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MRL/lpr mice displayed specific cognitive impairment. MRL/lpr (LPR) mice had deficits in visuospatial memory tested in the novel object placement test (Panel A ), assessed as preference scores and as proportion had preference for moved (novel) object. LPR mice had higher object exploration than MRL+/+ (MRL) mice. However, LPR mice were not significantly different from MRL mice in the novel object recognition test (Panel B ). The dotted line at 50% preference indicates chance performance *, significant difference between LPR and MRL mice ( p < 0.05 or p < 0.01). RI: retention interval.
Source publication
Neuropsychiatric symptoms of systemic lupus erythematosus (NP-SLE) have been understudied compared to end-organ failure and peripheral pathology. Neuropsychiatric symptoms, particularly affective and cognitive indications, may be among the earliest manifestations of SLE. Among the potential pathophysiological mechanisms responsible for NP-SLE are i...
Context in source publication
Context 1
... and anxiety-like behavior were measured between 10–15 weeks of age in MRL/lpr (LPR) mice and their congenic background strain MRL+/+ (MRL) mice. As shown in Figure 2A, MRL/lpr (LPR) mice exhibited increased depression-like behavior, assessed as immobility in forced swim test ( t = 4.49, df = 37, p < 0.01), consistent with previous results [9,12]. Even though LPR mice had modestly lower locomotor activity (total tracklength in open field MRL: 2920 ± 130 cm, LPR: 2419 ± 97 cm), there was no significant correlation between the total tracklength and the immobility in forced swim test in either genotype and these activity levels were within normal ranges. Furthermore, exploration of novel objects, also an active process, was also normal in LPR mice (Figure 3). LPR mice also displayed anhedonic behavior in the saccharin preference test ( t = 2.64, df = 22, p < 0.05, Figure 2B), similar to previous reports [57] despite the equivalent total liquid consumption between groups (MRL: 0.95 ± 0.06 mL, LPR: 0.82 ± 0.10 mL). There was no difference in anxiety-like behavior between MRL and LPR mice, assessed as center activities in the open field test (Figure 2C), latency to feed in novelty suppressed of feeding (Figure 2D), or the amount of time spent in the ...
Citations
... This process can lead to synaptic stripping and neuronal damage, exacerbating neuropsychiatric symptoms (Abe et al., 2022;Zhou et al., 2024). The kynurenine pathway, activated by increased peripheral cytokines, produces neurotoxic metabolites that affect mood and cognition (Li et al., 2015). Lastly, thrombotic pathways, particularly those involving antibodies like anticardiolipin, are linked to depression and anxiety in SLE, suggesting that ischemic processes may contribute to these psychiatric symptoms (Duca et al., 2023). ...
... In addition, early systemic lupus erythematosus often presents with neuropsychiatric symptoms. In mouse models, cognitive dysfunction has been observed alongside elevated plasma MCP-3 levels [62]. Therefore, based on this limited evidence, it can be inferred that the elevation of chemotactic factors may play a regulatory role in subtle changes in brain function. ...
Background
Cognitive impairment is a core symptom of schizophrenia. Metabolic abnormalities impact cognition, and although the influence of blood lipids on cognition has been documented, it remains unclear. We conducted a small cross-sectional study to investigate the relationship between blood lipids and cognition in patients with stable-phase schizophrenia. Using Olink proteomics, we explored the potential mechanisms through which blood lipids might affect cognition from an inflammatory perspective.
Methods
A total of 107 patients with stable-phase schizophrenia and cognitive impairment were strictly included. Comprehensive data collection included basic patient information, blood glucose, blood lipids, and body mass index. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) and the MATRICS Consensus Cognitive Battery (MCCB). After controlling for confounding factors, we identified differential metabolic indicators between patients with mild and severe cognitive impairment and conducted correlation and regression analyses. Furthermore, we matched two small sample groups of patients with lipid metabolism abnormalities and used Olink proteomics to analyze inflammation-related differential proteins, aiming to further explore the association between lipid metabolism abnormalities and cognition.
