bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2024–09–22
seventeen papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. Cardiac NAD+ depletion in mice promotes hypertrophic cardiomyopathy and arrhythmias prior to impaired bioenergetics.
  2. Activation induces shift in nutrient utilization that differentially impacts cell functions in human neutrophils.
  3. SLC4A11 mediates ammonia import and promotes cancer stemness in hepatocellular carcinoma.
  4. Integrated metabolic-transcriptomic network identifies immunometabolic modulations in human macrophages.
  5. Acetyl-CoA carboxylase Inhibition increases retinal pigment epithelial cell fatty acid flux and restricts apolipoprotein efflux.
  6. Profiling of metabolic dysregulation in ovarian cancer tissues and biofluids.
  7. Protocol for monitoring phagocytosis of cancer cells by TAM-like macrophages using imaging cytometry.
  8. Krebs cycle derivatives, dimethyl fumarate and itaconate, control metabolic reprogramming in inflammatory human microglia cell line.
  9. PPARγ drives mitochondrial stress signaling and the loss of atrial cardiomyocytes in newborn mice exposed to hyperoxia.
  10. GPX4 restricts ferroptosis of NKp46+ILC3s to control intestinal inflammation.
  11. Pericyte phenotype switching alleviates immunosuppression and sensitizes vascularized tumors to immunotherapy in preclinical models.
  12. Nutrient Levels and Nutrient Sources in Pancreatic Tumors.
  13. Overactive mitochondrial DNA replication disrupts perinatal cardiac maturation.
  14. TREM2 macrophages mediate the beneficial effects of bariatric surgery against MASH.
  15. Progesterone promotes Cxcl2-dependent vaginal neutrophil killing by activating cervical resident macrophage-neutrophil crosstalk.
  16. Targeting aryl hydrocarbon receptor functionally restores tolerogenic dendritic cells derived from patients with multiple sclerosis.
  17. Nitric oxide in the cardio-cerebrovascular system: source, regulation and application.
  1. Nat Cardiovasc Res. 2024 Sep 18.
    Cardiac NAD+ depletion in mice promotes hypertrophic cardiomyopathy and arrhythmias prior to impaired bioenergetics.
    Khanh V Doan, Timothy S Luongo, Thato T Ts'olo, Won Dong Lee, David W Frederick, Sarmistha Mukherjee, Gabriel K Adzika, Caroline E Perry, Ryan B Gaspar, Nicole Walker, Megan C Blair, Nicole Bye, James G Davis, Corey D Holman, Qingwei Chu, Lin Wang, Joshua D Rabinowitz, Daniel P Kelly, Thomas P Cappola, Kenneth B Margulies, Joseph A Baur.
      Nicotinamide adenine dinucleotide (NAD+) is an essential co-factor in metabolic reactions and co-substrate for signaling enzymes. Failing human hearts display decreased expression of the major NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (Nampt) and lower NAD+ levels, and supplementation with NAD+ precursors is protective in preclinical models. Here we show that Nampt loss in adult cardiomyocytes caused depletion of NAD+ along with marked metabolic derangements, hypertrophic remodeling and sudden cardiac deaths, despite unchanged ejection fraction, endurance and mitochondrial respiratory capacity. These effects were directly attributable to NAD+ loss as all were ameliorated by restoring cardiac NAD+ levels with the NAD+ precursor nicotinamide riboside (NR). Electrocardiograms revealed that loss of myocardial Nampt caused a shortening of QT intervals with spontaneous lethal arrhythmias causing sudden cardiac death. Thus, changes in NAD+ concentration can have a profound influence on cardiac physiology even at levels sufficient to maintain energetics.
    DOI:  https://doi.org/10.1038/s44161-024-00542-9
  2. Proc Natl Acad Sci U S A. 2024 Sep 24. 121(39): e2321212121
    Activation induces shift in nutrient utilization that differentially impacts cell functions in human neutrophils.
