bims-imicid 2024-12-08 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024–12–08
twenty-six papers selected by
Dylan Ryan, University of Cambridge

An acute microglial metabolic response controls metabolism and improves memory.
PI3K-dependent reprogramming of hexokinase isoforms controls glucose metabolism and functional responses of B lymphocytes.
Human airway macrophages are metabolically reprogrammed by IFN-γ resulting in glycolysis-dependent functional plasticity.
Intrinsic Factors Behind the Long-COVID: V. Immunometabolic Disorders.
LXR regulation of adipose tissue inflammation during obesity is associated with dysregulated macrophage function.
The role of the interplay between macrophage glycolytic reprogramming and NLRP3 inflammasome activation in acute lung injury/acute respiratory distress syndrome.
Epi-microRNA mediated metabolic reprogramming counteracts hypoxia to preserve affinity maturation.
Nanomaterial-enabled metabolic reprogramming strategies for boosting antitumor immunity.
Sex, cells, and metabolism: Androgens temper Th17-mediated immunity.
NIR-II Imaging for Tracking the Spatiotemporal Immune Microenvironment in Atherosclerotic Plaques.
Regulation of Inflammation, Lipid Metabolism, and Liver Fibrosis by Core Genes of M1 Macrophages in NASH.
Mitochondrial calcium uniporter complex controls T-cell-mediated immune responses.
DOCK8 gene mutation alters cell subsets, BCR signaling, and cell metabolism in B cells.
Mitochondrial metabolic reprogramming of macrophages and T cells enhances CD47 antibody-engineered oncolytic virus antitumor immunity.
Fructo-oligosaccharides Alleviated Ulcerative Colitis via Gut Microbiota-Dependent Tryptophan Metabolism in Association with Aromatic Hydrocarbon Receptor Activation in Mice.
Assessment of Glutamine as a Fuel Source for Alveolar Macrophages Exposed to Chronic Ethanol Using an Extracellular Flux Bioanalyzer.
Impact of gut microbiota and its metabolites on immunometabolism in colorectal cancer.
The amino acid metabolism pathway of peripheral T lymphocytes and ketamine-induced schizophrenia-like phenotype.
Dietary caloric restriction protects experimental autoimmune uveitis by regulating Teff/Treg balance.
β-Hydroxybutyrate suppresses M1 macrophage polarization through β-hydroxybutyrylation of the STAT1 protein.
Central and peripheral kynurenine pathway metabolites in COVID-19: Implications for neurological and immunological responses.
Depression with immuno-metabolic dysregulation: Testing pragmatic criteria to stratify patients.
Chemical activation of mitochondrial ClpP to modulate energy metabolism of CD4+ T cell for inflammatory bowel diseases treatment.
Dissecting metabolic landscape of alveolar macrophage.
Palmitoleic acid inhibits Pseudomonas aeruginosa quorum sensing activation and protects lungs from infectious injury.
Effect of sodium butyrate on kidney and liver mitochondrial dysfunction in a lipopolysaccharide mouse model.

Elife. 2024 Dec 03. pii: RP87120. [Epub ahead of print]12

An acute microglial metabolic response controls metabolism and improves memory.

Anne Drougard, Eric H Ma, Vanessa Wegert, Ryan Sheldon, Ilaria Panzeri, Naman Vatsa, Stefanos Apostle, Luca Fagnocchi, Judith Schaf, Klaus Gossens, Josephine Völker, Shengru Pang, Anna Bremser, Erez Dror, Francesca Giacona, Sagar Sagar, Michael X Henderson, Marco Prinz, Russell G Jones, John Andrew Pospisilik.

  Chronic high-fat feeding triggers metabolic dysfunction including obesity, insulin resistance, and diabetes. How high-fat intake first triggers these pathophysiological states remains unknown. Here, we identify an acute microglial metabolic response that rapidly translates intake of high-fat diet (HFD) to a surprisingly beneficial effect on metabolism and spatial/learning memory. High-fat intake rapidly increases palmitate levels in cerebrospinal fluid and triggers a wave of microglial metabolic activation characterized by mitochondrial membrane activation and fission as well as metabolic skewing toward aerobic glycolysis. These effects are detectable throughout the brain and can be detected within as little as 12 hr of HFD exposure. In vivo, microglial ablation and conditional DRP1 deletion show that the microglial metabolic response is necessary for the acute effects of HFD. 13C-tracing experiments reveal that in addition to processing via β-oxidation, microglia shunt a substantial fraction of palmitate toward anaplerosis and re-release of bioenergetic carbons into the extracellular milieu in the form of lactate, glutamate, succinate, and intriguingly, the neuroprotective metabolite itaconate. Together, these data identify microglia as a critical nutrient regulatory node in the brain, metabolizing away harmful fatty acids and liberating the same carbons as alternate bioenergetic and protective substrates for surrounding cells. The data identify a surprisingly beneficial effect of short-term HFD on learning and memory.

Keywords:  cell biology; diabetes; inflammation; memory; metabolism; microglia; mitochondria; mouse; neuroscience

DOI:  https://doi.org/10.7554/eLife.87120
iScience. 2024 Oct 18. 27(10): 110939

PI3K-dependent reprogramming of hexokinase isoforms controls glucose metabolism and functional responses of B lymphocytes.

Brandon T Paradoski, Sen Hou, Edgard M Mejia, Folayemi Olayinka-Adefemi, Danielle Fowke, Grant M Hatch, Ayesha Saleem, Versha Banerji, Nissim Hay, Hu Zeng, Aaron J Marshall.

  B lymphocyte activation triggers metabolic reprogramming essential for B cell differentiation and mounting a healthy immune response. Here, we investigate the regulation and function of glucose-phosphorylating enzyme hexokinase 2 (HK2) in B cells. We report that both activation-dependent expression and mitochondrial localization of HK2 are regulated by the phosphatidylinositol 3-kinase (PI3K) signaling pathway. B cell-specific deletion of HK2 in mice caused mild perturbations in B cell development. HK2-deficient B cells show impaired functional responses in vitro and adapt to become less dependent on glucose and more dependent on glutamine. HK2 deficiency impairs glycolysis, alters metabolite profiles, and alters flux of labeled glucose carbons into downstream pathways. Upon immunization, HK2-deficient mice exhibit impaired germinal center, plasmablast, and antibody responses. HK2 expression in primary human chronic lymphocytic leukemia (CLL) cells was associated with recent proliferation and could be reduced by PI3K inhibition. Our study implicates PI3K-dependent modulation of HK2 in B cell metabolic reprogramming.

Keywords:  Cell biology; Cellular physiology; Immunology

DOI:  https://doi.org/10.1016/j.isci.2024.110939
Elife. 2024 Dec 02. pii: RP98449. [Epub ahead of print]13

Human airway macrophages are metabolically reprogrammed by IFN-γ resulting in glycolysis-dependent functional plasticity.

