bims-imicid 2024-12-01 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024–12–01
33 papers selected by
Dylan Ryan, University of Cambridge

Dietary Restriction Enhances CD8⁺ T Cell Ketolysis to Limit Exhaustion and Boost Anti-Tumor Immunity.
Myeloid Drp1 deficiency limits revascularization in ischemic muscles via inflammatory macrophage polarization and metabolic reprograming.
Emerging role of metabolic reprogramming in the immune microenvironment and immunotherapy of thyroid cancer.
Metabolic Reprogramming of Immune Cells in the Tumor Microenvironment.
The nutrient-sensing Rag-GTPase complex in B cells controls humoral immunity via TFEB/TFE3-dependent mitochondrial fitness.
Treponema Pallidum protein Tp47 triggers macrophage inflammatory senescence via PKM2-mediated metabolic reprogramming.
Circadian immunometabolism: A future insight for targeted therapy in cancer.
HMGB1 Modulates Macrophage Metabolism and Polarization in Ulcerative Colitis by Inhibiting Cpt1a Expression.
Approaches to investigate tissue-resident innate lymphocytes metabolism at the single-cell level.
Assessment of mitochondrial function and its prognostic role in sepsis: a literature review.
Metabolomic Analysis of Murine Tissues Infected with Brucella melitensis.
Cholesterol overload in macrophages drives metabolic dysfunction-associated steatohepatitis via inhibiting 7-dehydrocholesterol reductase in mice.
Macrophages are activated toward phagocytic lymphoma cell clearance by pentose phosphate pathway inhibition.
Inhibition of Glycolysis Alleviates Chronic Unpredictable Mild Stress Induced Neuroinflammation and Depression-like Behavior.
Branched-chain amino acid catabolism promotes M2 macrophage polarization.
Nutrient transporter pattern in CD56dim NK cells: CD16 (FcγRIIIA)-dependent modulation and association with memory NK cell functional profile.
Dynamic metabolic modeling of ATP allocation during viral infection.
N-acetylaspartate mitigates pro-inflammatory responses in microglial cells by intersecting lipid metabolism and acetylation processes.
Rewiring Tryptophan Metabolism via Programmable Probiotic Integrated by Dual-Layered Microcapsule Protects against Inflammatory Bowel Disease in Mice.
The interplay of EBV virus and cell metabolism in lung cancer.
Adipocyte microRNA-802 promotes adipose tissue inflammation and insulin resistance by modulating macrophages in obesity.
Modulation of Urea Transport Attenuates TLR2-Mediated Microglial Activation and Upregulates Microglial Metabolism In Vitro.
Calcium Channel Blocker Lacidipine Promotes Antitumor Immunity by Reprogramming Tryptophan Metabolism.
Salmonella-induced cholesterol accumulation in infected macrophages suppresses autophagy via mTORC1 activation.
Xylose utilization promotes Salmonella replication within macrophages and systemic infection in mice.
Mesenchymal stromal cells can block palmitate training of macrophages via cyclooxygenase-2 and interleukin-1 receptor antagonist.
Cholesterol metabolism and intrabacterial potassium homeostasis are intrinsically related in Mycobacterium tuberculosis.
Host metabolic inflammation fueled by bacterial DNA.
Longitudinal 1H NMR-Based Metabolomics in Saliva Unveils Signatures of Transition from Acute to Post-Acute Phase of SARS-CoV-2 Infection.
Longitudinal mitochondrial bioenergetic signatures of blood monocytes and lymphocytes improve during treatment of drug-susceptible pulmonary tuberculosis patients Monocyte/lymphocyte bioenergetic signatures post-TB treatment.
Adipocyte FGF21 Signaling Defect Aggravated Adipose Tissue Inflammation in Gestational Diabetes Mellitus.
Blockade of purine metabolism reverses macrophage immunosuppression and enhances anti-tumor immunity in non-small cell lung cancer.
Succinate-producing microbiota drives tuft cell hyperplasia to protect against Clostridioides difficile.

bioRxiv. 2024 Nov 15. pii: 2024.11.14.621733. [Epub ahead of print]

Dietary Restriction Enhances CD8⁺ T Cell Ketolysis to Limit Exhaustion and Boost Anti-Tumor Immunity.

Brandon M Oswald, Lisa M DeCamp, Joseph Longo, Michael S Dahabieh, Nicholas Bunda, Shixin Ma, McLane J Watson, Ryan D Sheldon, Michael P Vincent, Benjamin K Johnson, Abigail E Ellis, Molly T Soper-Hopper, Christine N Isaguirre, Hui Shen, Kelsey S Williams, Peter A Crawford, Susan Kaech, H Josh Jang, Connie M Krawczyk, Russell G Jones.