    Emily C Britt, Xin Qing, James A Votava, Jorgo Lika, Andrew S Wagner, Simone Shen, Nicholas L Arp, Hamidullah Khan, Stefan M Schieke, Christopher D Fletcher, Anna Huttenlocher, Jing Fan.
      Neutrophils utilize a variety of metabolic sources to support their crucial functions as the first responders in innate immunity. Here, through in vivo and ex vivo isotopic tracing, we examined the contributions of different nutrients to neutrophil metabolism under specific conditions. Human peripheral blood neutrophils, in contrast to a neutrophil-like cell line, rely on glycogen storage as a major metabolic source under resting state but rapidly switch to primarily using extracellular glucose upon activation with various stimuli. This shift is driven by a substantial increase in glucose uptake, enabled by rapidly increased GLUT1 on cell membrane, that dominates the simultaneous increase in gross glycogen cycling capacity. Shifts in nutrient utilization impact neutrophil functions in a function-specific manner: oxidative burst depends on glucose utilization, whereas NETosis and phagocytosis can be flexibly supported by either glucose or glycogen, and neutrophil migration and fungal control are enhanced by the shift from glycogen utilization to glucose utilization. This work provides a quantitative and dynamic understanding of fundamental features in neutrophil metabolism and elucidates how metabolic remodeling shapes neutrophil functions, which has broad health relevance.
    Keywords:  immunometabolism; neutrophil; nutrient dependence; nutrient preference switch
    DOI:  https://doi.org/10.1073/pnas.2321212121
  3. JCI Insight. 2024 Sep 17. pii: e184826. [Epub ahead of print]
    SLC4A11 mediates ammonia import and promotes cancer stemness in hepatocellular carcinoma.
    Ameer L Elaimy, Marwa O El-Derany, Jadyn James, Zhuwen Wang, Ashley N Pearson, Erin A Holcomb, Amanda K Huber, Miguel A Gijón, Hannah N Bell, Viraj R Sanghvi, Timothy L Frankel, Grace L Su, Elliot B Tapper, Andrew W Tai, Nithya Ramnath, Christopher P Centonze, Irina Dobrosotskaya, Julie A Moeller, Alex K Bryant, David A Elliott, Enid Choi, Joseph R Evans, Kyle C Cuneo, Thomas J FitzGerald, Daniel R Wahl, Meredith A Morgan, Daniel T Chang, Max S Wicha, Theodore S Lawrence, Yatrik M Shah, Michael D Green.
      End stage liver disease is marked by portal hypertension, systemic elevations in ammonia, and development of hepatocellular carcinoma (HCC). While these clinical consequences of cirrhosis are well described, it remains poorly understood whether hepatic insufficiency and the accompanying elevations in ammonia contribute to HCC carcinogenesis. Using preclinical models, we discovered that ammonia entered the cell through the transporter SLC4A11 and served as a nitrogen source for amino acid and nucleotide biosynthesis. Elevated ammonia promoted cancer stem cell properties in vitro and tumor initiation in vivo. Enhancing ammonia clearance reduced HCC stemness and tumor growth. In patients, elevations in serum ammonia were associated with an increased incidence of HCC. Taken together, this study forms the foundation for clinical investigations using ammonia lowering agents as potential therapies to mitigate HCC incidence and aggressiveness.
    Keywords:  Amino acid metabolism; Liver cancer; Metabolism; Oncogenes; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.184826
  4. Cell Rep. 2024 Sep 13. pii: S2211-1247(24)01092-1. [Epub ahead of print]43(9): 114741
    Integrated metabolic-transcriptomic network identifies immunometabolic modulations in human macrophages.
    Hung-Jen Chen, Daniel C Sévin, Guillermo R Griffith, Johanna Vappiani, Lee M Booty, Cindy P A A van Roomen, Johan Kuiper, Jeroen den Dunnen, Wouter J de Jonge, Rab K Prinjha, Palwinder K Mander, Paola Grandi, Beata S Wyspianska, Menno P J de Winther.
