD, was documented, suggesting that attenuation of neuroinflammation combined with increased clearance is sufficient to produce beneficial effects on learning and memory. Indeed, the results reported here demonstrate that expression of an anti-inflammatory IL-37 cytokine is able to reduce neuroinflammation and cognitive decline in a mouse model of Alzheimer’s disease. Furthermore, recent studies in spinal cord injury (Coll-Miró et al., 2016; Amo-Aparicio et al., 2021) and in a mouse model of multiple sclerosis (MS) Cavalli et al., 2019; Sánchez-Fernández et al., 2021 have shown that IL-37 signaling has protective properties in two other neuroinflammatory models by both transgenic expression and recombinant delivery (Su and Tao, 2021). Overall, the results of this study highlight the role of IL-37 in alleviating acute and chronic neuroinflammatory conditions and provide the basis for recombinant IL-37 as a potential future therapeutic approach. Furthermore, the IL-37tg mouse is a novel and important model system to explore therapeutic options while gaining mechanistic insights into human neurodegenerative diseases.

All experiments were performed and analyzed blinded to the experimenter.

All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for all Figures.

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Author details

1. Niklas Lonnemann

   Department of Cellular Neurobiology, Zoological Institute, Braunschweig, Germany

   Contribution

   Data curation, Formal analysis, Visualization, Methodology, Writing - original draft

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7285-9995

2. Shirin Hosseini

   1. Department of Cellular Neurobiology, Zoological Institute, Braunschweig, Germany
   2. Neuroinflammation and Neurodegeneration Group, Helmholtz Centre for Infection Research, Braunschweig, Germany

   Contribution

   Formal analysis, Writing - original draft

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7949-862X

3. Melanie Ohm

   1. Department of Cellular Neurobiology, Zoological Institute, Braunschweig, Germany
   2. BRICS - Braunschweig Integrated Centre of Systems Biology, Braunschweig, Germany

   Contribution

   Formal analysis, Visualization, Methodology

   Competing interests

   No competing interests declared

4. Robert Geffers

   Genome Analytics Group, Helmholtz Center for Infection Research, Braunschweig, Germany

   Contribution

   Formal analysis, Methodology

   Competing interests

   No competing interests declared

5. Karsten Hiller

   1. BRICS - Braunschweig Integrated Centre of Systems Biology, Braunschweig, Germany
   2. Department of Computational Biology of Infection Research, Helmholtz Centre for Infection Research, Braunschweig, Germany

   Contribution

   Resources, Supervision, Methodology

   Competing interests

   No competing interests declared

6. Charles A Dinarello

   1. Department of Medicine, University of Colorado Denver, Aurora, United States
   2. Department of Medicine, Radboud University, Medical Center, Nijmegen, Netherlands

   Contribution

   Conceptualization, Writing – review and editing

   For correspondence

   cdinare333@aol.com

   Competing interests

   No competing interests declared

7. Martin Korte

   1. Department of Cellular Neurobiology, Zoological Institute, Braunschweig, Germany
   2. Neuroinflammation and Neurodegeneration Group, Helmholtz Centre for Infection Research, Braunschweig, Germany

   Contribution

   Conceptualization, Data curation, Software, Supervision, Funding acquisition, Writing - original draft, Project administration, Writing – review and editing

   For correspondence

   m.korte@tu-bs.de

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-6956-5913

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