Reducing calorie intake without malnutrition limits tumor progression but the underlying mechanisms are poorly understood. Here we show that dietary restriction (DR) suppresses tumor growth by enhancing CD8 + T cell-mediated anti-tumor immunity. DR reshapes CD8 + T cell differentiation within the tumor microenvironment (TME), promoting the development of effector T cell subsets while limiting the accumulation of exhausted T (Tex) cells, and synergizes with anti-PD1 immunotherapy to restrict tumor growth. Mechanistically, DR enhances CD8 + T cell metabolic fitness through increased ketone body oxidation (ketolysis), which boosts mitochondrial membrane potential and fuels tricarboxylic acid (TCA) cycle-dependent pathways essential for T cell function. T cells deficient for ketolysis exhibit reduced mitochondrial function, increased exhaustion, and fail to control tumor growth under DR conditions. Our findings reveal a critical role for the immune system in mediating the anti-tumor effects of DR, highlighting nutritional modulation of CD8 + T cell fate in the TME as a critical determinant of anti-tumor immunity.

DOI: https://doi.org/10.1101/2024.11.14.621733
JCI Insight. 2024 Nov 26. pii: e177334. [Epub ahead of print]

Myeloid Drp1 deficiency limits revascularization in ischemic muscles via inflammatory macrophage polarization and metabolic reprograming.

Shikha Yadav, Vijay C Ganta, Sudhahar Varadarajan, Vy Ong, Yang Shi, Archita Das, Dipankar Ash, Sheela Nagarkoti, Malgorzata McMenamin, Stephanie Kelley, Tohru Fukai, Masuko Ushio-Fukai.

  Macrophage plays a crucial role in promoting perfusion recovery and revascularization after ischemia through anti-inflammatory polarization, a process essential for the treatment of peripheral arterial disease (PAD). Mitochondrial dynamics, particularly regulated by the fission protein DRP1, are closely linked to macrophage metabolism and inflammation. However, the role of DRP1 in reparative neovascularization remains unexplored. Here we show that DRP1 expression was increased in F4/80+ macrophages within ischemic muscle at day 3 after hindlimb ischemia (HLI), an animal model of PAD. Mice lacking Drp1 in myeloid cells exhibited impaired limb perfusion recovery, angiogenesis and muscle regeneration post-HLI. These effects were associated with increased pro-inflammatory M1-like macrophages, p-NFkB and TNFα, and reduced anti-inflammatory M2-like macrophages and p-AMPK in ischemic muscle of myeloid Drp1-/- mice. In vitro, Drp1-deficient macrophages under hypoxia serum starvation (HSS), an in vitro PAD model, demonstrated enhanced glycolysis via reducing p-AMPK as well as mitochondrial dysfunction, and excessive mitochondrial ROS production, resulting in increased pro-inflammatory M1-gene and reduced anti-inflammatory M2-gene expression. Conditioned media from HSS-treated Drp1-/- macrophages exhibited increased pro-inflammatory cytokine secretion, leading to suppressed angiogenesis in endothelial cells. Thus, macrophage DRP1 deficiency under ischemia drives pro-inflammatory metabolic reprogramming and macrophage polarization, limiting revascularization in experimental PAD.

Keywords:  Angiogenesis; Inflammation; Macrophages

DOI:  https://doi.org/10.1172/jci.insight.177334
Int Immunopharmacol. 2024 Nov 26. pii: S1567-5769(24)02224-0. [Epub ahead of print]144 113702

Emerging role of metabolic reprogramming in the immune microenvironment and immunotherapy of thyroid cancer.

Shouhua Li, Hengtong Han, Kaili Yang, Xiaoxiao Li, Libin Ma, Ze Yang, Yong-Xun Zhao.

  The metabolic reprogramming of cancer cells is a hallmark of many malignancies. To meet the energy acquisition needs of tumor cells for rapid proliferation, tumor cells reprogram their nutrient metabolism, which is caused by the abnormal expression of transcription factors and signaling molecules related to energy metabolic pathways as well as the upregulation and downregulation of abnormal metabolic enzymes, receptors, and mediators. Thyroid cancer (TC) is the most common endocrine tumor, and immunotherapy has become the mainstream choice for clinical benefit after the failure of surgical, endocrine, and radioiodine therapies. TC change the tumor microenvironment (TME) through nutrient competition and metabolites, causing metabolic reprogramming of immune cells, profoundly changing immune cell function, and promoting immune evasion of tumor cells. A deeper understanding of how metabolic reprogramming alters the TME and controls immune cell fate and function will help improve the effectiveness of TC immunotherapy and patient outcomes. This paper aims to elucidate the metabolic communication that occurs between immune cells around TC and discusses how metabolic reprogramming in TC affects the immune microenvironment and the effectiveness of anti-cancer immunotherapy. Finally, targeting key metabolic checkpoints during metabolic reprogramming, combined with immunotherapy, is a promising strategy.