      Macrophages exhibit diverse phenotypes and respond flexibly to environmental cues through metabolic remodeling. In this study, we present a comprehensive multi-omics dataset integrating intra- and extracellular metabolomes with transcriptomic data to investigate the metabolic impact on human macrophage function. Our analysis establishes a metabolite-gene correlation network that characterizes macrophage activation. We find that the concurrent inhibition of tryptophan catabolism by IDO1 and IL4I1 inhibitors suppresses the macrophage pro-inflammatory response, whereas single inhibition leads to pro-inflammatory activation. We find that a subset of anti-inflammatory macrophages activated by Fc receptor signaling promotes glycolysis, challenging the conventional concept of reduced glycolysis preference in anti-inflammatory macrophages. We demonstrate that cholesterol accumulation suppresses macrophage IFN-γ responses. Our integrated network enables the discovery of immunometabolic features, provides insights into macrophage functional metabolic reprogramming, and offers valuable resources for researchers exploring macrophage immunometabolic characteristics and potential therapeutic targets for immune-related disorders.
    Keywords:  CP: Immunology; CP: Metabolism; Fc receptor; IDO1; IL4I1; cholesterol; glycolysis; immunometabolism; interferon; macrophage; metabolomics; tryptophan metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2024.114741
  5. J Biol Chem. 2024 Sep 12. pii: S0021-9258(24)02273-7. [Epub ahead of print] 107772
    Acetyl-CoA carboxylase Inhibition increases retinal pigment epithelial cell fatty acid flux and restricts apolipoprotein efflux.
    Daniel T Hass, Kriti Pandey, Abbi Engel, Noah Horton, Cameron D Haydinger, Brian M Robbings, Rayne R Lim, Martin Sadilek, Qitao Zhang, Gillian A Gulette, Amy Li, Libin Xu, Jason M L Miller, Jennifer R Chao, James B Hurley.
      Lipid-rich deposits called drusen accumulate under the retinal pigment epithelium (RPE) in the eyes of patients with age-related macular degeneration (AMD) and Sorsby's fundus dystrophy (SFD). Drusen may contribute to photoreceptor and RPE degeneration in these blinding diseases. We hypothesize that stimulating β-oxidation of fatty acids could decrease the availability of lipid with which RPE cells can generate drusen. Inhibitors of acetyl-CoA carboxylase (ACC) stimulate β-oxidation and diminish lipid accumulation in fatty liver disease. In this report we test the hypothesis that an ACC inhibitor, Firsocostat, can diminish lipid deposition by RPE cells. We probed metabolism and cellular function in mouse RPE-choroid tissue and in cultured human RPE cells. We used 13C6-glucose, 13C16-palmitate, and gas chromatography-linked mass spectrometry to monitor effects of Firsocostat on glycolytic, Krebs cycle, and fatty acid metabolism. We quantified lipid abundance, apolipoprotein E (ApoE) and vascular endothelial growth factor (VEGF) release using liquid chromatography-mass spectrometry, enzyme-linked immunosorbent assays and localized ApoE deposits by immunostaining. RPE barrier function was assessed by trans-epithelial electrical resistance (TEER). Firsocostat-mediated ACC inhibition increases β-oxidation, decreases intracellular lipid levels, diminishes lipoprotein release, and increases TEER. When human serum or outer segments are used to stimulate lipoprotein release, fewer lipoproteins are released in the presence of either lipid source and Firsocostat. In a culture model of SFD, Firsocostat stimulates fatty acid oxidation, increases TEER, and decreases ApoE release. We conclude that Firsocostat remodels RPE metabolism and can limit lipid deposition. This suggests that ACC inhibition could be an effective strategy for diminishing pathologic drusen in the eyes of patients with AMD or SFD.
    Keywords:  Retinal pigment epithelium; age-related macular degeneration; apolipoprotein E (ApoE); beta‐oxidation; energy metabolism; fatty acid; retinal degeneration
    DOI:  https://doi.org/10.1016/j.jbc.2024.107772
  6. Sci Rep. 2024 09 16. 14(1): 21555
    Profiling of metabolic dysregulation in ovarian cancer tissues and biofluids.