Donal J Cox, Sarah A Connolly, Cilian Ó Maoldomhnaigh, Aenea A I Brugman, Olivia Sandby Thomas, Emily Duffin, Karl M Gogan, Oisin Ó Gallchobhair, Dearbhla M Murphy, Sinead A O'Rourke, Finbarr O'Connell, Parthiban Nadarajan, James J Phelan, Laura E Gleeson, Sharee A Basdeo, Joseph Keane.

  Airway macrophages (AM) are the predominant immune cell in the lung and play a crucial role in preventing infection, making them a target for host directed therapy. Macrophage effector functions are associated with cellular metabolism. A knowledge gap remains in understanding metabolic reprogramming and functional plasticity of distinct human macrophage subpopulations, especially in lung resident AM. We examined tissue-resident AM and monocyte-derived macrophages (MDM; as a model of blood derived macrophages) in their resting state and after priming with IFN-γ or IL-4 to model the Th1/Th2 axis in the lung. Human macrophages, regardless of origin, had a strong induction of glycolysis in response to IFN-γ or upon stimulation. IFN-γ significantly enhanced cellular energetics in both AM and MDM by upregulating both glycolysis and oxidative phosphorylation. Upon stimulation, AM do not decrease oxidative phosphorylation unlike MDM which shift to 'Warburg'-like metabolism. IFN-γ priming promoted cytokine secretion in AM. Blocking glycolysis with 2-deoxyglucose significantly reduced IFN-γ driven cytokine production in AM, indicating that IFN-γ induces functional plasticity in human AM, which is mechanistically mediated by glycolysis. Directly comparing responses between macrophages, AM were more responsive to IFN-γ priming and dependent on glycolysis for cytokine secretion than MDM. Interestingly, TNF production was under the control of glycolysis in AM and not in MDM. MDM exhibited glycolysis-dependent upregulation of HLA-DR and CD40, whereas IFN-γ upregulated HLA-DR and CD40 on AM independently of glycolysis. These data indicate that human AM are functionally plastic and respond to IFN-γ in a manner distinct from MDM. These data provide evidence that human AM are a tractable target for inhalable immunomodulatory therapies for respiratory diseases.

Keywords:  Mycobacterium tuberculosis; airway macrophages; cytokines; human; immunology; inflammation; lipopolysaccharide; metabolism; polarization

DOI:  https://doi.org/10.7554/eLife.98449
J Cell Biochem. 2024 Dec 05. e30683

Intrinsic Factors Behind the Long-COVID: V. Immunometabolic Disorders.

Muhamed Adilović, Altijana Hromić-Jahjefendić, Lejla Mahmutović, Jasmin Šutković, Alberto Rubio-Casillas, Elrashdy M Redwan, Vladimir N Uversky.

  The complex link between COVID-19 and immunometabolic diseases demonstrates the important interaction between metabolic dysfunction and immunological response during viral infections. Severe COVID-19, defined by a hyperinflammatory state, is greatly impacted by underlying chronic illnesses aggravating the cytokine storm caused by increased levels of Pro-inflammatory cytokines. Metabolic reprogramming, including increased glycolysis and altered mitochondrial function, promotes viral replication and stimulates inflammatory cytokine production, contributing to illness severity. Mitochondrial metabolism abnormalities, strongly linked to various systemic illnesses, worsen metabolic dysfunction during and after the pandemic, increasing cardiovascular consequences. Long COVID-19, defined by chronic inflammation and immune dysregulation, poses continuous problems, highlighting the need for comprehensive therapy solutions that address both immunological and metabolic aspects. Understanding these relationships shows promise for effectively managing COVID-19 and its long-term repercussions, which is the focus of this review paper.

Keywords:  cytokine storm; immunometabolism; long COVID; metabolic syndrome; therapeutic approaches

DOI:  https://doi.org/10.1002/jcb.30683
Obesity (Silver Spring). 2024 Dec 04.

LXR regulation of adipose tissue inflammation during obesity is associated with dysregulated macrophage function.

Jessica Aparecida da Silva Pereira, Gerson Profeta de Souza, João V Virgilio-da-Silva, Juliana S Prodonoff, Gisele de Castro, Leonardo F Pimentel, Felippe Mousovich-Neto, Gustavo G Davanzo, Cristhiane F Aguiar, Cristiane N S Breda, Marcia G Guereschi, Ronaldo C Araújo, Marcelo A Mori, Niels O S Câmara, Diorge P Souza, Alexandre S Basso, Pedro M Moraes-Vieira.

OBJECTIVE: Liver X receptors (LXRs) play essential roles in cholesterol homeostasis and immune response. In obesity, elevated cholesterol levels trigger proinflammatory responses; however, the specific contributions of LXRs to adipose tissue (AT) macrophage (ATM) phenotype and metabolic programming are not fully understood. In this study, we determine the role of LXR isoforms in diet-induced obesity AT inflammation and insulin resistance.
METHODS: For in vivo studies, to evaluate the effects of LXR activation on AT inflammation, obese and insulin-resistant wild-type mice were treated with 10 mg/kg of the LXR modulator naringenin (NAR) for 4 weeks, and systemic insulin sensitivity and AT inflammation were assessed. To evaluate the effects of LXR deficiency on AT inflammation, we used LXRα, LXRβ, and LXRαβ knockout (KO) mice. For in vitro studies, to assess the role of LXRs specifically in macrophages, bone marrow-derived macrophages from wild-type, LXRαKO, LXRβKO, and LXRαβKO mice were treated with 0.5μM NAR 1 h prior to lipopolysaccharide (LPS) stimulation (100 ng/mL), and the effects on macrophage function and metabolism were evaluated 24 h after LPS stimulation.
RESULTS: We found that LXR deletion intensifies AT inflammation in an LXRβ-dependent manner. LXR deficiency in immune cells exacerbates obesity-induced AT inflammation, increasing the numbers of CD11c+, TNF-α+, and IL-1β+ ATMs. We also identified NAR as a novel LXR agonist in macrophages that reduces proinflammatory cytokine secretion by mitigating glycolysis and mitochondrial dysfunction in LPS - and LPS + IFNγ-activated macrophages. Furthermore, NAR-treated obese mice display reduced AT inflammation, characterized by decreased CD11c+, IL-1β+, and TNF-α+ ATM numbers and monocyte infiltration compared with vehicle-treated obese mice.
CONCLUSIONS: Our study highlights distinct roles for each LXR isoform in AT inflammation regulation, with LXRβ being crucial for maintaining the anti- and proinflammatory balance in ATMs. Thus, LXRβ holds therapeutic potential as a target to treat AT inflammation and insulin resistance.

DOI: https://doi.org/10.1002/oby.24158
Clin Transl Med. 2024 Dec;14(12): e70098

The role of the interplay between macrophage glycolytic reprogramming and NLRP3 inflammasome activation in acute lung injury/acute respiratory distress syndrome.

