Histone Deacetylase 3 Couples Mitochondria to Drive IL-1ß-Dependent Inflammation by Configuring Fatty Acid Oxidation.

Immune cell function depends on specific metabolic programs dictated by mitochondria, including nutrient oxidation, macromolecule synthesis, and post-translational modifications. Mitochondrial adaptations have been linked to acute and chronic inflammation, but the metabolic cues and precise mechanisms remain unclear. Here we reveal that histone deacetylase 3 (HDAC3) is essential for shaping mitochondrial adaptations for IL-1ß production in macrophages through non-histone deacetylation. In vivo, HDAC3 promoted lipopolysaccharide-induced acute inflammation and high-fat diet-induced chronic inflammation by enhancing NLRP3-dependent caspase-1 activation. HDAC3 configured the lipid profile in stimulated macrophages and restricted fatty acid oxidation (FAO) supported by exogenous fatty acids for mitochondria to acquire their adaptations and depolarization. Rather than affecting nuclear gene expression, HDAC3 translocated to mitochondria to deacetylate and inactivate an FAO enzyme, mitochondrial trifunctional enzyme subunit α. HDAC3 may serve as a controlling node that balances between acquiring mitochondrial adaptations and sustaining their fitness for IL-1ß-dependent inflammation.

One-Carbon Metabolism Supports S-Adenosylmethionine and Histone Methylation to Drive Inflammatory Macrophages.

Activated macrophages adapt their metabolic pathways to drive the pro-inflammatory phenotype, but little is known about the biochemical underpinnings of this process. Here, we find that lipopolysaccharide (LPS) activates the pentose phosphate pathway, the serine synthesis pathway, and one-carbon metabolism, the synergism of which drives epigenetic reprogramming for interleukin-1ß (IL-1ß) expression. Glucose-derived ribose and one-carbon units fed by both glucose and serine metabolism are synergistically integrated into the methionine cycle through de novo ATP synthesis and fuel the generation of S-adenosylmethionine (SAM) during LPS-induced inflammation. Impairment of these metabolic pathways that feed SAM generation lead to anti-inflammatory outcomes, implicating SAM as an essential metabolite for inflammatory macrophages. Mechanistically, SAM generation maintains a relatively high SAM:S-adenosylhomocysteine ratio to support histone H3 lysine 36 trimethylation for IL-1ß production. We therefore identify a synergistic effect of glucose and amino acid metabolism on orchestrating SAM availability that is intimately linked to the chromatin state for inflammation.

Increased interleukin-22 levels in lupus nephritis and its associated with disease severity: a study in both patients and lupus-like mice model.

OBJECTIVES: Interleukin-22 (IL-22) has been considered as an inflammatory cytokine. In the present study, we investigated the potential role of IL-22 in lupus nephritis (LN). METHODS: We examined the IL-22 levels of serum and kidney tissue from LN patients and MRL/lpr mice. An intraperitoneal injection of saline, isotype control antibody (IgG), prednisone (3mg/kg/mouse), or anti-IL-22 mAb (5µg/kg/mouse or 25µg/kg/mouse) was administered twice a week from 6 to 18 weeks of age. RESULTS: IL-22 levels in both serum and kidney were significantly higher in LN patients as compared with those in healthy controls. The serum and renal levels of IL-22 in MRL/lpr mice were significantly increased over time. After MRL/lpr mice were treated with anti-IL-22 monoclonal antibody (mAb) for 12 weeks, significantly less urine protein and lower serum levels of creatinine and urea nitrogen were found. In addition, less renal injury score and few number of inflammatory cells per glomerulus were observed in MRL/lpr mice treated with anti-IL-22 mAb as compared with control groups. CONCLUSIONS: Our results suggest that IL-22 as a pathogenic cytokine might be a potential target for treatment of lupus nephritis.

Altered Amplitude of Low-Frequency Fluctuations in Inactive Patients with Nonneuropsychiatric Systemic Lupus Erythematosus.