Keywords:  Immune microenvironment; Immunometabolism; Immunotherapy; Metabolic reprogramming; Thyroid cancers

DOI:  https://doi.org/10.1016/j.intimp.2024.113702
Int J Mol Sci. 2024 Nov 14. pii: 12223. [Epub ahead of print]25(22):

Metabolic Reprogramming of Immune Cells in the Tumor Microenvironment.

Jing Wang, Yuanli He, Feiming Hu, Chenchen Hu, Yuanjie Sun, Kun Yang, Shuya Yang.

  Metabolic reprogramming of immune cells within the tumor microenvironment (TME) plays a pivotal role in shaping tumor progression and responses to therapy. The intricate interplay between tumor cells and immune cells within this ecosystem influences their metabolic landscapes, thereby modulating the immune evasion tactics employed by tumors and the efficacy of immunotherapeutic interventions. This review delves into the metabolic reprogramming that occurs in tumor cells and a spectrum of immune cells, including T cells, macrophages, dendritic cells, and myeloid-derived suppressor cells (MDSCs), within the TME. The metabolic shifts in these cell types span alterations in glucose, lipid, and amino acid metabolism. Such metabolic reconfigurations can profoundly influence immune cell function and the mechanisms by which tumors evade immune surveillance. Gaining a comprehensive understanding of the metabolic reprogramming of immune cells in the TME is essential for devising novel cancer therapeutic strategies. By targeting the metabolic states of immune cells, it is possible to augment their anti-tumor activities, presenting new opportunities for immunotherapeutic approaches. These strategies hold promise for enhancing treatment outcomes and circumventing the emergence of drug resistance.

Keywords:  immune cells; immunotherapy; metabolic reprogramming; the tumor microenvironment

DOI:  https://doi.org/10.3390/ijms252212223
Nat Commun. 2024 Nov 23. 15(1): 10163

The nutrient-sensing Rag-GTPase complex in B cells controls humoral immunity via TFEB/TFE3-dependent mitochondrial fitness.

Xingxing Zhu, Yue Wu, Yanfeng Li, Xian Zhou, Jens O Watzlawik, Yin Maggie Chen, Ariel L Raybuck, Daniel D Billadeau, Virginia Smith Shapiro, Wolfdieter Springer, Jie Sun, Mark R Boothby, Hu Zeng.

Germinal center (GC) formation, which is an integrant part of humoral immunity, involves energy-consuming metabolic reprogramming. Rag-GTPases are known to signal amino acid availability to cellular pathways that regulate nutrient distribution such as the mechanistic target of rapamycin complex 1 (mTORC1) pathway and the transcription factors TFEB and TFE3. However, the contribution of these factors to humoral immunity remains undefined. Here, we show that B cell-intrinsic Rag-GTPases are critical for the development and activation of B cells. RagA/RagB deficient B cells fail to form GCs, produce antibodies, and to generate plasmablasts during both T-dependent (TD) and T-independent (TI) humoral immune responses. Deletion of RagA/RagB in GC B cells leads to abnormal dark zone (DZ) to light zone (LZ) ratio and reduced affinity maturation. Mechanistically, the Rag-GTPase complex constrains TFEB/TFE3 activity to prevent mitophagy dysregulation and maintain mitochondrial fitness in B cells, which are independent of canonical mTORC1 activation. TFEB/TFE3 deletion restores B cell development, GC formation in Peyer's patches and TI humoral immunity, but not TD humoral immunity in the absence of Rag-GTPases. Collectively, our data establish the Rag GTPase-TFEB/TFE3 pathway as a likely mTORC1 independent mechanism to coordinating nutrient sensing and mitochondrial metabolism in B cells.

DOI: https://doi.org/10.1038/s41467-024-54344-5
Int J Biol Macromol. 2024 Nov 22. pii: S0141-8130(24)08802-0. [Epub ahead of print] 137991

Treponema Pallidum protein Tp47 triggers macrophage inflammatory senescence via PKM2-mediated metabolic reprogramming.