Lan Luo, Xiaoli Zhuang, Lin Fu, Ziyuan Dong, Shuyuan Yi, Kan Wang, Yu Jiang, Ju Zhao, Xiaofang Yang, Feilong Hei.

  Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a severe respiratory condition associated with elevated morbidity and mortality. Understanding their complex pathophysiological mechanisms is crucial for developing new preventive and therapeutic strategies. Recent studies highlight the significant role of inflammation involved in ALI/ARDS, particularly the hyperactivation of the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome in macrophages. This activation drives pulmonary inflammation by releasing inflammatory signalling molecules and is linked to metabolic reprogramming, marked by increased glycolysis and reduced oxidative phosphorylation. However, the relationship between NLRP3 inflammasome activation and macrophage glycolytic reprogramming in ALI/ARDS, as well as the molecular mechanisms regulating these processes, remain elusive. This review provides a detailed description of the interactions and potential mechanisms linking NLRP3 inflammasome activation with macrophage glycolytic reprogramming, proposing that glycolytic reprogramming may represent a promising therapeutic target for mitigating inflammatory responses in ALI/ARDS. KEY POINTS: NLRP3 inflammasome activation is pivotal in mediating the excessive inflammatory response in ALI/ARDS. Glycolytic reprogramming regulates NLRP3 inflammasome activation. Therapeutic potential of targeting glycolytic reprogramming to inhibit NLRP3 inflammasome activation in ALI/ARDS.

Keywords:  NLRP3 inflammasome; acute lung injury/acute respiratory distress syndrome; glycolytic reprogramming; macrophage

DOI:  https://doi.org/10.1002/ctm2.70098
Nat Commun. 2024 Dec 03. 15(1): 10516

Epi-microRNA mediated metabolic reprogramming counteracts hypoxia to preserve affinity maturation.

Rinako Nakagawa, Miriam Llorian, Sunita Varsani-Brown, Probir Chakravarty, Jeannie M Camarillo, David Barry, Roger George, Neil P Blackledge, Graham Duddy, Neil L Kelleher, Robert J Klose, Martin Turner, Dinis P Calado.

To increase antibody affinity against pathogens, positively selected GC-B cells initiate cell division in the light zone (LZ) of germinal centers (GCs). Among these, higher-affinity clones migrate to the dark zone (DZ) and vigorously proliferate by utilizing energy provided by oxidative phosphorylation (OXPHOS). However, it remains unknown how positively selected GC-B cells adapt their metabolism for cell division in the glycolysis-dominant, cell cycle arrest-inducing, hypoxic LZ microenvironment. Here, we show that microRNA (miR)-155 mediates metabolic reprogramming during positive selection to protect high-affinity clones. Mechanistically, miR-155 regulates H3K36me2 levels in hypoxic conditions by directly repressing the histone lysine demethylase, Kdm2a, whose expression increases in response to hypoxia. The miR-155-Kdm2a interaction is crucial for enhancing OXPHOS through optimizing the expression of vital nuclear mitochondrial genes under hypoxia, thereby preventing excessive production of reactive oxygen species and subsequent apoptosis. Thus, miR-155-mediated epigenetic regulation promotes mitochondrial fitness in high-affinity GC-B cells, ensuring their expansion and consequently affinity maturation.

DOI: https://doi.org/10.1038/s41467-024-54937-0
Chem Soc Rev. 2024 Dec 02.

Nanomaterial-enabled metabolic reprogramming strategies for boosting antitumor immunity.

Muye Ma, Yongliang Zhang, Kanyi Pu, Wei Tang.

Immunotherapy has become a crucial strategy in cancer treatment, but its effectiveness is often constrained. Most cancer immunotherapies focus on stimulating T-cell-mediated immunity by driving the cancer-immunity cycle, which includes tumor antigen release, antigen presentation, T cell activation, infiltration, and tumor cell killing. However, metabolism reprogramming in the tumor microenvironment (TME) supports the viability of cancer cells and inhibits the function of immune cells within this cycle, presenting clinical challenges. The distinct metabolic needs of tumor cells and immune cells require precise and selective metabolic interventions to maximize therapeutic outcomes while minimizing adverse effects. Recent advances in nanotherapeutics offer a promising approach to target tumor metabolism reprogramming and enhance the cancer-immunity cycle through tailored metabolic modulation. In this review, we explore cutting-edge nanomaterial strategies for modulating tumor metabolism to improve therapeutic outcomes. We review the design principles of nanoplatforms for immunometabolic modulation, key metabolic pathways and their regulation, recent advances in targeting these pathways for the cancer-immunity cycle enhancement, and future prospects for next-generation metabolic nanomodulators in cancer immunotherapy. We expect that emerging immunometabolic modulatory nanotechnology will establish a new frontier in cancer immunotherapy in the near future.

DOI: https://doi.org/10.1039/d4cs00679h
J Clin Invest. 2024 Dec 02. pii: e186520. [Epub ahead of print]134(23):

Sex, cells, and metabolism: Androgens temper Th17-mediated immunity.

Nikita L Mani, Samuel E Weinberg.

Sex-based differences in autoimmune disease susceptibility have long been recognized, prompting investigations into how sex hormones influence immunity. Recent advances suggest that hormones may shape immune responses by altering cellular metabolism. In this issue of the JCI, Chowdhury et al. authenticates this model, showing that androgen receptor signaling modulates T helper 17 (Th17) cell metabolism, specifically glutaminolysis, reducing airway inflammation in males. This work provides insight into sex-specific regulation of immunity, highlighting the interplay between hormones, metabolism, and immune function. The findings raise intriguing questions about how hormonal fluctuations affect immunity and how sex-specific metabolic pathways might be leveraged for targeted therapies in autoimmune diseases.

DOI: https://doi.org/10.1172/JCI186520
ACS Nano. 2024 Dec 04.

NIR-II Imaging for Tracking the Spatiotemporal Immune Microenvironment in Atherosclerotic Plaques.

Lin Shen, Minjiang Chen, Yanping Su, Yanran Bi, Gaofeng Shu, Weiqian Chen, Chenying Lu, Zhongwei Zhao, Lingchun Lv, Jianhua Zou, Xiaoyuan Chen, Jiansong Ji.