    Tsuyoshi Ohta, Masahiro Sugimoto, Yasufumi Ito, Shota Horikawa, Yosuke Okui, Hirotsugu Sakaki, Manabu Seino, Makoto Sunamura, Satoru Nagase.
      Ovarian cancer (OC) is the most lethal gynecologic cancer, mainly due to late diagnosis with widespread peritoneal spread at first presentation. We performed metabolomic analyses of ovarian and paired control tissues using capillary electrophoresis-mass spectrometry and liquid chromatography-mass spectrometry to understand its metabolomic dysregulation. Of the 130 quantified metabolites, 96 metabolites of glycometabolism, including glycolysis, tricarboxylic acid cycles, urea cycles, and one-carbon metabolites, showed significant differences between the samples. To evaluate the local and systemic metabolomic differences in OC, we also analyzed low or non-invasively available biofluids, including plasma, urine, and saliva collected from patients with OC and benign gynecological diseases. All biofluids and tissue samples showed consistently elevated concentrations of N1,N12-diacetylspermine compared to controls. Four metabolites, polyamines, and betaine, were significantly and consistently elevated in both plasma and tissue samples. These data indicate that plasma metabolic dysregulation, which the most reflected by those of OC tissues. Our metabolomic profiles contribute to our understanding of metabolomic abnormalities in OC and their effects on biofluids.
    Keywords:  Biofluids; Cancer tissues; Metabolomic dysfunction; Normal tissue; Ovarian cancer
    DOI:  https://doi.org/10.1038/s41598-024-72938-3
  7. STAR Protoc. 2024 Sep 18. pii: S2666-1667(24)00485-4. [Epub ahead of print]5(4): 103320
    Protocol for monitoring phagocytosis of cancer cells by TAM-like macrophages using imaging cytometry.
    Alok K Mishra, Shahid Banday, Ritesh P Thakare, Sunil K Malonia, Michael R Green.
      Here, we present a protocol for monitoring phagocytosis by M2-type macrophages using automated counting of phagocytic events with an imaging cytometer. We describe steps for isolating and differentiating peripheral blood mononuclear cell (PBMC)-derived monocytes into M2-like macrophages, preparing cancer cells expressing a green fluorescence marker, labeling with a pH-sensitive dye, and co-culturing with macrophages. We then outline procedures for enumerating phagocytic events using an imaging cytometer. For complete details on the use and execution of this protocol, please refer to Mishra et al.1.
    Keywords:  Biotechnology and bioengineering; Cancer; Cell Biology; Cell culture; Immunology; Microscopy
    DOI:  https://doi.org/10.1016/j.xpro.2024.103320
  8. Mitochondrion. 2024 Sep 12. pii: S1567-7249(24)00124-7. [Epub ahead of print] 101966
    Krebs cycle derivatives, dimethyl fumarate and itaconate, control metabolic reprogramming in inflammatory human microglia cell line.
    Moris Sangineto, Martina Ciarnelli, Archana Moola, Vidyasagar Naik Bukke, Tommaso Cassano, Rosanna Villani, Antonino D Romano, Giuseppe Di Gioia, Carlo Avolio, Gaetano Serviddio.
      Metabolic reprogramming drives inflammatory activity in macrophages, including microglia, with Krebs cycle (KC) intermediates playing a crucial role as signaling molecules. Here, we show that the bioenergetic profile of LPS-activated human microglialclone 3 cell line (HMC3) is characterized by high levels of glycolysis and mitochondrial (mt) respiration, and the treatment with KC derivatives, namely dimethyl-fumarate (DMF) and itaconate (ITA), almost restores normal metabolism. However, despite comparable bioenergetic and anti-inflammatory effects, the mt hyper-activity was differentially modulated by DMF and ITA. DMF normalized complex I activity, while ITA dampened both complex I and II hyper-activity counteracting oxidative stress more efficiently.
