Serine synthesis controls mitochondrial biogenesis in macrophages.

Mitochondrial dysfunction is the pivotal driving factor of multiple inflammatory diseases, and targeting mitochondrial biogenesis represents an efficacious approach to ameliorate such dysfunction in inflammatory diseases. Here, we demonstrated that phosphoglycerate dehydrogenase (PHGDH) deficiency promotes mitochondrial biogenesis in inflammatory macrophages. Mechanistically, PHGDH deficiency boosts mitochondrial reactive oxygen species (mtROS) by suppressing cytoplasmic glutathione synthesis. mtROS provokes hypoxia-inducible factor-1α signaling to direct nuclear specificity protein 1 and nuclear respiratory factor 1 transcription. Moreover, myeloid Phgdh deficiency reverses diet-induced obesity. Collectively, this study reveals that a mechanism involving de novo serine synthesis orchestrates mitochondrial biogenesis via mitochondrial-to-nuclear communication, and provides a potential therapeutic target for tackling inflammatory diseases and mitochondria-mediated diseases.

Targeting methionine metabolism in cancer: opportunities and challenges.

Reprogramming of methionine metabolism is a conserved hallmark of tumorigenesis. Recent studies have revealed mechanisms regulating methionine metabolism within the tumor microenvironment (TME) that drive both cancer development and antitumor immunity evasion. In this review article we summarize advancements in our understanding of tumor regulation of methionine metabolism and therapies in development that target tumor methionine metabolism. We also delineate the challenges of methionine blockade therapies in cancer and discuss emerging strategies to address them.

Excitatory amino acid transporter supports inflammatory macrophage responses.

Excitatory amino acid transporters (EAATs) are responsible for excitatory amino acid transportation and are associated with auto-immune diseases in the central nervous system and peripheral tissues. However, the subcellular location and function of EAAT2 in macrophages are still obscure. In this study, we demonstrated that LPS stimulation increases expression of EAAT2 (coded by Slc1a2) via NF-κB signaling. EAAT2 is necessary for inflammatory macrophage polarization through sustaining mTORC1 activation. Mechanistically, lysosomal EAAT2 mediates lysosomal glutamate and aspartate efflux to maintain V-ATPase activation, which sustains macropinocytosis and mTORC1. We also found that mice with myeloid depletion of Slc1a2 show alleviated inflammatory responses in LPS-induced systemic inflammation and high-fat diet induced obesity. Notably, patients with type II diabetes (T2D) have a higher level of expression of lysosomal EAAT2 and activation of mTORC1 in blood macrophages. Taken together, our study links the subcellular location of amino acid transporters with the fate decision of immune cells, which provides potential therapeutic targets for the treatment of inflammatory diseases.

Gut microbiota regulates host melatonin production through epithelial cell MyD88.

Melatonin has various physiological effects, such as the maintenance of circadian rhythms, anti-inflammatory functions, and regulation of intestinal barriers. The regulatory functions of melatonin in gut microbiota remodeling have also been well clarified; however, the role of gut microbiota in regulating host melatonin production remains poorly understood. To address this, we studied the contribution of gut microbiota to host melatonin production using gut microbiota-perturbed models. We demonstrated that antibiotic-treated and germ-free mice possessed diminished melatonin levels in the serum and elevated melatonin levels in the colon. The influence of the intestinal microbiota on host melatonin production was further confirmed by fecal microbiota transplantation. Notably, Lactobacillus reuteri (L. R) and Escherichia coli (E. coli) recapitulated the effects of gut microbiota on host melatonin production. Mechanistically, L. R and E. coli activated the TLR2/4/MyD88/NF-κB signaling pathway to promote expression of arylalkylamine N-acetyltransferase (AANAT, a rate-limiting enzyme for melatonin production), and MyD88 deficiency in colonic epithelial cells abolished the influence of intestinal microbiota on colonic melatonin production. Collectively, we revealed a specific underlying mechanism of gut microbiota to modulate host melatonin production, which might provide novel therapeutic ideas for melatonin-related diseases.