  The inflammatory immune microenvironment is responsible for atherosclerotic plaque erosion and rupture. Near-infrared-II (NIR-II) fluorescence imaging has the potential to continuously monitor the spatiotemporal changes in the plaque immune microenvironment. Herein, we constructed three different NIR-II probes based on benzo[1,2-c;4,5-c']bis[1,2,5]thiadiazole-4,7-bis(9,9-dioctyl-9H-fluoren-2-yl)thiophene (denoted as BBT-2FT): VHPK/BBT-2FT NPs, where VHPK is a specific peptide targeting vascular cell adhesion molecule-1; iNOS/BBT-2FT NPs for modulating the polarization of M1 macrophages by inducible NO synthase (iNOS) antibodies; and Arg-1/BBT-2FT for counterbalancing the inflammatory responses of M1 macrophages. These tracers enable precise tracking of atherosclerotic plaques and M1 and M2 macrophages through NIR-II imaging. VHPK/BBT-2FT NPs can accurately trace atherosclerotic plaques at various stages. Arg-1/BBT-2FT NPs precisely located M2 macrophages in the early plaque microenvironment with upregulation of peroxisome proliferator-activated receptor γ (PPAR-γ), signal transducer and activator of transcription (STAT) 6, and ATP-binding cassette transporter A1 (ABCA1), indicating that M2 macrophage polarization is crucial for early plaque lipid clearance. Meanwhile, iNOS/BBT-2FT NPs accurately tracked M1 macrophages in the advanced plaque microenvironment. The results showed that M1 macrophage polarization induces the formation of an inflammatory microenvironment through anaerobic glycolytic metabolism and pyroptosis in the advanced hypoxic plaque microenvironment, as indicated by the upregulation of hypoxia-inducible factor 1 alpha (HIF-1α), STAT1, NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3), pyruvate dehydrogenase kinase 1 (PDK1), and glucose transporter 1 (GLUT-1). Combining immunological approaches with NIR-II imaging has revealed that hypoxia-induced metabolic reprogramming of macrophages is a key factor in dynamic changes in the immune microenvironment of atherosclerotic plaques. Furthermore, our strategy shows the potential for real-time diagnosis and clinical prevention of unstable plaque rupture in atherosclerosis.

Keywords:  NIR-II imaging; atherosclerosis; cardiovascular disease; immune metabolism microenvironment; macrophage polarization

DOI:  https://doi.org/10.1021/acsnano.4c10739
J Inflamm Res. 2024 ;17 9975-9986

Regulation of Inflammation, Lipid Metabolism, and Liver Fibrosis by Core Genes of M1 Macrophages in NASH.

Xingyu Xu, Yaqin Dong, Jianjun Liu, Peng Zhang, Wenqi Yang, Longfei Dai.

   Background: Although immune cells play a critical role in lipid metabolism and inflammation regulation in patients with non-alcoholic steatohepatitis (NASH), the specific immune cells involved and associated genes remain unclear.
Methods: We identified differential immune cell profiles between normal liver and NASH specimens using the CIBERSORT algorithm. Next, we conducted a weighted gene co-expression network analysis (WGCNA) to identify genes highly correlated with these immune cells in NASH. Subsequently, core genes of immune cells were identified using machine learning algorithms.
Results: The abundance of M1 macrophages significantly increased in patients with NASH. The Random Forest (RF) algorithm identified six M1 macrophage-related genes (COL10A1, FAP, IL32, STMN2, SUSD2, and THY1) crucial in NASH. These six genes positively correlated with five inflammatory genes (CCL2, IL1B, TNF, CSF1, and IL15), lipid synthesis gene (FAS), collagen synthesis genes (COL1A1 and COL3A1), liver fibrosis stage, NASH activity score (NAS), and aspartate aminotransferase (AST) levels. These were negatively correlated with the lipid transport gene (CD36), beta fatty acid oxidation gene (PPARA), and M2 macrophage abundance. Moreover, a predictive model based on these six genes achieved a C-index of 0.902 for diagnosing NASH across four cohorts. The expression of these six genes accurately stratified patients with NASH into low disease activity cluster 1 and high disease activity cluster 2.
Conclusion: These six core genes of M1 macrophages contribute to NASH progression by regulating inflammation, lipid metabolism, and liver fibrosis.

Keywords:  M1 macrophages; NASH; cluster; diagnosis; machine learning

DOI:  https://doi.org/10.2147/JIR.S480574
EMBO Rep. 2024 Dec 02.

Mitochondrial calcium uniporter complex controls T-cell-mediated immune responses.

Magdalena Shumanska, Dmitri Lodygin, Christine S Gibhardt, Christian Ickes, Ioana Stejerean-Todoran, Lena C M Krause, Kira Pahl, Lianne J H C Jacobs, Andrea Paluschkiwitz, Shuya Liu, Angela Boshnakovska, Niels Voigt, Tobias J Legler, Martin Haubrock, Miso Mitkovski, Gereon Poschmann, Peter Rehling, Sven Dennerlein, Jan Riemer, Alexander Flügel, Ivan Bogeski.

  T-cell receptor (TCR)-induced Ca2+ signals are essential for T-cell activation and function. In this context, mitochondria play an important role and take up Ca2+ to support elevated bioenergetic demands. However, the functional relevance of the mitochondrial-Ca2+-uniporter (MCU) complex in T-cells was not fully understood. Here, we demonstrate that TCR activation causes rapid mitochondrial Ca2+ (mCa2+) uptake in primary naive and effector human CD4+ T-cells. Compared to naive T-cells, effector T-cells display elevated mCa2+ and increased bioenergetic and metabolic output. Transcriptome and proteome analyses reveal molecular determinants involved in the TCR-induced functional reprogramming and identify signalling pathways and cellular functions regulated by MCU. Knockdown of MCUa (MCUaKD), diminishes mCa2+ uptake, mitochondrial respiration and ATP production, as well as T-cell migration and cytokine secretion. Moreover, MCUaKD in rat CD4+ T-cells suppresses autoimmune responses in an experimental autoimmune encephalomyelitis (EAE) multiple sclerosis model. In summary, we demonstrate that mCa2+ uptake through MCU is essential for proper T-cell function and has a crucial role in autoimmunity. T-cell specific MCU inhibition is thus a potential tool for targeting autoimmune disorders.

Keywords:  Autoimmunity; Calcium; MCU; Mitochondria; T-cell

DOI:  https://doi.org/10.1038/s44319-024-00313-4
Cell Death Dis. 2024 Dec 01. 15(11): 871

DOCK8 gene mutation alters cell subsets, BCR signaling, and cell metabolism in B cells.

Heng Gu, Miaomiao Xie, Siyu Zhao, Xi Luo, Yanmei Huang, Lu Yang, Fei Guan, Jiahui Lei, Chaohong Liu.

DOCK8 deficiency has been shown to affect the migration, function, and survival of immune cells in innate and adaptive immune responses. The immunological mechanisms underlying autosomal recessive (AR) hyper-IgE syndrome (AR-HIES) caused by DOCK8 mutations remain unclear, leading to a lack of specific therapeutic options. In this study, we used CRISPR/Cas9 technology to develop a mouse model with a specific DOCK8 point mutation in exon 45 (c.5846C>A), which is observed in patients with AR-HIES. We then investigated the effect of this mutation on B cell development, cell metabolism, and function in a mouse model with Dock8 gene mutation. The results demonstrated that Dock8 gene mutation inhibited splenic MZ and GC B cell development and crippled BCR signaling. In addition, it resulted in enhanced glycolysis in B cells. Mechanistically, the reduced BCR signaling was related to decreased B cell spreading, BCR clustering, and signalosomes, mediated by inhibited activation of WASP. Furthermore, the DOCK8 mutation led to increased expression of c-Myc in B cells, which plays an important role in glycolysis. As such, GC B cells' formation and immune responses were disturbed in LCMV-infected mice. These findings will provide new insights into the immunological pathogenesis of primary immunodeficiency disorder caused by DOCK8 mutation.