    Keywords:  Dimethyl fumarate; Immunometabolism; Itaconate; Krebs cycle; Microglia; Mitochondria
    DOI:  https://doi.org/10.1016/j.mito.2024.101966
  9. Redox Biol. 2024 Sep 12. pii: S2213-2317(24)00329-X. [Epub ahead of print]76 103351
    PPARγ drives mitochondrial stress signaling and the loss of atrial cardiomyocytes in newborn mice exposed to hyperoxia.
    E David Cohen, Kyle Roethlin, Min Yee, Collynn F Woeller, Paul S Brookes, George A Porter, Michael A O'Reilly.
      Diastolic dysfunction is increasingly common in preterm infants exposed to supplemental oxygen (hyperoxia). Previous studies in neonatal mice showed hyperoxia suppresses fatty acid synthesis genes required for proliferation and survival of atrial cardiomyocytes. The loss of atrial cardiomyocytes creates a hypoplastic left atrium that inappropriately fills the left ventricle during diastole. Here, we show that hyperoxia stimulates adenosine monophosphate-activated kinase (AMPK) and peroxisome proliferator activated receptor-gamma (PPARγ) signaling in atrial cardiomyocytes. While both pathways can regulate lipid homeostasis, PPARγ was the primary pathway by which hyperoxia inhibits fatty acid gene expression and inhibits proliferation of mouse atrial HL-1 cells. It also enhanced the toxicity of hyperoxia by increasing expression of activating transcription factor (ATF) 5 and other mitochondrial stress response genes. Silencing PPARγ signaling restored proliferation and survival of HL-1 cells as well as atrial cardiomyocytes in neonatal mice exposed to hyperoxia. Our findings reveal PPARγ enhances the toxicity of hyperoxia on atrial cardiomyocytes, thus suggesting inhibitors of PPARγ signaling may prevent diastolic dysfunction in preterm infants.
    Keywords:  Cardiomyocytes; Hyperoxia; Mitochondria; Peroxisome proliferator activated receptor; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.redox.2024.103351
  10. Cell Death Dis. 2024 Sep 19. 15(9): 687
    GPX4 restricts ferroptosis of NKp46+ILC3s to control intestinal inflammation.
    Xinyao Li, Junyu He, Xiang Gao, Guilang Zheng, Chunling Chen, Yimin Chen, Zhe Xing, Tianci Wang, Jian Tang, Yuxiong Guo, Yumei He.
      Group 3 innate lymphoid cells (ILC3s) are essential for both pathogen defense and tissue homeostasis in the intestine. Dysfunction of ILC3s could lead to increased susceptibility to intestinal inflammation. However, the precise mechanisms governing the maintenance of intestinal ILC3s are yet to be fully elucidated. Here, we demonstrated that ferroptosis is vital for regulating the survival of intestinal ILC3. Ferroptosis-related genes, including GPX4, a key regulator of ferroptosis, were found to be upregulated in intestinal mucosal ILC3s from ulcerative colitis patients. Deletion of GPX4 resulted in a decrease in NKp46+ILC3 cell numbers, impaired production of IL-22 and IL-17A, and exacerbated intestinal inflammation in a T cell-independent manner. Our mechanistic studies revealed that GPX4-mediated ferroptosis in NKp46+ILC3 cells was regulated by the LCN2-p38-ATF4-xCT signaling pathway. Mice lacking LCN2 in ILC3s or administration of a p38 pathway inhibitor exhibited similar phenotypes of ILC3 and colitis to those observed in GPX4 conditional knock-out mice. These observations provide novel insights into therapeutic strategies for intestinal inflammation by modulating ILC3 ferroptosis.
    DOI:  https://doi.org/10.1038/s41419-024-07060-3
  11. J Clin Invest. 2024 Sep 17. pii: e179860. [Epub ahead of print]134(18):
    Pericyte phenotype switching alleviates immunosuppression and sensitizes vascularized tumors to immunotherapy in preclinical models.