Results
The proportion of patients with severe cognitive impairment (SCI) was 34.58%. Compared to patients with mild cognitive impairment (MCI), those with SCI performed worse in the Attention/Alertness (t = 2.668, p = 0.009) and Working Memory (t = 2.496, p = 0.014) cognitive dimensions. Blood lipid metabolism indicators were correlated with cognitive function, specifically showing that higher levels of TG (r = -0.447, p < 0.001), TC (r = -0.307, p = 0.002), and LDL-C (r = -0.607, p < 0.001) were associated with poorer overall cognitive function. Further regression analysis indicated that TG (OR = 5.578, P = 0.003) and LDL-C (OR = 5.425, P = 0.001) may be risk factors for exacerbating cognitive impairment in individuals with stable-phase schizophrenia. Proteomics analysis revealed that, compared to individuals with stable-phase schizophrenia and normal lipid metabolism, those with hyperlipidemia had elevated levels of 10 inflammatory proteins and decreased levels of 2 inflammatory proteins in plasma, with these changes correlating with cognitive function. The differential proteins were primarily involved in pathways such as cytokine-cytokine receptor interaction, chemokine signaling pathway, and IL-17 signaling pathway.
Conclusion
Blood lipids are associated with cognitive function in individuals with stable-phase schizophrenia, with higher levels of TG, TC, and LDL-C correlating with poorer overall cognitive performance. TG and LDL-C may be risk factors for exacerbating cognitive impairment in these patients. From an inflammatory perspective, lipid metabolism abnormalities might influence cognition by activating or downregulating related proteins, or through pathways such as cytokine-cytokine receptor interaction, chemokine signaling pathway, and IL-17 signaling pathway.
... An MRL/mpj control group was not included in the IL-6 KO/WT cohorts for behavioral testing due to the comprehensive existing characterizations of this strain relative to IL-6 competent MLR/lpr mice. While inclusion of this group might have been ideal, we did find that knocking out IL-6 was associated with a higher novelty preference (+ 25% preference) relative to MRL/lpr mice that was comparable to historical MRL/mpj controls (+ 10-30% preference) [99,100]. Therefore, abrogation of IL-6 signaling appears to return the memory and learning functions of MRL/lpr mice to those of non-lupus controls, at least in this indirect comparison. ...
Background
Neuropsychiatric lupus (NPSLE) describes the cognitive, memory, and affective emotional burdens faced by many lupus patients. While NPSLE’s pathogenesis has not been fully elucidated, clinical imaging studies and cerebrospinal fluid (CSF) findings, namely elevated interleukin-6 (IL-6) levels, point to ongoing neuroinflammation in affected patients. Not only linked to systemic autoimmunity, IL-6 can also activate neurotoxic glial cells the brain. A prior pre-clinical study demonstrated that IL-6 can acutely induce a loss of sucrose preference; the present study sought to assess the necessity of chronic IL-6 exposure in the NPSLE-like disease of MRL/lpr lupus mice.
Methods
We quantified 1308 proteins in individual serum or pooled CSF samples from MRL/lpr and control MRL/mpj mice using protein microarrays. Serum IL-6 levels were plotted against characteristic NPSLE neurobehavioral deficits. Next, IL-6 knockout MRL/lpr (IL-6 KO; n = 15) and IL-6 wildtype MRL/lpr mice (IL-6 WT; n = 15) underwent behavioral testing, focusing on murine correlates of learning and memory deficits, depression, and anxiety. Using qPCR, we quantified the expression of inflammatory genes in the cortex and hippocampus of MRL/lpr IL-6 KO and WT mice. Immunofluorescent staining was performed to quantify numbers of microglia (Iba1 +) and astrocytes (GFAP +) in multiple cortical regions, the hippocampus, and the amygdala.