DOI: https://doi.org/10.1038/s41419-024-07180-w
J Immunother Cancer. 2024 Dec 04. pii: e009768. [Epub ahead of print]12(12):

Mitochondrial metabolic reprogramming of macrophages and T cells enhances CD47 antibody-engineered oncolytic virus antitumor immunity.

Jing Zhao, Shichuan Hu, Zhongbing Qi, Xianglin Xu, Xiangyu Long, Anliang Huang, Jiyan Liu, Ping Cheng.

   BACKGROUND: Although immunotherapy can reinvigorate immune cells to clear tumors, the response rates are poor in some patients. Here, CD47 antibody-engineered oncolytic viruses (oAd-αCD47) were employed to lyse tumors and activate immunity. The oAd-αCD47 induced comprehensive remodeling of the tumor microenvironment (TME). However, whether the acidic TME affects the antitumor immunotherapeutic effects of oncolytic viruses-αCD47 has not been clarified.
METHODS: To assess the impact of oAd-αCD47 treatment on the TME, we employed multicolor flow cytometry. Glucose uptake was quantified using 2NBDG, while mitochondrial content was evaluated with MitoTracker FM dye. pH imaging of tumors was performed using the pH-sensitive fluorophore SNARF-4F. Moreover, changes in the calmodulin-dependent protein kinase II (CaMKII)/cyclic AMP activates-responsive element-binding proteins (CREB) and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1α) signaling pathway were confirmed through western blotting and flow cytometry.
RESULTS: Here, we identified sodium bicarbonate (NaBi) as the potent metabolic reprogramming agent that enhanced antitumor responses in the acidic TME. The combination of NaBi and oAd-αCD47 therapy significantly inhibited tumor growth and produced complete immune control in various tumor-bearing mouse models. Mechanistically, combination therapy mainly reduced the number of regulatory T cells and enriched the ratio of M1-type macrophages TAMs (M1.TAMs) to M2-type macrophages TAMs (M2.TAMs), while decreasing the abundance of PD-1+TIM3+ expression and increasing the expression of CD107a in the CD8+ T cells. Furthermore, the combination therapy enhanced the metabolic function of T cells and macrophages by upregulating PGC1α, a key regulator of mitochondrial biogenesis. This metabolic improvement contributed to a robust antitumor response. Notably, the combination therapy also promoted the generation of memory T cells, suggesting its potential as an effective neoadjuvant treatment for preventing postoperative tumor recurrence and metastasis.
CONCLUSIONS: Tumor acidic microenvironment impairs mitochondrial energy metabolism in macrophages and T cells inducing oAd-αCD47 immunotherapeutic resistance. NaBi improves the acidity of the TME and activates the CaMKII/CREB/PGC1α mitochondrial biosynthesis signaling pathway, which reprograms the energy metabolism of macrophages and T cells in the TME, and oral NaBi enhances the antitumor effect of oAd-αCD47.

Keywords:  Combination therapy; Immunosuppression; Immunotherapy; Oncolytic virus

DOI:  https://doi.org/10.1136/jitc-2024-009768
J Agric Food Chem. 2024 Dec 06.

Fructo-oligosaccharides Alleviated Ulcerative Colitis via Gut Microbiota-Dependent Tryptophan Metabolism in Association with Aromatic Hydrocarbon Receptor Activation in Mice.

Chengcheng Yang, Yao Du, Qimei Li, Lu Liu, Lu Zhao, Chang Gao, Zhengwei Tang, Xiangnan Zhang, Yan Zhao, Xingbin Yang.

  Fructo-oligosaccharide (FOS) is a typical prebiotic with intestinal health-promoting effects. Here, we explored the anticolitis activity of FOS and clarified the underlying mechanisms. Dextran sulfate sodium (DSS)-induced mice were gavaged with FOS (400 mg/kg) for 37 days, and administration of FOS alleviated DSS-induced colitis symptoms. Besides, FOS improved gut microbiota dysbiosis and modulated the intestinal microbiota-controlled tryptophan metabolic pathways. Targeted metabolomic results showed that FOS significantly increased the colonic levels of indole-3-acetic acid (IAA) and indole-3-propionic acid (IPA) and subsequently increased the expressions of aromatic hydrocarbon receptors (AhR) in the colon and further promoted the expressions of interleukin-22 (IL-22) and intestinal tight junction proteins in the colitis mice. These findings for the first time highlight a novel anticolitis mechanism of FOS by alleviating intestinal microbiota dysbiosis and modulating microbial tryptophan metabolism to promote IAA and IPA production for triggering AhR/IL-22 axis activation.

Keywords:  fructo-oligosaccharides; gut barrier function; gut microbiota; tryptophan catabolites; ulcerative colitis

DOI:  https://doi.org/10.1021/acs.jafc.4c07248
J Vis Exp. 2024 Nov 15.

Assessment of Glutamine as a Fuel Source for Alveolar Macrophages Exposed to Chronic Ethanol Using an Extracellular Flux Bioanalyzer.

Kathryn M Crotty, Samantha M Yeligar.

Alveolar macrophages (AMs) are the first line of cellular defense in the lower airway against pathogens. However, chronic and excessive alcohol use impairs the ability of AMs to phagocytize and clear pathogens from the alveolar space, in part through dysregulated fuel metabolism and bioenergetics. Our prior work has shown that chronic ethanol (EtOH) consumption impairs mitochondrial bioenergetics and increases lactate levels in AMs. Further, we recently demonstrated that EtOH increases glutamine dependency and glutamine-dependent maximal respiration while decreasing flexibility, shifting away from pyruvate-dependent respiration and towards glutamine-dependent respiration. Glutaminolysis is an important compensatory pathway for mitochondrial respiration when pyruvate is used for lactic acid production or when other fuel sources are insufficient. Using a mouse AM cell line, MH-S cells, exposed to either no EtOH or EtOH (0.08%) for 72 h, we determined the dependency of mitochondrial respiration and bioenergetics on glutamine as a fuel source using an extracellular flux bioanalyzer. Real-time measures were done in response to bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES), an inhibitor of glutaminase 1, which prevents the enzymatic conversion of glutamine to glutamate, in media vehicle or in response to vehicle alone, followed by testing mitochondrial stress. The step-by-step protocol provided herein describes our methods and calculations for analyzing average levels of glutamine-dependent basal mitochondrial respiration, mitochondrial ATP-linked respiration, maximal mitochondrial respiration, and mitochondrial spare respiratory capacity across multiple biological and experimental replicates.