Jia-Wen Xie, Yin-Feng Guo, Shu-Hao Fan, Ying Zheng, Hui-Lin Zhang, Yan Zhang, Yi Zhang, Li-Rong Lin.

  Syphilis is a sexually transmitted disease caused by Treponema pallidum. The mechanisms enabling T. pallidum to persist despite macrophage eradication efforts in syphilis remain unclear. Pathogens can exploit senescent cells to enhance host susceptibility, and cellular senescence can be induced by pyroptosis, which known as inflammatory senescence. While recent studies have linked metabolic reprogramming to inflammatory senescence, their role in syphilis remained to be clarified. This study investigated the mechanisms of Tp47 on metabolic reprogramming and inflammatory senescence in macrophages. The results demonstrated that Tp47 triggered NLRP3 inflammasome-mediated pyroptosis by activating the phosphorylation of EIF2AK2 (a protein kinase), increasing senescence-associated pro-inflammatory cytokines secretion and leading to inflammatory senescence in macrophages. Additionally, Tp47 competitively bound to pyruvate kinase M2 (PKM2) with STUB1(a ubiquitin ligase), thereby inhibiting PKM2 ubiquitination degradation. By promoting the Y105 phosphorylation of PKM2, Tp47 modulated the intracellular function of PKM2, and facilitated PKM2-mediated metabolic reprogramming, which produced lactate that subsequently led to EIF2AK2 phosphorylation. Furthermore, inhibitors targeting EIF2AK2, lactate, glycolysis, and PKM2 effectively suppressed the inflammatory senescence induced by Tp47. In conclusion, Tp47 could mediate immune metabolic reprogramming through interaction with PKM2 to trigger macrophage inflammatory senescence. These discoveries offer a novel perspective for targeted therapies against syphilis.

Keywords:  Inflammatory senescence; Metabolic reprogramming; Syphilis

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.137991
Sleep Med Rev. 2024 Nov 19. pii: S1087-0792(24)00135-7. [Epub ahead of print]80 102031

Circadian immunometabolism: A future insight for targeted therapy in cancer.

Manendra Singh Tomar, Mohit, Ashok Kumar, Ashutosh Shrivastava.

  Circadian rhythms send messages to regulate the sleep-wake cycle in living beings, which, regulate various biological activities. It is well known that altered sleep-wake cycles affect host metabolism and significantly deregulate the host immunity. The dysregulation of circadian-related genes is critical for various malignancies. One of the hallmarks of cancer is altered metabolism, the effects of which spill into surrounding microenvironments. Here, we review the emerging literature linking the circadian immunometabolic axis to cancer. Small metabolites are the products of various metabolic pathways, that are usually perturbed in cancer. Genes that regulate circadian rhythms also regulate host metabolism and control metabolite content in the tumor microenvironment. Immune cell infiltration into the tumor site is critical to perform anticancer functions, and altered metabolite content affects their trafficking to the tumor site. A compromised immune response in the tumor microenvironment aids cancer cell proliferation and immune evasion, resulting in metastases. The role of circadian rhythms in these processes is largely overlooked and demands renewed attention in the search for targets against cancer growth and spread. The precision medicine approach requires targeting the circadian immune metabolism in cancer.

Keywords:  Cancer; Circadian rhythms; Clock genes; Immune cells; Immunometabolism; Metabolism

DOI:  https://doi.org/10.1016/j.smrv.2024.102031
Front Biosci (Landmark Ed). 2024 Nov 19. 29(11): 387

HMGB1 Modulates Macrophage Metabolism and Polarization in Ulcerative Colitis by Inhibiting Cpt1a Expression.

Fenfen Wang, Linfei Luo, Zhengqiang Wu, Lijun Wan, Fan Li, Zhili Wen.