Objective: This study is aimed at investigating the characteristics of the spontaneous brain activity in inactive patients with nonneuropsychiatric systemic lupus erythematosus (non-NPSLE). Methods: Thirty-one female inactive patients with non-NPSLE and twenty healthy controls were examined by resting-state functional magnetic resonance imaging (RS-fMRI). Three amplitude methods including amplitude of low-frequency fluctuations (ALFF), fractional amplitude of low-frequency fluctuations (fALFF), and percent amplitude of fluctuation (PerAF) (with and without standardization) were applied to evaluate the spontaneous brain activity. The correlation was performed between low-frequency oscillations and clinical and neuropsychological factors in inactive patients with non-NPSLE. Results: Compared to healthy controls, patients with non-NPSLE showed increased standardized ALFF (mALFF) in the left inferior temporal gyrus and left putamen, decreased PerAF in the right postcentral gyrus and bilateral precentral gyrus, and increased standardized PerAF (mPerAF) in the left putamen and decreased mPerAF in the right postcentral gyrus and bilateral precentral gyrus. By standardized fALFF (mfALFF), no significant brain regions were found between the two groups. Correlation analysis revealed significantly positive correlations between glucocorticoid dose and PerAF in the right precentral gyrus and mPerAF in the left putamen, and Complement 3 (C3) and mPerAF in the right postcentral gyrus. There was a significant negative correlation between C3 and mALFF in the left putamen. Conclusion: Abnormal low-frequency oscillations in multiple brain regions were found in inactive patients with non-NPSLE, indicating that the alteration of mALFF, PerAF, and mPerAF in specific brain regions might be an imaging biomarker of brain dysfunction in inactive patients with non-NPSLE.

[Research progress on systemic lupus erythematosus overlapping organ-specific autoimmune diseases].

Systemic lupus erythematosus (SLE) is a multiorgan-involved autoimmune disease, and it can overlap organ-specific autoimmune diseases such as autoimmune thyroid diseases, autoimmune hepatitis and inflammatory bowel disease. There may be some association between SLE and these autoimmune diseases, such as common immunological and genetic basis, but the pathogenic mechanism is still unclear. This review focuses on current knowledge regarding the prevalence and possible pathogenesis of SLE overlapping the above three autoimmune diseases.

Effects of Structural Flexibility on the Kinetics of DNA Y-Junction Assembly and Gelation.

The kinetics of DNA assembly is determined not only by temperature but also by the flexibility of the DNA tiles. In this work, the flexibility effect was studied with a model system of Y-junctions, which contain single-stranded thymine (T) loops in the center. It was demonstrated that the incorporation of a loop with only one thymine prominently improved the assembly rate and tuned the final structure of the assembly, whereas the incorporation of a loop of two thymines exhibited the opposite effect. These observations could be explained by the conformation adjustment rate and the intermotif binding strength. Increasing DNA concentration hindered the conformational adjustment rate of DNA strands, leading to the formation of hydrogels in which the network was connected by ribbons. Therefore, the gel can be treated as a metastable state during the phase transition.

Evaluation of the Role of IgE Responses to Der p 1 and Der p 2 in Chinese House Dust Mite-Allergic Patients.

BACKGROUND: The role of specific IgE (sIgE) against Der p 1 and Der p 2 in Chinese patients with house dust mite (HDM) allergy has not yet been well investigated. METHODS: One hundred patients were enrolled, based on sensitization and doctor-diagnosed allergy to HDM. Questionnaires were administered to document demographic and clinical characteristics. Serum IgE reactivity to Dermatophagoides pteronyssinus (Dp) extract, Der p 1, Der p 2 and Der p 10 was measured by ImmunoCAP. RESULTS: Almost all patients were sensitized to Der p 1 (95%) and Der p 2 (93%), with both allergens together being largely responsible for the total anti-HDM IgE response. No evidence for a significant role of Der p 10 was found. Overall, IgE responses to HDM and its 2 major allergens were higher in children than in adults in this cross-sectional study. With increasing age, IgE responses to Der p 2 become more important. A positive correlation was observed between the reaction of sIgE against Dp, Der p 1 and Der p 2 and the number of organs (including the eyes, nose, lungs and skin) that were affected in patients. CONCLUSIONS: In China, Der p 1 and Der p 2 are the dominant allergens in patients with HDM allergy. The relative importance of Der p 1 and Der p 2 changes with age, in favor of Der p 2. Overall, sIgE titers were positively associated with the number of organs affected.