Serine synthesis sustains macrophage IL-1ß production via NAD+-dependent protein acetylation.

Serine metabolism is involved in the fate decisions of immune cells; however, whether and how de novo serine synthesis shapes innate immune cell function remain unknown. Here, we first demonstrated that inflammatory macrophages have high expression of phosphoglycerate dehydrogenase (PHGDH, the rate-limiting enzyme of de novo serine synthesis) via nuclear factor κB signaling. Notably, the pharmacological inhibition or genetic modulation of PHGDH limits macrophage interleukin (IL)-1ß production through NAD+ accumulation and subsequent NAD+-dependent SIRT1 and SIRT3 expression and activity. Mechanistically, PHGDH not only sustains IL-1ß expression through H3K9/27 acetylation-mediated transcriptional activation of Toll-like receptor 4 but also supports IL-1ß maturation via NLRP3-K21/22/24/ASC-K21/22/24 acetylation-mediated activation of the NLRP3 inflammasome. Moreover, mice with myeloid-specific depletion of Phgdh show alleviated inflammatory responses in lipopolysaccharide-induced systemic inflammation. This study reveals a network by which a metabolic enzyme, involved in de novo serine synthesis, mediates post-translational modifications and epigenetic regulation to orchestrate IL-1ß production, providing a potential inflammatory disease target.

Carbon metabolism in the regulation of macrophage functions.

Carbon metabolism, including one-carbon (1C) metabolism and central carbon metabolism (CCM), provides energy for the cell and generates metabolites with signaling activities. The regulation of macrophage polarization involves complex signals and includes an epigenetic level. Epigenetic modifications through changes in carbon metabolism allow macrophages to respond in a timely manner to their environment and adapt to metabolic demands during macrophage polarization. Here we summarize the current understanding of the crosstalk between carbon metabolism and epigenetic modifications in macrophages under physiological conditions and in the tumor microenvironment (TME) and provide targets and further directions for macrophage-associated diseases.

Melatonin in food allergy: Mechanism and potential therapy.

Food allergy affects more than 500 million people in the world, and its prevalence is increasing at an alarming rate causing serious public health concerns; however, prevention and treatment methods are still under investigation and are relatively scarce so far. Insights on pathophysiology reveal a complex interplay of the immune cells (e.g., DCs, T cells, and B cells) resulting in allergy or tolerance. Studies have shown that melatonin metabolisms are altered in patients with allergic diseases, suggesting that melatonin might impact allergic diseases. Notably, melatonin can orchestrate the differentiation and function of immune cells. Additionally, the disease severities of many allergic diseases and the function of the immune system exhibit circadian rhythmicity. Therefore, melatonin, a rhythm regulator, may also act indirectly on the immune system through the circadian clock to regulate food allergies. Herein, we reviewed the impacts of melatonin on food allergy and its underlying regulatory mechanisms, providing a theoretical reference for melatonin as effective means of prevention and treatment for food allergy in the future.

Gut microbiota bridges dietary nutrients and host immunity.

Dietary nutrients and the gut microbiota are increasingly recognized to cross-regulate and entrain each other, and thus affect host health and immune-mediated diseases. Here, we systematically review the current understanding linking dietary nutrients to gut microbiota-host immune interactions, emphasizing how this axis might influence host immunity in health and diseases. Of relevance, we highlight that the implications of gut microbiota-targeted dietary intervention could be harnessed in orchestrating a spectrum of immune-associated diseases.

Phenylalanine diminishes M1 macrophage inflammation.

Emerging evidence suggests that amino acids dictate the effector functions of immune cells; however, whether and how phenylalanine (Phe) orchestrates the polarization of macrophages is not understood. Here, we determined that Phe attenuated lipopolysaccharide (LPS) and P. multocida serotype A strain CQ2 (PmCQ2) infection-induced inflammation in vivo. Furthermore, we demonstrated that Phe inhibited the production of interleukin (IL)-1ß and tumor necrosis factor (TNF)-α in proinflammatory (M1) macrophages. Phe reprogrammed the transcriptomic and metabolic profiles and enhanced oxidative phosphorylation in M1 macrophages, which reduced the activation of caspase-1. Notably, the valine-succinyl-CoA axis played a critical role in Phe-mediated inhibition of IL-1ß production in M1 macrophages. Taken together, our findings suggest that manipulating the valine-succinyl-CoA axis provides a potential target for preventing and/or treating macrophage-related diseases.