DOI: https://doi.org/10.3791/67579
Immunometabolism (Cobham). 2024 Oct;6(4): e00050

Impact of gut microbiota and its metabolites on immunometabolism in colorectal cancer.

Madison Flory, Paloma Bravo, Ashfaqul Alam.

  Colorectal cancer (CRC) is highly prevalent, accounting for approximately one-tenth of cancer cases and deaths globally. It stands as the second most deadly and third most common cancer type. Although the gut microbiota has been implicated in CRC carcinogenesis for the last several decades, it remains one of the least understood risk factors for CRC development, as the gut microbiota is highly diverse and variable. Many studies have uncovered unique microbial signatures in CRC patients compared with healthy matched controls, with variations dependent on patient age, disease stage, and location. In addition, mechanistic studies revealed that tumor-associated bacteria produce diverse metabolites, proteins, and macromolecules during tumor development and progression in the colon, which impact both cancer cells and immune cells. Here, we summarize microbiota's role in tumor development and progression, then we discuss how the metabolic alterations in CRC tumor cells, immune cells, and the tumor microenvironment result in the reprogramming of activation, differentiation, functions, and phenotypes of immune cells within the tumor. Tumor-associated microbiota also undergoes metabolic adaptation to survive within the tumor environment, leading to immune evasion, accumulation of mutations, and impairment of immune cells. Finally, we conclude with a discussion on the interplay between gut microbiota, immunometabolism, and CRC, highlighting a complex interaction that influences cancer development, progression, and cancer therapy efficacy.

Keywords:  colorectal cancer; gut microbiota; immunometabolism; metabolites; microbiome

DOI:  https://doi.org/10.1097/IN9.0000000000000050
J Psychiatry Neurosci. 2024 Nov-Dec;49(6):49(6): E413-E426

The amino acid metabolism pathway of peripheral T lymphocytes and ketamine-induced schizophrenia-like phenotype.

Peipei Wang, Linzhi Jiang, Junmei Hu, Zihan Jiang, Yu Zhang, Congliang Chen, Yanchen Lin, Mi Su, Xia Wang, Linchuan Liao.

BACKGROUND: The intricate interplay between peripheral adaptive immune cells and the central nervous system (CNS) has garnered increasing recognition. Given that alterations in cell quantities often translate into modifications in metabolite profiles and that these metabolic changes can potentially traverse the bloodstream and enter the CNS, thereby modulating the progression of mental illnesses, we sought to explore the metabolic profiles of peripheral immune cells in a ketamine-treated mouse model of schizophrenia.
METHODS: We used flow cytometry to scrutinize the alterations in peripheral adaptive immune cells in a ketamine-induced schizophrenia mouse model. Subsequently, we implemented an untargeted metabolomic approach with ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to detect the metabolite profiles of peripheral abnormal lymphocytes and identify differential metabolites present in plasma. We then employed targeted metabolomics using UPLC-MS/MS to quantify the common differential metabolites detected in mouse plasma.
RESULTS: Flow cytometry analysis detected a notable increase in the count of peripheral CD3+ T cells in a ketamine-induced schizophrenia mouse model. Subsequent untargeted metabolomics analysis revealed that the amino acid metabolism pathway underwent substantial alterations. A detailed quantification of 22 amino acid profiles in the peripheral plasma indicated significant elevation in the levels of glycine, alanine, asparagine, and aspartic acid.
LIMITATIONS: Our ongoing research has yet to conclusively identify the precise amino acid metabolism pathway that serves as the pivotal factor in the manifestation of the schizophrenia-like phenotype induced by ketamine.
CONCLUSION: The peripheral amino acid metabolism pathway is involved in the ketamine-induced schizophrenia-like phenotype. The metabolic profile of peripheral immune cells could provide accurate biomarkers for the diagnosis and treatment of psychiatric diseases.

DOI: https://doi.org/10.1503/jpn-240038
iScience. 2024 Dec 20. 27(12): 111279

Dietary caloric restriction protects experimental autoimmune uveitis by regulating Teff/Treg balance.

Zhaohuai Li, Runping Duan, Qi Jiang, Jiaying Liu, Jialing Chen, Loujing Jiang, Tianfu Wang, He Li, Yihan Zhang, Xuening Peng, Zhaohao Huang, Lei Zhu, Wenjun Zou, Ying Lin, Wenru Su.

  Uveitis, an autoimmune disease, often leads to blindness. CD4+ T cells, including regulatory T cells (Tregs) and effector T cells (Th1 and Th17), play a critical role in its pathogenesis. Caloric restriction (CR) has been shown to alleviate autoimmune diseases. However, careful characterization of the impact of CR on experimental autoimmune uveitis (EAU) is poorly understood. This study used single-cell RNA sequencing to analyze cervical draining lymph nodes in mice under ad libitum (AL) and CR diets, with or without EAU. CR increased Tregs, altered immune cell metabolism, reduced EAU symptoms, and downregulated inflammatory and glycolysis genes. Flow cytometry confirmed CR's inhibitory effect on Th1 and Th17 proliferation and its promotion of Treg proliferation. CR also balanced CD4+ T cells by inhibiting the PI3K/AKT/c-Myc pathway and reducing GM-CSF in Th17 cells. These findings suggest CR as a potential therapeutic strategy for autoimmune diseases.

Keywords:  Diet; Immune response; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2024.111279
Cell Death Dis. 2024 Dec 03. 15(12): 874

β-Hydroxybutyrate suppresses M1 macrophage polarization through β-hydroxybutyrylation of the STAT1 protein.

Ya-Ping Bai, Yu-Jie Xing, Tao Ma, Kai Li, Teng Zhang, De-Guo Wang, Shu-Jun Wan, Cui-Wei Zhang, Yue Sun, Meng-Yan Wang, Guo-Dong Wang, Wen-Jun Pei, Kun Lv, Yan Zhang, Xiang Kong.

β-Hydroxybutyrate (β-OHB), the primary ketone body, is a bioactive metabolite that acts as both an energy substrate and a signaling molecule. Recent studies found that β-OHB inhibits the production of pro-inflammatory cytokines in macrophages, but its underlying molecular mechanisms have not yet been fully elucidated. Lysine β-hydroxybutyrylation (Kbhb), a post-translational modification mediated by β-OHB, plays a key role in regulating the expression and activity of modified proteins. However, whether macrophages undergo protein Kbhb and whether Kbhb modification regulates macrophage polarization remains largely unknown. In this study, treatment with β-OHB and ketone ester significantly decreased the lipopolysaccharide (LPS)-induced enhancement of the M1 phenotype of mouse bone marrow-derived macrophages (BMDMs), RAW264.7 cells, and peritoneal macrophages (PMs) in vitro and in vivo. Moreover, β-OHB treatment induced global protein Kbhb, which is associated with the regulation of macrophage M1 polarization. Proteome-wide Kbhb analysis in β-OHB-treated BMDMs revealed 3469 Kbhb modification sites within 1549 proteins, among which interleukin-12-responding proteins were significantly upregulated. Our results indicated that β-OHB regulated M1 macrophage polarization by inducing Kbhb modification of the signal transducer and activator of transcription 1 (STAT1) K679 site, which inhibited its LPS-induced phosphorylation and transcription. Altogether, our study demonstrated the presence of a widespread Kbhb landscape in the β-OHB-treated macrophages and provided novel insights into the anti-inflammatory effects of β-OHB.