    Zhi-Jie Li, Bo He, Alice Domenichini, Jiulia Satiaputra, Kira H Wood, Devina D Lakhiani, Abate A Bashaw, Lisa M Nilsson, Ji Li, Edward R Bastow, Anna Johansson-Percival, Elena Denisenko, Alistair Rr Forrest, Suraj Sakaram, Rafael Carretero, Günter J Hämmerling, Jonas A Nilsson, Gabriel Yf Lee, Ruth Ganss.
      T cell-based immunotherapies are a promising therapeutic approach for multiple malignancies, but their efficacy is limited by tumor hypoxia arising from dysfunctional blood vessels. Here, we report that cell-intrinsic properties of a single vascular component, namely the pericyte, contribute to the control of tumor oxygenation, macrophage polarization, vessel inflammation, and T cell infiltration. Switching pericyte phenotype from a synthetic to a differentiated state reverses immune suppression and sensitizes tumors to adoptive T cell therapy, leading to regression of melanoma in mice. In melanoma patients, improved survival is correlated with enhanced pericyte maturity. Importantly, pericyte plasticity is regulated by signaling pathways converging on Rho kinase activity, with pericyte maturity being inducible by selective low-dose therapeutics that suppress pericyte MEK, AKT, or notch signaling. We also show that low-dose targeted anticancer therapy can durably change the tumor microenvironment without inducing adaptive resistance, creating a highly translatable pathway for redosing anticancer targeted therapies in combination with immunotherapy to improve outcome.
    Keywords:  Cancer immunotherapy; Mouse models; Oncology; Pericytes; Therapeutics
    DOI:  https://doi.org/10.1172/JCI179860
  12. Cancer Res. 2024 Sep 16. 84(18): 2947-2949
    Nutrient Levels and Nutrient Sources in Pancreatic Tumors.
    Sven Groessl, Wilhelm Palm.
      It has been known that poor tumor perfusion and dysregulated cancer cell metabolism give rise to tumor microenvironments with unphysiologic nutrient levels, but the precise alterations in metabolite abundance are not well defined. In a 2015 study in Cancer Research, Kamphorst and colleagues published a detailed comparison of the metabolome from human pancreatic tumors and benign tissues. Tumors were depleted in glucose and various nonessential amino acids but, surprisingly, enriched in essential amino acids. The authors attributed these nutrient imbalances to macropinocytosis of extracellular proteins, a RAS-driven amino acid acquisition pathway that was found to be increased in human tumors and supports pancreatic cancer cell growth during amino acid starvation. These findings substantially contributed to the understanding of altered nutrient levels in tumors and extracellular proteins as noncanonical nutrients. Intratumoral nutrient levels in different cancer contexts and signaling pathways that regulate nutrient acquisition by cancer cells remain a focus of current research. See related article by Kamphorst and colleagues, Cancer Res 2015;75:544-53.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-2447
  13. Nat Commun. 2024 Sep 14. 15(1): 8066
    Overactive mitochondrial DNA replication disrupts perinatal cardiac maturation.
    Juan C Landoni, Semin Erkul, Tuomas Laalo, Steffi Goffart, Riikka Kivelä, Karlo Skube, Anni I Nieminen, Sara A Wickström, James Stewart, Anu Suomalainen.
      High mitochondrial DNA (mtDNA) amount has been reported to be beneficial for resistance and recovery of metabolic stress, while increased mtDNA synthesis activity can drive aging signs. The intriguing contrast of these two mtDNA boosting outcomes prompted us to jointly elevate mtDNA amount and frequency of replication in mice. We report that high activity of mtDNA synthesis inhibits perinatal metabolic maturation of the heart. The offspring of the asymptomatic parental lines are born healthy but manifest dilated cardiomyopathy and cardiac collapse during the first days of life. The pathogenesis, further enhanced by mtDNA mutagenesis, involves prenatal upregulation of mitochondrial integrated stress response and the ferroptosis-inducer MESH1, leading to cardiac fibrosis and cardiomyocyte death after birth. Our evidence indicates that the tight control of mtDNA replication is critical for early cardiac homeostasis. Importantly, ferroptosis sensitivity is a potential targetable mechanism for infantile-onset cardiomyopathy, a common manifestation of mitochondrial diseases.