Echinacea purpurea-derived homogeneous polysaccharide exerts anti-tumor efficacy via facilitating M1 macrophage polarization.

Echinacea purpurea modulates tumor progression, but the underlying mechanism is poorly defined. We isolated and purified a novel homogeneous polysaccharide from E. purpurea (EPPA), which was shown to be an arabinogalactan with a mean molecular mass (Mr) of 3.8 × 104 Da and with α- (1 → 5) -L-Arabinan as the backbone and α-L-Araf-(1→, →6)-ß-D-Galp-(1→, and →4)-α-D-GalpA-(1→ as the side chains. Interestingly, oral administration of EPPA suppresses tumor progression in vivo and shapes the immune cell profile (e.g., facilitating M1 macrophages) in tumor microenvironment by single-cell RNA sequencing (scRNA-seq) analysis. More importantly, EPPA activates the inflammasome through a phagocytosis-dependent mechanism and rewires transcriptomic and metabolic profile, thereby potentiating M1 macrophage polarization. Collectively, we propose that EPPA supplementation could function as an adjuvant therapeutic strategy for tumor suppression.

Circadian orchestration of host and gut microbiota in infection.

Circadian rhythms are present in almost every organism and regulate multiple aspects of biological and physiological processes (e.g. metabolism, immune responses, and microbial exposure). There exists a bidirectional circadian interaction between the host and its gut microbiota, and potential circadian orchestration of both host and gut microbiota in response to invading pathogens. In this review, we summarize what is known about these intestinal microbial oscillations and the relationships between host circadian clocks and various infectious agents (bacteria, fungi, parasites, and viruses), and discuss how host circadian clocks prime the immune system to fight pathogen infections as well as the direct effects of circadian clocks on viral activity (e.g. SARS-CoV-2 entry and replication). Finally, we consider strategies employed to realign normal circadian rhythmicity for host health, such as chronotherapy, dietary intervention, good sleep hygiene, and gut microbiota-targeted therapy. We propose that targeting circadian rhythmicity may provide therapeutic opportunities for the treatment of infectious diseases.

GABA regulates IL-1ß production in macrophages.

Neurotransmitters have been well documented to determine immune cell fates; however, whether and how γ-amino butyric acid (GABA) shapes the function of innate immune cells is still obscure. Here, we demonstrate that GABA orchestrates macrophage maturation and inflammation. GABA treatment during macrophage maturation inhibits interleukin (IL)-1ß production from inflammatory macrophages. Mechanistically, GABA enhances succinate-flavin adenine dinucleotide (FAD)-lysine specific demethylase1 (LSD1) signaling to regulate histone demethylation of Bcl2l11 and Dusp2, reducing formation of the NLRP3-ASC-Caspase-1 complex. The GABA-succinate axis reduces succinylation of mitochondrial proteins to promote oxidative phosphorylation (OXPHOS). We also find that GABA alleviates lipopolysaccharides (LPS)-induced sepsis as well as high-fat-diet-induced obesity in mice. Our study shows that GABA regulates pro-inflammatory macrophage responses associated with metabolic reprogramming and protein succinylation, suggesting a strategy for treating macrophage-related inflammatory diseases.

Characterizing the influence of gut microbiota on host tryptophan metabolism with germ-free pigs.