Results
MRL/lpr CSF analyses revealed increases in IL-17, MCP-1, TNF-α, and IL-6 (a priori p-value < 0.1). Serum levels of IL-6 correlated with learning and memory performance (R² = 0.58; p = 0.03), but not motivated behavior, in MRL/lpr mice. Compared to MRL/lpr IL-6 WT, IL-6 KO mice exhibited improved novelty preference on object placement (45.4% vs 60.2%, p < 0.0001) and object recognition (48.9% vs 67.9%, p = 0.002) but equivalent performance in tests for anxiety-like disease and depression-like behavior. IL-6 KO mice displayed decreased cortical expression of aif1 (microglia; p = 0.049) and gfap (astrocytes; p = 0.044). Correspondingly, IL-6 KO mice exhibited decreased density of GFAP + cells compared to IL-6 WT in the entorhinal cortex (89 vs 148 cells/mm², p = 0.037), an area vital to memory.
Conclusions
The inflammatory composition of MRL/lpr CSF resembles that of human NPSLE patients. Increased in the CNS, IL-6 is necessary to the development of learning and memory deficits in the MRL/lpr model of NPSLE. Furthermore, the stimulation of entorhinal astrocytosis appears to be a key mechanism by which IL-6 promotes these behavioral deficits.
... Neuroimaging has recently identified a loss of the mitochondrial translocator TSPO protein in SLE patients with cognitive impairment [202]. The accumulation of kynurenine has been associated with neurobehavioral abnormalities in mice [203] and in patients with SLE [204]. Kynurenine has been found the most potent metabolite capable of discriminating lupus from control metabolome [123,205]. ...
... In addition, both microglial activation [4] and blood-brain barrier (BBB) weakening [5], which may be involved in the pathogenesis of NPSLE, occur in these mice. Moreover, they demonstrate impairments in spatial working memory and visual cognitive memory [6] and exhibit hippocampal astrogliosis [7] and brain cell apoptosis [8]. ...
Neuropsychiatric systemic lupus erythematosus (NPSLE) is an incurable disease characterised by neuropsychiatric symptoms, particularly depression. Novel therapeutic options for NPSLE are urgently needed. Several previous reports have suggested that both microglial activation and impaired neurogenesis may be involved in the progression of depression. In contrast, the administration of lysophosphatidic acid (LPA) ameliorates depression and anxiety. Therefore, in the present study, we determined whether treatment with LPA affects microglial activation, impaired neurogenesis, and abnormal behaviour in MRL/lpr mice.
In both tail suspension test and forced swim test, the MRL/lpr mice exhibited a significant increase in total immobility time compared with MRL/+ mice. Treatment with LPA significantly suppressed the prolonged immobility time in MRL/lpr mice. In contrast, pretreatment with ki16425 (a specific antagonist of LPA receptor 1 and 3) significantly reversed the effects of LPA. Furthermore, MRL/lpr mice exhibited impairments in spatial working memory and visual cognitive memory, which were suppressed by LPA treatment. The expression levels of TMEM119, CD68, GFAP, and caspase-3 in the hippocampus and prefrontal cortex of MRL/lpr mice were significantly higher than those in MRL/+ mice. Treatment with LPA inhibited these increases in MRL/lpr mice. Pretreatment with ki16425 reversed LPA-mediated inhibition of microglial activation. The quantity of sodium fluorescein that leaked into the brain tissues in MRL/lpr mice was significantly higher than that in MRL/+ mice. Treatment with LPA tended to decrease the sodium fluorescein leakage.
These findings suggest that treatment with LPA may regulate microglial activation, which is important in the pathogenesis of NPSLE, as well as blood-brain-barrier weakening and abnormal behaviour.