    DOI:  https://doi.org/10.1038/s41467-024-52164-1
  14. Hepatology. 2024 Sep 18.
    TREM2 macrophages mediate the beneficial effects of bariatric surgery against MASH.
    Gavin Fredrickson, Kira Florczak, Fanta Barrow, Shamsed Mahmud, Katrina Dietsche, Haiguang Wang, Preethy Parthiban, Andrew Hakeem, Rawan Almutlaq, Oyedele Adeyi, Adam Herman, Alessandro Bartolomucci, Christopher Staley, Xiao Dong, Cyrus Jahansouz, Jesse W Williams, Douglas G Mashek, Sayeed Ikramuddin, Xavier S Revelo.
      For patients with obesity and metabolic syndrome, bariatric procedures such as vertical sleeve gastrectomy (VSG) have a clear benefit in ameliorating metabolic dysfunction-associated steatohepatitis (MASH). While the effects of bariatric surgeries have been mainly attributed to nutrient restriction and malabsorption, whether immuno-modulatory mechanisms are involved remains unclear. Using murine models, we report that VSG ameliorates MASH progression in a weight loss-independent manner. Single-cell RNA sequencing revealed that hepatic lipid-associated macrophages (LAMs) expressing the triggering receptor expressed on myeloid cells 2 (TREM2) repress inflammation and increase their lysosomal activity in response to VSG. Remarkably, TREM2 deficiency in mice ablates the reparative effects of VSG, suggesting that TREM2 is required for MASH resolution. Mechanistically, TREM2 prevents the inflammatory activation of macrophages and is required for their efferocytic function. Overall, our findings indicate that bariatric surgery improves MASH through a reparative process driven by TREM2+ macrophages, providing insights into the mechanisms of disease reversal that may result in new therapies and improved surgical interventions.
    DOI:  https://doi.org/10.1097/HEP.0000000000001098
  15. JCI Insight. 2024 Sep 19. pii: e177899. [Epub ahead of print]
    Progesterone promotes Cxcl2-dependent vaginal neutrophil killing by activating cervical resident macrophage-neutrophil crosstalk.
    Carla Gómez-Oro, Maria C Latorre, Patricia Arribas-Poza, Alexandra Ibáñez-Escribano, Katia R Baca-Cornejo, Jorge Gallego-Valle, Natalia López-Escobar, Mabel Mondéjar-Palencia, Marjorie Pion, Luis A López-Fernández, Enrique Mercader-Cidoncha, Federico Pérez-Milán, Miguel Relloso.
      Vaginal infections in women of reproductive age represent a clinical dilemma with significant socio-economic implications. The understanding of mucosal immunity failure during early pathogenic invasions that allow the pathogen to grow and thrive is far from complete. Neutrophils infiltrate most tissues following circadian patterns as part of normal repair, regulation of microbiota, or immune surveillance and become more numerous after infection. Neutrophils are responsible for maintaining vaginal immunity. Specific to the vagina, neutrophils continuously infiltrate at high levels, although during ovulation they retreat to avoid sperm damage and permit reproduction. Here we show that after ovulation, progesterone promotes resident vaginal macrophage-neutrophils crosstalk by up-regulating Yolk sac and early fetal organs (Folr2+ (folate receptor 2)) macrophage Cxcl2 expression, in a Tnfa-monocyte-derived macrophage (Cx3cr1hi MHCIIhi) mediated manner, to activate neutrophils' capacity to eliminate sex-transmitted and opportunistic microorganisms. Indeed, progesterone plays an essential role in conciliating the balance between the commensal microbiota, sperm, and the threat of pathogens: because progesterone not only promotes a flurry of neutrophils but also increases neutrophilic fury to restore immunity after ovulation to thwart pathogenic invasion post-intercourse. Therefore, modest progesterone dysregulations could lead to a suboptimal neutrophilic response, resulting in insufficient mucosal defense and recurrent unresolved infections.