Intestinal microbes are closely associated with host health, depending on metabolic crosstalk between the microbiota and host. Tryptophan metabolism is one of the best examples of metabolic crosstalk between intestinal microbiota and host; however, our understanding about the influence of intestinal microbiota on host tryptophan metabolism is limited. Thus, we established germ-free (GF) pig models to systemically explore the influence of intestinal microbiota on tryptophan metabolism. Five GF pigs were kept in GF conditions throughout the experiment (GF group). Six GF pigs were transplanted with fecal microbiota from donor sows to act as control pigs. Compared with control pigs, the GF pigs had remarkable alterations in tryptophan metabolism. The differential metabolites (P < 0.05) were mainly found in the liver, circulation system and large intestine. Notably, the alteration of metabolites in tryptophan metabolism varied among organs, especially for the serotonin pathway. In GF pigs, tryptophan and kynurenine in the large intestine and 5-hydroxytryptophan in most organs were increased (P < 0.05), while metabolites in the indole pathway in most organs were decreased (P < 0.05). Collectively, our study reveals changes in tryptophan metabolism in GF pigs, highlighting the critical role of gut microbes in shaping host tryptophan metabolism.

GABA signaling enforces intestinal germinal center B cell differentiation.

Recent compelling results indicate possible links between neurotransmitters, intestinal mucosal IgA+ B cell responses, and immunoglobulin A nephropathy (IgAN) pathogenesis. Here, we demonstrated that γ-amino butyric acid (GABA) transporter-2 (GAT-2) deficiency induces intestinal germinal center (GC) B cell differentiation and worsens the symptoms of IgAN in a mouse model. Mechanistically, GAT-2 deficiency enhances GC B cell differentiation through activation of GABA-mammalian target of rapamycin complex 1 (mTORC1) signaling. In addition, IgAN patients have lower GAT-2 expression but higher activation of mTORC1 in blood B cells, and both are correlated with kidney function in IgAN patients. Collectively, this study describes GABA signaling-mediated intestinal mucosal immunity as a previously unstudied pathogenesis mechanism of IgAN and challenges the current paradigms of IgAN.

Nomogram Model Based on Clinical Risk Factors and Heart Rate Variability for Predicting All-Cause Mortality in Stage 5 CKD Patients.

Background: Heart rate variability (HRV), reflecting circadian rhythm of heart rate, is reported to be associated with clinical outcomes in stage 5 chronic kidney disease (CKD5) patients. Whether CKD related factors combined with HRV can improve the predictive ability for their death remains uncertain. Here we evaluated the prognosis value of nomogram model based on HRV and clinical risk factors for all-cause mortality in CKD5 patients. Methods: CKD5 patients were enrolled from multicenter between 2011 and 2019 in China. HRV parameters based on 24-h Holter and clinical risk factors associated with all-cause mortality were analyzed by multivariate Cox regression. The relationships between HRV and all-cause mortality were displayed by restricted cubic spline graphs. The predictive ability of nomogram model based on clinical risk factors and HRV were evaluated for survival rate. Results: CKD5 patients included survival subgroup (n = 155) and all-cause mortality subgroup (n = 45), with the median follow-up time of 48 months. Logarithm of standard deviation of all sinus R-R intervals (lnSDNN) (4.40 ± 0.39 vs. 4.32 ± 0.42; p = 0.007) and logarithm of standard deviation of average NN intervals for each 5 min (lnSDANN) (4.27 ± 0.41 vs. 4.17 ± 0.41; p = 0.008) were significantly higher in survival subgroup than all-cause mortality subgroup. On the basis of multivariate Cox regression analysis, the lnSDNN (HR = 0.35, 95%CI: 0.17-0.73, p = 0.01) and lnSDANN (HR = 0.36, 95% CI: 0.17-0.77, p = 0.01) were associated with all-cause mortality, their relationships were negative linear. Spearman's correlation analysis showed that lnSDNN and lnSDANN were highly correlated, so we chose lnSDNN, sex, age, BMI, diabetic mellitus (DM), ß-receptor blocker, blood glucose, phosphorus and ln intact parathyroid hormone (iPTH) levels to build the nomogram model. The area under the curve (AUC) values based on lnSDNN nomogram model for predicting 3-year and 5-year survival rates were 79.44% and 81.27%, respectively. Conclusion: In CKD5 patients decreased SDNN and SDANN measured by HRV were related with their all-cause mortality, meanwhile, SDNN and SDANN were highly correlated. Nomogram model integrated SDNN and clinical risk factors are promising for evaluating their prognosis.