... MRL/lpr mice show lupus-like signs at approximately 12 weeks of age, such as increased levels of urinary protein, serum IgG, and autoantibodies [20]. In addition, they develop behavioral deficits or cognitive dysfunction from 10 to 12 weeks of age, and their behavioral phenotype stabilizes after 10-15 weeks of age [21,22]. Forty-eight 11-week-old MRL/lpr mice were included in this study, and the mice were divided into a VitD3-treated group and a control group by the random number table method, with 24 mice in each group. ...
... MRL/lpr mice develop behavioral deficits or cognitive dysfunction from 10 to 12 weeks of age, and their behavioral phenotype stabilizes after 10-15 weeks of age [21,22]. In the present study, the Enpp2 gene expression in the hippocampus in MRL/lpr mice increased significantly with time and the other genes also increased with time to varying degrees, which was consistent with a previous report in an AD model [31], suggesting that MRL/ lpr mice may have cognitive dysfunction and it worsened with time. ...
Neuropsychiatric systemic lupus erythematosus (NPSLE) is a serious complication of systemic lupus erythematosus (SLE) involving the nervous system with high morbidity and mortality. A key hypothesis in NPSLE is that a disrupted barrier allows autoantibodies and immune components of peripheral blood to penetrate into the central nervous system (CNS), resulting in inflammation and damage. The blood cerebrospinal fluid barrier (BCSFB), which consists of the choroid plexus and the hypothalamic tanycytes, has long been regarded as an immunological sanctuary site. 1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] is the active form of vitamin D, which plays multiple roles in inflammation and immunoregulation. In this study, we investigated the possible protective effects of 1,25-dihydroxyvitamin D3 against BCSFB dysfunction in NPSLE in MRL/lpr mice and explored the mechanism by which 1,25-dihydroxyvitamin D3 inhibits the progression of NPSLE. In this study, we found that supplementation with 1,25-dihydroxyvitamin D3 markedly improved serological and immunological indices, delayed inflammatory infiltration, delayed neuronal deformation, and upregulated the expression of brain-derived neurotrophic factor (BDNF) proteins in the brain. Furthermore, 1,25-dihydroxyvitamin D3 downregulated proinflammatory cytokines such as nuclear factor kappa-B (NF-κB) and tumor necrosis factor-α (TNF-α) by activating peroxisome proliferator-activated receptor γ (PPARγ), and it reduced the expression of the TGF-β/Smad signaling pathway. Our findings demonstrate that 1,25-dihydroxyvitamin D3 delayed cell infiltration into the choroid plexus and decreased markers suggestive of cognitive decline in MRL/lpr mice, and the mechanism may be related to protection against BCSFB disruption through activation of the anti-inflammatory PPARγ/NF-κB/TNF-α pathway as well as upregulation of BDNF and inhibition of the TGF-β/Smad signaling pathway. These findings provide a novel direction for the study of NPSLE.
... Possible biological mechanisms linking SLE with psychiatric disorders include the neuroendocrine dysregulation of the immune system [22] The dysregulation of the HPA axis reported in suicidal behavior [23,24] is linked to inflammatory processes such as lowgrade inflammation, and interleukin dysregulation [25]. Immunological and neurochemical changes were also associated to depressionlike behavior and cognitive impairment in a mouse model for neuropsychiatric Lupus [26]. This neuroendocrine dysregulation was proposed as the linkage between psychiatric disorders and autoimmune diseases such as SLE [22,27] Shared genetic risk was also reported between schizophrenia and immune-mediated diseases, including SLE [28]. ...
Background
: Previous studies suggested that patients with Systematic Lupus Erythematosus (SLE) have a higher risk of suicidal behaviour, including suicidal ideation, attempt and complete suicide. Systematic data describing the SLE patients’ clinical characteristics and risk factors of suicidal behavior are lacking.
Objectives
: To determine the magnitude of suicidal behavior among SLE patients and to examine predictors associated with suicidal behavior. An additional aim was to identify common genes or coinherited single nucleotide polymorphisms (SNP) implicated in suicidal behavior and SLE.