    Keywords:  Bacterial infections; Endocrinology; Infectious disease; Innate immunity; Macrophages
    DOI:  https://doi.org/10.1172/jci.insight.177899
  16. J Clin Invest. 2024 Sep 17. pii: e178949. [Epub ahead of print]
    Targeting aryl hydrocarbon receptor functionally restores tolerogenic dendritic cells derived from patients with multiple sclerosis.
    Federico Fondelli, Jana Willemyns, Roger Domenech-Garcia, Maria José Mansilla, Gerard Godoy-Tena, Anna G Ferreté-Bonastre, Alex Agúndez-Moreno, Silvia Presas-Rodriguez, Cristina Ramo-Tello, Esteban Ballestar, Eva Martínez-Cáceres.
      Multiple Sclerosis (MS) is a chronic disease characterized by dysregulated self-reactive immune responses that damage the neurons' myelin sheath, leading to progressive disability. The primary therapeutic option, immunosuppressants, inhibits pathogenic anti-myelin responses but depresses the immune system. Antigen-specific monocyte-derived autologous tolerogenic dendritic cells (tolDCs) offer alternative therapeutic approaches to restore tolerance to auto-antigens without causing generalized immunosuppression. However, immune dysregulation in MS could impact the properties of the monocytes used as starting material for this cell therapy. Here, we characterized CD14+ monocytes, mature dendritic cells (mDCs) and Vitamin-D3-tolDCs (VitD3-tolDCs) from active, treatment-naive MS patients and healthy donors (HD). Using multi-omics, we identified a switch in these cell types towards proinflammatory features characterized by alterations in the AhR and NF-kB pathways. MS patient-derived VitD3-tolDCs showed reduced tolerogenic properties compared to those from HD, which were fully restored through direct AhR agonism and using in vivo or in vitro Dimethyl Fumarate (DMF) supplementation. Additionally, in the experimental autoimmune encephalomyelitis (EAE) mouse model, combined therapy of DMF and VitD3-tolDCs was more efficient than monotherapies in reducing the clinical score of mice. We propose that a combined therapy with DMF and VitD3-tolDCs offers enhanced therapeutic potential in treating MS.
    Keywords:  Autoimmunity; Demyelinating disorders; Dendritic cells; Immunotherapy; Therapeutics
    DOI:  https://doi.org/10.1172/JCI178949
  17. Nitric Oxide. 2024 Sep 17. pii: S1089-8603(24)00115-0. [Epub ahead of print]
    Nitric oxide in the cardio-cerebrovascular system: source, regulation and application.
    Xiaoming Fu, Haowei Lu, Meng Gao, Pinghe Li, Yan He, Yu He, Xiaojian Luo, Xiaoyong Rao, Wei Liu.
      Nitric oxide (NO) plays a crucial role as a messenger or effector in the body, yet it presents a dual impact on cardio-cerebrovascular health. Under normal physiological conditions, NO exhibits vasodilatory effects, regulates blood pressure, inhibits platelet aggregation, and offers neuroprotective actions. However, in pathological situations, excessive NO production contributes to or worsens inflammation within the body. Moreover, NO may combine with reactive oxygen species (ROS), generating harmful substances that intensify physical harm. This paper succinctly reviews pertinent literature to clarify the in vivo and in vitro origins of NO, its regulatory function in the cardio-cerebrovascular system, and the advantages and disadvantages associated with NO donor drugs, NO delivery systems, and vascular stent materials for treating cardio-cerebrovascular disease. The findings provide a theoretical foundation for the application of NO in cardio-cerebrovascular diseases.
    Keywords:  Cardio-cerebrovascular; NO delivery systems; Nitric oxide; Nitric oxide synthase; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.niox.2024.09.005
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