A risk prediction model for contrast-induced nephropathy associated with gadolinium-based contrast agents.

OBJECTIVE: This is the first study to explore the risk factors for nephropathy caused by gadolinium-based contrast agents and establish a prediction model to identify high-risk patients. METHODS: A total of 1404 patients who received gadolinium-based contrast agents in our hospital were included. The participants were randomly assigned in a 7:3 ratio to the modeling and validation groups. The modeling group was divided into a contrast-induced nephropathy group and a non-contrast-induced nephropathy group. The clinical characteristics before the use of contrast agents were compared between the two groups. The risk factors for contrast-induced nephropathy were analyzed by logistic regression. A nomogram that could predict the incidence of contrast-induced nephropathy was plotted. The validation group was used to verify the predictive model. RESULTS: The incidence of contrast-induced nephropathy caused by gadolinium-based contrast agents was 3.92% (55/1404). The logistic stepwise regression analysis showed that sex, systolic pressure (SBP), absolute neutrophil count, albumin, fasting blood glucose level, and furosemide use were significant predictors of contrast-induced nephropathy caused by gadolinium-based contrast agents. The above predictors were then included in the nomogram construction. The area under the receiver operating characteristic (ROC) curve was 0.82 (p < 0.001). The specificity and sensitivity corresponding to the optimal cutoff point (0.039) based on the area under the ROC curve were 71.9% and 80.5%, respectively. CONCLUSION: Sex, SBP, absolute neutrophil count, albumin, fasting blood glucose levels, and furosemide use are significant predictors of contrast-induced nephropathy caused by gadolinium-based contrast agents. Therefore, the incidence of contrast-induced nephropathy may be estimated by the prediction model established in this study before the use of contrast agents.

Melatonergic signalling instructs transcriptional inhibition of IFNGR2 to lessen interleukin-1ß-dependent inflammation.

BACKGROUND: Immunotransmitters (e.g., neurotransmitters and neuromodulators) could orchestrate diverse immune responses; however, the elaborated mechanism by which melatonergic activation governs inflammation remains less defined. METHODS: Primary macrophages, various cell lines, and Pasteurella multocida (PmCQ2)-infected mice were respectively used to illustrate the influence of melatonergic signalling on inflammation in vitro and in vivo. A series of methods (e.g., RNA-seq, metabolomics, and genetic manipulation) were conducted to reveal the mechanism whereby melatonergic signalling reduces macrophage inflammation. RESULTS: Here, we demonstrate that melatonergic activation substantially lessens interleukin (IL)-1ß-dependent inflammation. Treatment of macrophages with melatonin rewires metabolic program, as well as remodels signalling pathways which depends on interferon regulatory factor (IRF) 7. Mechanistically, melatonin acts via membrane receptor (MT) 1 to increase heat shock factor (Hsf) 1 expression through lowering the inactive glycogen synthase kinase (GSK3) ß, thereby transcriptionally inhibiting interferon (IFN)-γ receptor (IFNGR) 2 and ultimately causing defective canonical signalling events [Janus kinase (JAK) 1/2-signal transducer and activator of transcription (STAT) 1-IRF7] and lower IL-1ß production in macrophages. Moreover, we find that melatonin amplifies host protective responses to PmCQ2 infection-induced pneumonia. CONCLUSIONS: Our conceptual framework provides potential therapeutic targets to prevent and/or treat inflammatory diseases associating with excessive IL-1ß production.

A novel long-term intravenous combined with local treatment with human amnion-derived mesenchymal stem cells for a multidisciplinary rescued uremic calciphylaxis patient and the underlying mechanism.