Therapeutic potential of MCC950, a specific inhibitor of NLRP3 inflammasome in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder with a pathogenesis that remains incompletely understood, resulting in limited treatment options. MCC950, a highly specific NLRP3 inflammasome inhibitor, effectively suppresses the activation of NLRP3, thus reducing the production of caspase-1, the pro-inflammatory cytokines IL-1ß and IL-18. This review highlights the pivotal role of NLRP3 inflammasome activation pathways in the pathogenesis of SLE and discusses the potential therapeutic application of MCC950 in SLE. Notably, it comprehensively elucidates the mechanism of MCC950 targeting the NLRP3 pathway in SLE treatment, outlining its potential role in regulating autophagy and necroptosis. The insights gained contribute to a deeper understanding of the value of MCC950 in SLE therapy, serving as a robust foundation for further research and potential clinical applications.

Influence of transcatheter arterial embolization on symptom distress and fatigue in liver cancer patients.

BACKGROUND: Hepatocellular carcinoma (HCC) is a prevalent malignancy, and transcatheter arterial embolization (TAE) has emerged as a pivotal therapeutic modality. However, TAE may induce symptom distress and fatigue, adversely affecting the quality of life of patients. AIM: To investigate symptom distress, fatigue, and associated factors in HCC patients undergoing TAE. METHODS: We used a cross-sectional design and purposive sampling to enroll HCC patients who underwent TAE at our institution from January to December 2022. Questionnaires were utilized to collect data on symptom distress and fatigue scores from the first to the third day after TAE. RESULTS: Our study revealed a significant reduction in fatigue and symptom distress among patients after TAE. Pain, fatigue, insomnia, fever and abdominal distension were the most common symptoms troubling patients during the first 3 d post-TAE. Marital status, presence of family support, physical functional status, age, and symptom distress were identified as predictors of fatigue in patients. CONCLUSION: Healthcare professionals should educate HCC patients on symptom distress and fatigue, offering personalized relief strategies to lessen their psychological burden.

Th22, but not Th17 might be a good index to predict the tissue involvement of systemic lupus erythematosus.

PURPOSE: T-helper (Th) cells abnormalities are considered to be associated with the pathogenesis of Systemic lupus erythematosus (SLE). Recently, The Th22 cells have been identified and implicated in the pathogenesis of autoimmune diseases such as Rheumatoid arthritis (RA), although therir role in Systemic lupus erythematosus (SLE) remains unclear. The present study intends to investigate their roles in SLE. METHODS: Clinical data were collected in 65 SLE patients and 30 healthy controls. The patients were divided into active and inactive groups. CD4(+)IFN-γ(-)IL-17(-)IL-22(+)Tcells (Th22 cells),CD4(+) IFN-γ(-)IL-22(-)IL-17(+)T cells (Th17 cells),and CD4(+) IFN-γ(+) (Th1 cells) were assayed by flow cytometry. Serum interleukin-22 (IL-22) and IL-17 levels were measured by enzyme-linked immunosorbent assay. RESULTS: The main observation focused on increased Th22 cells in patients with sole lupus skin disease and decreased Th22 cells in patients with sole lupus nephritis. Likewise, concentrations of serum IL-22 were increased in patients with sole lupus skin disease, and decreased in patients with sole lupus nephritis. Additionally, there was a positive correlation between the percentage of Th22 cells and IL-22 production. The percentage of Th17 cells or concentration of serum IL-17 correlated positively with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). CONCLUSION: Th22 seems to be a more significant index to predict the tissue involvement of SLE than Th17, although Th17 may play a role in the activity of SLE.

Salt tolerance in Brassicaceae crops: physiological responses and molecular mechanisms.