Methods
: We conducted a systematic literature review based on PRISMA guidelines using the online databases PubMed/Medline, EMBASE and Web of Science, from inception to August 2021. Full-text original articles that examined the relationship between SLE patients with suicidal behavior were eligible for our review. Two reviewers independently reviewed articles to assess eligibility using the Newcastle-Ottawa Scale and the Joanna Briggs Institute criteria. Systematic reviews, metanalysis, narrative review, case reports, case series, including less than 10 patients, and conference abstracts, were excluded. All registered genome-wide association study (GWAS) data in the GWAS catalogue database for SLE and psychiatric traits (suicidal behavior, depression, anxiety, psychosis) were downloaded for further analysis. Special in silico tools were used to examine if any genetic polymorphisms (SNPs) that predispose for SLE or psychiatric traits can be inherited together as a single haplotype. This could be posing a risk factor for a coexisting psychiatric condition in SLE patients.
Results
: Of the 64 articles identified, 22 were relevant to the study question; cross-sectional (n=8) and prospective cohorts (n=6) were the most frequently retrieved studies. Among the 27106 SLE patients with SLE, 802 had suicidal behavior (2.9%), and of those, 87.9% were female. Suicide attempt occurred in 573/802 (71.4%) and complete suicide in 18/802 (3%). Major depressive disorder was the most frequently reported coexisting psychiatric condition associated with suicidal behavior, followed by psychosis and social phobia. In addition, several clinical manifestations were linked to suicidal behavior, particularly neuropsychiatric lupus, serositis, mucocutaneous, and renal involvement. Further, high scores in disease activity and damage indices were associated with suicidal behaviour. A haplotype in chromosomal region 6p21.33 was found to contain a combination of risk alleles predisposing for SLE and depression, the most common psychiatric disorder associated with suicidal behavior.
Conclusion
: Suicide behavior in SLE patients was associated with depression, neuropsychiatric lupus, active disease and damage. Further evidence supports a genetic origin of psychiatric symptoms in SLE patients. Awareness of these findings can guide clinicians to recognize suicide behavior promptly and prevent suicide attempts.
... 27,28 MRL+/+ mice are autoimmune-prone and spontaneously develop a relatively mild lupus-like disease late in life (50% mortality at 17 months). These mice are also used as a model of neuropsychiatric lupus [36][37][38] and to study pharmacologically-induced neurotoxicity. 39,40 Because many immunologic and neurologic disorders such as ASD are accompanied by immune dysfunction and autoimmunity, 41 MRL+/+ mice were used in the current study. ...
Trichloroethylene (TCE) is an environmental contaminant associated with immune-mediated inflammatory disorders and neurotoxicity. Based on known negative effects of developmental overnutrition on neurodevelopment, we hypothesized that developmental exposure to high fat diet (HFD) consisting of 40% kcal fat would enhance neurotoxicity of low-level (6 μg per kg per day) TCE exposure in offspring over either stressor alone. Male offspring were evaluated at ∼6 weeks of age after exposure beginning 4 weeks preconception in the dams until weaning. TCE, whether used as a single exposure or together with HFD, appeared to be more robust than HFD alone in altering one-carbon metabolites involved in glutathione redox homeostasis and methylation capacity. In contrast, opposing effects of expression of key enzymes related to DNA methylation related to HFD and TCE exposure were observed. The mice generated unique patterns of anti-brain antibodies detected by western blotting attributable to both TCE and HFD. Taken together, developmental exposure to TCE and/or HFD appear to act in complex ways to alter brain biomarkers in offspring.