Calciphylaxis is a rare disease characterized histologically by microvessel calcification and microthrombosis, with high mortality and no proven therapy. Here, we reported a severe uremic calciphylaxis patient with progressive skin ischemia, large areas of painful malodorous ulcers, and mummified legs. Because of the worsening symptoms and signs refractory to conventional therapies, treatment with human amnion-derived mesenchymal stem cells (hAMSCs) was approved. Preclinical release inspections of hAMSCs, efficacy, and safety assessment, including cytokine secretory ability, immunocompetence, tumorigenicity, and genetics analysis in vitro, were introduced. We further performed acute and long-term hAMSC toxicity evaluations in C57BL/6 mice and rats, abnormal immune response tests in C57BL/6 mice, and tumorigenicity tests in neonatal Balbc-nu nude mice. After the preclinical research, the patient was treated with hAMSCs by intravenous and local intramuscular injection and external supernatant application to the ulcers. When followed up to 15 months, the blood-based markers of bone and mineral metabolism improved, with skin soft tissue regeneration and a more favorable profile of peripheral blood mononuclear cells. Skin biopsy after 1-month treatment showed vascular regeneration with mature noncalcified vessels within the dermis, and 20 months later, the re-epithelialization restored the integrity of the damaged site. No infusion or local treatment-related adverse events occurred. Thus, this novel long-term intravenous combined with local treatment with hAMSCs warrants further investigation as a potential regenerative treatment for uremic calciphylaxis due to effects of inhibiting vascular calcification, stimulating angiogenesis and myogenesis, anti-inflammatory and immune modulation, multidifferentiation, re-epithelialization, and restoration of integrity.

Melatonin inhibits Gram-negative pathogens by targeting citrate synthase.

Bacterial infections caused by Gram-negative pathogens represent a growing burden for public health worldwide. Despite the urgent need for new antibiotics that effectively fight against pathogenic bacteria, very few compounds are currently under development or approved in the clinical setting. Repurposing compounds for other uses offers a productive strategy for the development of new antibiotics. Here we report that the multifaceted melatonin effectively improves survival rates of mice and decreases bacterial loads in the lung during infection. Mechanistically, melatonin specifically inhibits the activity of citrate synthase of Gram-negative pathogens through directly binding to the R300, D363, and H265 sites, particularly for the notorious Pasteurella multocida. These findings highlight that usage of melatonin is a feasible and alternative therapy to tackle the increasing threat of Gram-negative pathogen infections via disrupting metabolic flux of bacteria.

Parathyroidectomy Is Associated With Reversed Nondipping Heart Rate That Impacts Mortality in Chronic Kidney Disease Patients.

OBJECTIVE: Nondipping heart rate (HR), defined as a night/day HR ratio >0.90, has been associated with increased mortality in epidemiologic studies. However, its prognostic value in stage 5 chronic kidney disease (CKD5) patients and the effects of parathyroidectomy (PTX) on nondipping HR remain unknown. METHODS: This case-control study of 162 healthy controls and 502 CKD5 patients was performed between 2011 and 2018, in which CKD5 patients were further divided into non-PTX (n = 186) and severe secondary hyperparathyroidism (SHPT) with PTX (n = 316) subgroups. Each participant underwent 24-hour Holter monitoring for HR ratio. Mortality was followed up in CKD5 patients (median time: 46.0 months). RESULTS: The HR ratio in CKD5 patients was higher than in controls (0.92 ± 0.08 vs 0.81 ± 0.08, P <.001), associated with a 44% increase in mortality risk per 0.1 increment (hazard ratio, 1.44; 95% CI: 1.02-2.03; P =.04), and was positively related to serum intact parathyroid hormone levels (P <.001). PTX reversed nondipping HR in SHPT patients (n = 50, median time: 6.3 months, P <.001). Survival probabilities for PTX (n = 294) were better than non-PTX (n = 47) (hazard ratio, 0.31; 95% CI: 0.14-0.67; P <.01) in SHPT patients (serum intact parathyroid hormone >500.0 pg/mL). CONCLUSION: CKD5 patients displayed a nondipping HR pattern, which is a prognostic marker of all-cause mortality. PTX for SHPT patients was associated with a reversal in nondipping HR ratio, which may mediate a better outcome.