Soil salinisation is a growing threat to global agriculture, reducing crop yields. Brassicaceae crops are vital vegetables and cash crops. Salt stress significantly affects the growth and development of Brassicaceae crops. A better understanding of the molecular and physiological mechanisms of salt tolerance is of theoretical and practical importance to improve Brassicaceae crop's salt tolerance and crop quality. Combined with previous research results, we discuss recent advances in research on salt stress response and salt tolerance in Brassicaceae crops. We summarised recent research progress on the physiological and molecular mechanisms of ionic homeostasis, antioxidant regulation, hormonal regulation and accumulation of osmotic-adjustment substances. We also discussed the molecular mechanism of Brassicaceae crop salt tolerant varieties from the perspective of differentially expressed genes, differentially expressed proteins and metabolites through transcriptome, proteome and metabonomic analysis methods. This paper summarises the molecular mechanisms in the perspective of differentially expressed genes, differentially expressed proteins, and metabolites through transcriptomic, proteome and metabolomics analysis. The review provides abundant data for accelerating the breeding of salt-tolerant Brassicaceae and laid a foundation for understanding the mechanism of salt tolerance of Brassicaceae crops and breeding salt-tolerance varieties.

Corrigendum to: Salt tolerance in Brassicaceae crops: physiological responses and molecular mechanisms.

Soil salinisation is a growing threat to global agriculture, reducing crop yields. Brassicaceae crops are vital vegetables and cash crops. Salt stress significantly affects the growth and development of Brassicaceae crops. A better understanding of the molecular and physiological mechanisms of salt tolerance is of theoretical and practical importance to improve Brassicaceae crop's salt tolerance and crop quality. Combined with previous research results, we discuss recent advances in research on salt stress response and salt tolerance in Brassicaceae crops. We summarised recent research progress on the physiological and molecular mechanisms of ionic homeostasis, antioxidant regulation, hormonal regulation and accumulation of osmotic-adjustment substances. We also discussed the molecular mechanism of Brassicaceae crop salt tolerant varieties from the perspective of differentially expressed genes, differentially expressed proteins and metabolites through transcriptome, proteome and metabonomic analysis methods. This paper summarises the molecular mechanisms in the perspective of differentially expressed genes, differentially expressed proteins, and metabolites through transcriptomic, proteome and metabolomics analysis. The review provides abundant data for accelerating the breeding of salt-tolerant Brassicaceae and laid a foundation for understanding the mechanism of salt tolerance of Brassicaceae crops and breeding salt-tolerance varieties.

"Iron triangle" of regulating the uterine microecology: Endometrial microbiota, immunity and endometrium.

The uterus is the core place for breeding new life. The balance and imbalance of uterine microecology can directly affect or even dominate the female reproductive health. Emerging data demonstrate that endometrial microbiota, endometrium and immunity play an irreplaceable role in regulating uterine microecology, forming a dynamic iron triangle relationship. Up to nowadays, it remains unclear how the three factors affect and interact with each other, which is also a frontier topic in the emerging field of reproductive tract microecology. From this new perspective, we aim to clarify the relationship and mechanism of the interaction of these three factors, especially their pairwise interactions. Finally, the limitations and future perspectives of the current studies are summarized. In general, these three factors have a dynamic relationship of mutual dependence, promotion and restriction under the physiological or pathological conditions of uterus, among which the regulatory mechanism of microbiota and immunity plays a role of bridge. These findings can provide new insights and measures for the regulation of uterine microecology, the prevention and treatment of endometrial diseases, and the further multi-disciplinary integration between microbiology, immunology and reproductive medicine.

Kir2.1-mediated membrane potential promotes nutrient acquisition and inflammation through regulation of nutrient transporters.

Immunometabolism contributes to inflammation, but how activated macrophages acquire extracellular nutrients to fuel inflammation is largely unknown. Here, we show that the plasma membrane potential (Vm) of macrophages mediated by Kir2.1, an inwardly-rectifying K+ channel, is an important determinant of nutrient acquisition and subsequent metabolic reprogramming promoting inflammation. In the absence of Kir2.1 activity, depolarized macrophage Vm lead to a caloric restriction state by limiting nutrient uptake and concomitant adaptations in nutrient conservation inducing autophagy, AMPK (Adenosine 5'-monophosphate-activated protein kinase), and GCN2 (General control nonderepressible 2), which subsequently depletes epigenetic substrates feeding histone methylation at loci of a cluster of metabolism-responsive inflammatory genes, thereby suppressing their transcription. Kir2.1-mediated Vm supports nutrient uptake by facilitating cell-surface retention of nutrient transporters such as 4F2hc and GLUT1 by its modulation of plasma membrane phospholipid dynamics. Pharmacological targeting of Kir2.1 alleviated inflammation triggered by LPS or bacterial infection in a sepsis model and sterile inflammation in human samples. These findings identify an ionic control of macrophage activation and advance our understanding of the immunomodulatory properties of Vm that links nutrient inputs to inflammatory diseases.