DOI: https://doi.org/10.1038/s41419-024-07268-3
Brain Behav Immun. 2024 Nov 28. pii: S0889-1591(24)00720-7. [Epub ahead of print]

Central and peripheral kynurenine pathway metabolites in COVID-19: Implications for neurological and immunological responses.

Xueqi Li, Arvid Edén, Susmita Malwade, Janet L Cunningham, Jonas Bergquist, Jacob Ahlberg Weidenfors, Carl M Sellgren, Göran Engberg, Fredrik Piehl, Magnus Gisslen, Eva Kumlien, Johan Virhammar, Funda Orhan, Elham Rostami, Lilly Schwieler, Sophie Erhardt.

  Long-term symptoms such as pain, fatigue, and cognitive impairments are commonly observed in individuals affected by coronavirus disease 2019 (COVID-19). Metabolites of the kynurenine pathway have been proposed to account for cognitive impairment in COVID-19 patients. Here, cerebrospinal fluid (CSF) and plasma levels of kynurenine pathway metabolites in 53 COVID-19 patients and 12 non-inflammatory neurological disease controls in Sweden were measured with an ultra-performance liquid chromatography-tandem mass spectrometry system (UPLC-MS/MS) and correlated with immunological markers and neurological markers. Single cell transcriptomic data from a previous study of 130 COVID-19 patients was used to investigate the expression of key genes in the kynurenine pathway. The present study reveals that the neuroactive kynurenine pathway metabolites quinolinic acid (QUIN) and kynurenic acid (KYNA) are increased in CSF in patients with acute COVID-19. In addition, CSF levels of kynurenine, ratio of kynurenine/tryptophan (rKT) and QUIN correlate with neurodegenerative markers. Furthermore, tryptophan is significantly decreased in plasma but not in the CSF. In addition, the kynurenine pathway is strongly activated in the plasma and correlates with the peripheral immunological marker neopterin. Single-cell transcriptomics revealed upregulated gene expressions of the rate-limiting enzyme indoleamine 2,3- dioxygenase1 (IDO1) in CD14+ and CD16+ monocytes that correlated with type II-interferon response exclusively in COVID-19 patients. In summary, our study confirms significant activation of the peripheral kynurenine pathway in patients with acute COVID-19 and, notably, this is the first study to identify elevated levels of kynurenine metabolites in the central nervous system associated with the disease. Our findings suggest that peripheral inflammation, potentially linked to overexpression of IDO1 in monocytes, activates the kynurenine pathway. Increased plasma kynurenine, crossing the blood-brain barrier, serves as a source for elevated brain KYNA and neurotoxic QUIN. We conclude that blocking peripheral-to-central kynurenine transport could be a promising strategy to protect against neurotoxic effects of QUIN in COVID-19 patients.

Keywords:  Cognition; Infectious disease; Neuroinflammation

DOI:  https://doi.org/10.1016/j.bbi.2024.11.031
Brain Behav Immun. 2024 Nov 29. pii: S0889-1591(24)00722-0. [Epub ahead of print]124 115-122

Depression with immuno-metabolic dysregulation: Testing pragmatic criteria to stratify patients.

J C Zwiep, Y Milaneschi, E J Giltay, C H Vinkers, B W J H Penninx, F Lamers.

   INTRODUCTION: Inflammatory and metabolic processes are linked to depression, but only 25-30% of depressed patients show low-grade inflammation and metabolic dysregulation associated with atypical, energy-related symptoms (AES). Interventions targeting immuno-metabolic dysregulation could benefit depressed patients, but currently no consensus exists how to best select patients with immuno-metabolic dysregulations. Therefore, we investigated which combinations of circulating C-reactive protein (CRP) and AES could identify those depressed individuals with significant immuno-metabolic dysregulation.
METHODS: Data are from 1,077 persons with a current Major Depressive Disorder (MDD) of the Netherlands Study of Depression and Anxiety. Immuno-metabolic markers were Interleukin-6 (IL-6), Tumor Necrosis Factor alpha (TNF-α), glycoprotein acetyls, body mass index (BMI), waist circumference, triglycerides, high-density-lipoprotein cholesterol (HDL cholesterol), glucose and leptin. Strata for CRP (≤ 1, < 1 CRP ≤ 3, > 3 mg/L) and AES (score of ≤ 3, 4-5, ≥ 6) were compared on immuno-metabolic markers using analyses of covariance.
RESULTS: Across strata of CRP and AES, there was a dose-response pattern with all higher immuno-metabolic marker levels across higher strata of CRP and AES, with the exception for an association between AES and TNF-α. Persons with both elevated CRP (> 1 mg/L) and high AES (≥ 6) showed a more dysregulated inflammatory and metabolic profile compared to persons with lower CRP and/or AES (p < 0.001).
CONCLUSION: Our results show a dose-response relationship between both CRP levels and AES with immuno-metabolic risk biomarkers, indicating that CRP and AES combined can capture immuno-metabolic features of MDD. Combining these available and scalable indexes may be an effective strategy to select a patient sample with immuno-metabolic dysregulation who may benefit from treatments targeting inflammatory or metabolic pathways.

Keywords:  Depression; Immuno-metabolism; Inflammation; Major depressive disorder; Metabolism; Precision psychiatry; Symptomatology

DOI:  https://doi.org/10.1016/j.bbi.2024.11.033
Cell Rep Med. 2024 Nov 23. pii: S2666-3791(24)00611-6. [Epub ahead of print] 101840

Chemical activation of mitochondrial ClpP to modulate energy metabolism of CD4+ T cell for inflammatory bowel diseases treatment.

Jiangnan Zhang, Yunhan Jiang, Dongmei Fan, Zhiqiang Qiu, Xinlian He, Song Liu, Linjie Li, Zhengyi Dai, Lidan Zhang, Ziyi Shu, Lili Li, Hu Zhang, Tao Yang, Youfu Luo.