... However, in terms of NP-SLE, none of these models exhibit all of the clinical symptoms found in SLE patients. For example, the 564Igi strain exhibits anxiety-like behaviour and motor and coordination defects but lacks a depression-like phenotype [20]; the MRL/lpr strain exhibits depression-like behaviour and deficits in cognitive function without anxiety-like behaviour [21]; and NZB/NZW F1 mice exhibit congenital structural abnormalities of the brain and mental disorders such as increased anxiety-like behaviours and decreased locomotor activity [22]. The NZB/NZW F1 mouse model, which relies on inbred mouse strains, exhibits delayed and inconsistent disease onset, with SLE-related symptoms usually not appearing until 5-6 months of age; this remains a distinct limitation of this classic model. ...
Background:
Neuropsychiatric systemic lupus erythaematosus (NP-SLE) is one of the major manifestations of lupus. However, the mechanisms involved in NP-SLE are still largely unknown. The abnormal activation of the type I IFN signalling pathway is involved in SLE pathogenesis and is linked to NP-SLE, but the effect of IFN-α on NP-SLE encephalopathy has not been systematically studied.
Methods:
An intravenous injection of Adv-IFN-α (10 mice, 10 × 109 vp) was administered to the IFN-α-treated group, and Adv-ctrl (10 mice, 10 × 109 vp) (ViGene Biosciences, China) was administered to the control group. Gene expression was determined by real-time quantitative polymerase chain reaction (RT-qPCR). Enzyme-linked immunosorbent assay (ELISA) was used to detect antibodies in the serum, and urinary protein levels were measured with a BCA Protein Assay kit. Haematoxylin-eosin (H&E) and periodic acid-Schiff (PAS)-light green staining were used for kidney histology. The elevated plus-maze test, novelty-suppressed feeding assay, open-field test, tail suspension test, social dominance tube test, three-chamber social interaction test, step-down passive avoidance test and novelty Y-maze task were used to assess behaviour.
Results:
In this study, we performed a series of behavioural tests to assess the neuropsychiatric phenotypes of IFN-α-treated NZB/NZW F1 mice and found that these mice developed a series of mental disorders such as anxiety-like phenotypes, depression-like phenotypes, deficits in sociability and cognitive impairments, which mimic the neuropsychiatric manifestations of NP-SLE, with a consistent onset and progression.
Conclusions:
Our research verified that IFN-α plays a critical role in NP-SLE and provides a comprehensive NP-SLE mouse model for dissecting the mechanisms of NP-SLE and developing novel therapies for intervention.
... Notably, KA is an NMDAR antagonist (29), which can protect neurons from excitotoxic damage. An imbalance between QA and KA contributes to spatial memory deficits and functional and structural changes in the brain in animal models of neuroinflammation (31). In humans with SLE, an increased kynurenine-to-tryptophan ratio in blood has been reported (32) and correlates with IFNα gene expression (33). ...
Cognitive dysfunction (CD) is an insidious and underdiagnosed manifestation of systemic lupus erythematosus (SLE) that has a considerable impact on quality of life, which can be devastating. Given the inconsistencies in the modes of assessment and the difficulties in attribution to SLE, the reported prevalence of CD ranges from 5% to 80%. Although clinical studies of SLE‐related CD have been hampered by heterogeneous subject populations and a lack of sensitive and standardized cognitive tests or other validated objective biomarkers for CD, there are, nonetheless, strong data from mouse models and from the clinical arena that show CD is related to known disease mechanisms. Several cytokines, inflammatory molecules, and antibodies have been associated with CD. Proposed mechanisms for antibody‐ and cytokine‐mediated neuronal injury include the abrogation of blood–brain barrier integrity with direct access of soluble molecules in the circulation to the brain and ensuing neurotoxicity and microglial activation. No treatments for SLE‐mediated CD exist, but potential candidates include agents that inhibit microglial activation, such as angiotensin‐converting enzyme inhibitors, or that protect blood–brain barrier integrity, such as C5a receptor blockers. Structural and functional neuroimaging data have shown a range of regional abnormalities in metabolism and white matter microstructural integrity in SLE patients that correlate with CD and could in the future become diagnostic tools and outcome measures in clinical trials aimed at preserving cognitive function in SLE.