Slit2 is a potential biomarker for renal impairment in systemic lupus erythematosus.

Slit2 glycoprotein has been described to regulate the inflammatory response and be involved in autoimmune diseases. Here, we investigated the expression of Slit2 and its potential significance in systemic lupus erythematosus (SLE). A total of 103 patients with SLE participated in our study. The levels of serum Slit2 were measured by enzyme-linked immunosorbent assay, and the expression of Slit2 in renal tissue was detected by immunohistochemistry. Patients with active disease had higher levels of serum Slit2 than patients with inactive disease and controls. Patients with sole skin impairment or sole renal impairment or both skin and renal impairment had higher levels of serum Slit2 than patients with neither skin nor renal impairment. Patients with chronic kidney disease (CKD) had higher levels of serum Slit2 than patients with no CKD. Levels of serum Slit2 in patients with active disease were positively correlated with the SLE Disease Activity Index, complement C4, and anti-dsDNA antibody. Levels of serum Slit2 in patients with CKD were positively correlated with serum creatinine, urine protein, and glomerular filtration rate. The expression of Slit2 and its receptor Roundabout1 (Robo1) in the renal tissue of patients with lupus nephritis were higher than controls. Moreover, renal Slit2 was positively correlated with renal chronic index. Our data indicated that Slit2 may contribute to renal impairment and this may be a potential biomarker for SLE.

Interleukin-22 From Type 3 Innate Lymphoid Cells Aggravates Lupus Nephritis by Promoting Macrophage Infiltration in Lupus-Prone Mice.

Lupus nephritis (LN) is one of the most severe manifestations of systemic lupus erythematosus (SLE). Our previous studies demonstrated increased serum and renal Interleukin (IL)-22 in LN patients and MRL/lpr mice. This study investigated the role of IL-22 and its mechanism in LN. Here, we found that IL-22 was mainly produced by type 3 innate lymphoid cells (ILC3) in kidney of MRL/lpr mice. The systemic illness and local renal lesion were significantly alleviated in IL-22 or IL-22R gene knockout (KO) mice (IL-22 KO or IL-22R KO MRL/lpr mice) than control mice (MRL/lpr mice). IL-22 KO or IL-22R KO MRL/lpr mice had significantly slighter infiltration of macrophage in kidney than MRL/lpr mice. Consistently, by RNA-Seq, the expression of (CC motif) ligand 2 (CCL2) and (CXC motif) ligand 10 (CXCL10) was decreased in kidney of KO mice compared with control mice. By immunoblotting, significantly increased levels of STAT3 phosphorylation were found in the kidney of control mice compared to KO mice. In vitro, primary kidney epithelial cells from control mouse stimulated with recombinant IL-22 (rIL-22) expressed higher levels of CCL2, CXCL10, and phosphorylated STAT3. At the same time, when primary kidney epithelial cells were treated with rIL-22, transwell assay demonstrated their supernatant recruited more macrophages. In human kidney epithelial cell line (HK2) cells, when treated with rIL-22, we observed similar results with primary mouse kidney epithelial cells. Moreover, when cells were stimulated with rIL-22 following pre-treatment with STAT3 pathway inhibitor, the expression of CCL2 and CXCL10 were significantly reversed. Our findings demonstrate that IL-22 binding to IL-22R in kidney epithelial cells activated the STAT3 signaling pathway, enhanced the chemokine secretion and then promoted macrophage infiltration to the kidney of MRL/lpr mice, thus aggravated LN in lupus-prone mice. These findings indicate that IL-22 may play a pathogenic role in LN and may provide a promising novel therapeutic target for LN.

Altered Temporal Dynamics of Brain Activity in Multiple-Frequency Bands in Non-Neuropsychiatric Systemic Lupus Erythematosus Patients with Inactive Disease.