  Inflammatory bowel disease (IBD) is an autoimmune disorder, and despite the availability of multiple Food and Drug Administration (FDA)-approved therapies, current clinical needs remain unmet. In this study, we find that caseinolytic protease P (ClpP) expression is markedly upregulated in colonic tissues from IBD patients and preclinical colitis models, particularly in CD4+ T cells. Subsequently, a small molecule, namely NCA029, is identified, and its therapeutic efficacy and mechanism of action are investigated both in vitro and in vivo. Oral administration of NCA029 significantly alleviates symptoms associated with dextran sulfate sodium (DSS)-induced acute and interleukin (IL)-10-deficient chronic colitis. The effects of NCA029 are largely dependent on its selective binding to ClpP in CD4+ T cells, thereby mitigating inflammation and restoring intestinal barrier function. Furthermore, NCA029 activates ClpP to promote oxidative phosphorylation (OXPHOS) inhibition and concomitantly modulate the Th17/Treg balance. In conclusion, our study develops a therapeutic strategy for treating IBD through the chemical activation of ClpP.

Keywords:  ClpP; OXPHOS; inflammatory bowel diseases; mitochondrial

DOI:  https://doi.org/10.1016/j.xcrm.2024.101840
Sci Rep. 2024 Dec 05. 14(1): 30383

Dissecting metabolic landscape of alveolar macrophage.

Sunayana Malla, Karuna Anna Sajeevan, Bibek Acharya, Ratul Chowdhury, Rajib Saha.

The highly plastic nature of Alveolar Macrophage (AM) plays a crucial role in the defense against inhaled particulates and pathogens in the lungs. Depending on the signal, AM acquires either the classically activated M1 phenotype or the alternatively activated M2 phenotype. In this study, we investigate the metabolic shift in the activated phases of AM (M1 and M2 phases) by reconstructing context specific Genome-Scale Metabolic (GSM) models. Metabolic pathways such as pyruvate metabolism, arachidonic acid metabolism, chondroitin/heparan sulfate biosynthesis, and heparan sulfate degradation are found to be important driving forces in the development of the M1/M2 phenotypes. Additionally, we formulated a bilevel optimization framework named MetaShiftOptimizer to identify minimal modifications that shift one activated state (M1/M2) to the other. The identified reactions involve metabolites such as glycogenin, L-carnitine, 5-hydroperoxy eicosatetraenoic acid, and leukotriene B4, which show potential to be further investigated as significant factors for developing efficient therapy targets for severe respiratory disorders in the future. Overall, our study contributes to the understanding of the metabolic capabilities of the M1 and M2 phenotype of AM and identifies pathways and reactions that can be potential targets for polarization shift and also be used as therapeutic strategies against respiratory diseases.

DOI: https://doi.org/10.1038/s41598-024-81253-w
Respir Res. 2024 Dec 02. 25(1): 423

Palmitoleic acid inhibits Pseudomonas aeruginosa quorum sensing activation and protects lungs from infectious injury.

Lei Han, Jie Ren, Yishu Xue, Guogang Xie, Jianwei Gao, Qiang Fu, Ping Shao, Hui Zhu, Min Zhang, Fengming Ding.

   BACKGROUND: Unsaturated fatty acids targeting quorum sensing (QS) system have shown potential application in reducing bacterial virulence. We aim to investigate the effect of palmitoleic acid (PMA) on P. aeruginosa QS activation, and its impact on infection-induced lung injury.
METHODS: The influence of PMA on QS signaling molecule (3OC12-HSL and C4-HSL) concentrations, pyocyanin production, and QS gene transcription levels were examined in wildtype PAO1 culture. The roles of PMA in reducing infection-induced injury were assessed in human bronchial epithelial BEAS-2B cells and mouse lung infection models, respectively. PMA levels and QS signaling molecule concentrations were tested in the bronchoalveolar lavage fluid (BALF) of bronchiectasis patients with first-time detection of P. aeruginosa infection.
RESULTS: PMA administration dose-dependently suppressed the expression of QS signaling molecules, pyocyanin, and QS genes during the logarithmic stage of bacterial growth. In BEAS-2B cells, PMA-treated PAO1 filtrates significantly reduced cell apoptosis and expression of IL-8 and IL-6. In mouse lung infection models, prophylactically oral administration of PMA significantly downregulated the expression of P. aeruginosa QS signals and QS genes (lasR, rhlR, rhlI, lasB, rhlA, phzA1, phnA) in lungs, and relieved neutrophilic airway inflammation. Finally, PMA levels were negatively correlated with the concentrations of both 3OC12-HSL and C4-HSL in BALF of bronchiectasis patients, and positively correlated with their forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1.0).
CONCLUSION: Our findings show that PMA inhibits P. aeruginosa QS activation and protects lungs from injury caused by bacterial virulence. Hence, PMA may serve as a potential anti-QS agent against P. aeruginosa infection and would help to alleviate lung injury in bronchiectasis patients.

Keywords:   Pseudomonas aeruginosa ; Infection-induced injury; Lung infection; Palmitoleic acid; Quorum sensing

DOI:  https://doi.org/10.1186/s12931-024-03035-2
FASEB J. 2024 Dec 15. 38(23): e70228

Effect of sodium butyrate on kidney and liver mitochondrial dysfunction in a lipopolysaccharide mouse model.

Muznah Khan, Sumera Farooqi, Katherine L Mitchell, Subir Kumar Roy Chowdhury, Marian Cabrera-Ayala, Jessica Huang, Douglas C Wallace, Scott L Weiss.

  Sodium butyrate can reduce inflammation, but it is not known if butyrate can improve mitochondrial dysfunction during sepsis. We tested butyrate to prevent or reverse lipopolysaccharide (LPS)-induced mitochondrial dysfunction in murine kidney and liver. C57BL/6 mice were grouped as control (n = 9), intraperitoneal (IP) LPS (n = 8), pretreatment with IP butyrate 600 (n = 3) or 1200 mg/kg (n = 8) followed 2 h later by LPS, posttreatment with IP butyrate 600 (n = 3) or 1200 mg/kg (n = 7) 1 h after LPS, or butyrate 1200 mg/kg only (n = 8). Kidney and liver tissue were collected at 24 h to measure mitochondrial respiration, electron transport system (ETS) complex activity and subunit expression, and content (citrate synthase [CS] activity and mtDNA/nDNA). Kidney mitochondrial respiration was decreased after LPS compared to controls. Pretreatment with butyrate 1200 mg/kg increased kidney OXPHOSCI+II, ETSCI+II, ETSCII, and CIV respiration compared to LPS; posttreatment did not achieve significant increases except for OXPHOSCI. Liver mitochondrial respiration exhibited a similar pattern as in kidney, but differences were not significant. ETS complex and CS activity did not differ between groups, but CI and CII subunit expression trended higher with butyrate in kidney. Changes in mtDNA/nDNA followed a similar pattern as respiration in kidney and liver with a decrease after LPS that was not present with butyrate pretreatment. These data show that butyrate can prevent-but not significantly reverse-the LPS-induced decrease in kidney mitochondrial respiration without a clear effect in liver. Mitochondrial protection was not attributable to changes in ETS complex activity but may reflect maintenance of ETS subunit expression.

Keywords:  endotoxins; metabolism; mice; microbiota; mitochondria; sepsis

DOI:  https://doi.org/10.1096/fj.202401379RR