PURPOSE: In this study, we seek to investigate dynamic changes of brain activity in non-neuropsychiatric systemic lupus erythematosus (non-NPSLE) patients with inactive disease. PATIENTS AND METHODS: Thirty-one non-NPSLE patients with inactive disease and 20 matched healthy controls underwent the blood oxygenation level-dependent fMRI examination. Dynamic regional homogeneity (ReHo) and fractional amplitude of low-frequency fluctuations (fALFF) were used to analyze the brain activity in typical band (0.01-0.08 Hz), slow-4 (0.027-0.073 Hz) and slow-5 (0.01-0.027 Hz). Pearson's correlation analysis was performed to correlate dynamic regional homogeneity (dReHo) and dynamic fractional amplitude of low-frequency fluctuations (dfALFF) values for clusters of voxels where significant group differences were found with clinical variables in non-NPSLE patients with inactive disease. RESULTS: In typical band, non-NPSLE patients showed increased dReHo in left middle occipital gyrus (MOG) compared to healthy controls. Meanwhile, patients showed decreased dfALFF in right superior frontal gyrus (SFG) and bilateral middle frontal gyrus (MFG) in typical band. In slow-4, increased dReHo in left MOG was found in non-NPSLE patients. In slow-5, non-NPSLE patients showed increased dReHo in left MOG, left calcarine fissure and surrounding cortex, right precentral gyrus (PreCG) and left postcentral gyrus (PoCG). Meanwhile, non-NPSLE patients showed decreased dfALFF in left SFG, right MFG, and right PreCG in slow-5. Moreover, the glucocorticoid dose showed significantly negative correlations with dReHo values in right PreCG in slow-5, left PoCG in slow-5, and left MOG in typical band. CONCLUSION: dReHo and dfALFF abnormalities in different frequency bands may be the key characteristics in the pathogenesis mechanism of non-NPSLE.

Urinary metabolomic signatures in reticular oral lichen planus.

Oral lichen planus (OLP) is a chronic inflammatory disease. Among all the clinical forms in OLP, reticular type has the highest incidence rate. Previous studies have applied metabolomics to investigate the metabolic changes of oral mucosa and blood samples from reticular OLP patients. Urinary metabolomic signatures is also useful in analyzing the pathological changes of the patients, which was a complement to the previous studies. Through these researches, we may have a more comprehensive understanding of the disease. Metabolic profiles of urinary samples from OLP patients and control subjects were analyzed by liquid chromatography (LC)-mass spectrometry (MS) system. Differentially expressed metabolites were identified via OSI/SMMS software for the pathology analysis. Totally, 30 differentially expressed metabolites were identified. Pathological network showed that these metabolites participated in 8 pathological processes, that is, DNA damage and repair disorder, apoptosis process, inflammatory lesion, oxidative stress injury, carbohydrate metabolism disorder, mood dysfunction, abnormal energy expenditure, and other pathological process. These findings demonstrated that the analysis of human urine metabolome might be conducive to the achievement of the objectives of this study.

Serum-based metabolomics characterization of patients with reticular oral lichen planus.

OBJECTIVE: Oral lichen planus (OLP) is a chronic inflammatory mucosal lesion and systemic disease. In OLP, reticular type is the most common presentation of the disease. However, little is known about it. The aim of this study was to analyze the pathogenesis of reticular OLP and its possible associations with the pathological changes in other organ systems through serum-based metabolomics. METHODS: Blood samples were obtained from 16 reticular OLP patients and 24 control subjects. Liquid chromatography (LC)-mass spectrometry (MS) system was used to identify differentially expressed metabolites. The pathways analysis was performed by MetaboAnalyst. Pathological network was constructed by Cytoscape software. RESULTS: Totally, 31 modulated metabolites were identified, whose dysregulations affected 25 metabolic pathways and 7 pathological processes in the disease. Through an impact-value screen (impact-value＞0.1), 6 pathways were selected as the significantly dysregulated pathways. Pathological network showed that these metabolites participated in 7 pathological processes, that is, apoptosis process, DNA damage and repair disorder, oxidative stress injury, carbohydrate metabolism disorder, mood dysfunction, inflammatory lesion, and other pathological process. CONCLUSION: The study demonstrated that reticular OLP could cause the dysregulations of the metabolites in serum, which might be also further linked to other organ and systemic diseases through the blood system, such as diabetes, sleep disorders, and depression, etc.