   BACKGROUND: Macrophage polarization is involved in the development of ulcerative colitis (UC). This study investigated the mechanism by which high mobility group box-1 protein (HMGB1) regulates macrophage polarization through metabolic reprogramming, thereby contributing to the pathogenesis of UC.
METHODS: Dextran sulfate sodium (DSS) was used to induce colitis in mice. RAW264.7 cells were polarized to M1 or M2 macrophages in vitro by stimulating with lipopolysaccharide (LPS)/interferon-γ (IFN-γ) or Interleukin-4 (IL-4), respectively. Macrophage infiltration and distribution within colon tissue were assessed by immunohistochemistry and flow cytometry. Glycolysis, fatty acid oxidation (FAO), and inflammatory factors were evaluated using relevant reagent kits. Chromatin Immunoprecipitation (ChIP) and luciferase reporter experiments were performed to study the regulation of Carnitine palmitoyltransferase 1A (Cpt1a) promoter transcriptional activity by HMGB1.
RESULTS: The mouse UC model showed upregulated HMGB1 and increased macrophage infiltration. Overexpression of HMGB1 promoted M1 macrophage polarization, increased glycolysis, and reduced FAO, whereas knockdown of HMGB1 promoted M2 macrophage polarization, reduced glycolysis, and increased FAO. HMGB1 negatively regulated Cpt1a expression by inhibiting transcription of the Cpt1a promoter. Knockdown of Cpt1a reversed the effects of small interfering RNA targeting HMGB1 (si-HMGB1) on macrophage metabolism and polarization. Administration of adeno-associated virus (AAV)-shHMGB1 in vivo caused a reduction in UC symptoms and inflammation.
CONCLUSIONS: HMGB1 modulates macrophage metabolism in UC by inhibiting Cpt1a expression, leading to increased M1 polarization. This provides a theoretical basis for the clinical application of HMGB1 inhibitors in the treatment of UC.

Keywords:  Cpt1a; HMGB1; cell metabolism; macrophage polarization; ulcerative colitis

DOI:  https://doi.org/10.31083/j.fbl2911387
Nat Commun. 2024 Nov 30. 15(1): 10424

Approaches to investigate tissue-resident innate lymphocytes metabolism at the single-cell level.

Carrie Corkish, Cristhiane Favero Aguiar, David K Finlay.

Tissue-resident innate immune cells have important functions in both homeostasis and pathological states. Despite advances in the field, analyzing the metabolism of tissue-resident innate lymphocytes is still challenging. The small number of tissue-resident innate lymphocytes such as ILC, NK, iNKT and γδ T cells poses additional obstacles in their metabolic studies. In this review, we summarize the current understanding of innate lymphocyte metabolism and discuss potential pitfalls associated with the current methodology relying predominantly on in vitro cultured cells or bulk-level comparison. Meanwhile, we also summarize and advocate for the development and adoption of single-cell metabolic assays to accurately profile the metabolism of tissue-resident immune cells directly ex vivo.

DOI: https://doi.org/10.1038/s41467-024-54516-3
Intensive Care Med Exp. 2024 Nov 25. 12(1): 107

Assessment of mitochondrial function and its prognostic role in sepsis: a literature review.

Wagner Nedel, Nathan Ryzewski Strogulski, Afonso Kopczynski, Luis Valmor Portela.

  Sepsis is characterized by a dysregulated and excessive systemic inflammatory response to infection, associated with vascular and metabolic abnormalities that ultimately lead to organ dysfunction. In immune cells, both non-oxidative and oxidative metabolic rates are closely linked to inflammatory responses. Mitochondria play a central role in supporting these cellular processes by utilizing metabolic substrates and synthesizing ATP through oxygen consumption. To meet fluctuating cellular demands, mitochondria must exhibit adaptive plasticity underlying bioenergetic capacity, biogenesis, fusion, and fission. Given their role as a hub for various cellular functions, mitochondrial alterations induced by sepsis may hold significant pathophysiological implications and impact on clinical outcomes. In patients, mitochondrial DNA concentration, protein expression levels, and bioenergetic profiles can be accessed via tissue biopsies or isolated peripheral blood cells. Clinically, monocytes and lymphocytes serve as promising matrices for evaluating mitochondrial function. These mononuclear cells are highly oxidative, mitochondria-rich, routinely monitored in blood, easy to collect and process, and show a clinical association with immune status. Hence, mitochondrial assessments in immune cells could serve as biomarkers for clinical recovery, immunometabolic status, and responsiveness to oxygen and vasopressor therapies in sepsis. These characteristics underscore mitochondrial parameters in both tissues and immune cells as practical tools for exploring underlying mechanisms and monitoring septic patients in intensive care settings. In this article, we examine pathophysiological aspects, key methods for measuring mitochondrial function, and prominent studies in this field.

Keywords:  Inflammation; Mitochondria; Mitochondrial dysfunction; Oxidative phosphorylation; Respirometry; Sepsis

DOI:  https://doi.org/10.1186/s40635-024-00694-9
bioRxiv. 2024 Nov 16. pii: 2024.11.16.623915. [Epub ahead of print]

Metabolomic Analysis of Murine Tissues Infected with Brucella melitensis.

Bárbara Ponzilacqua-Silva, Alexis S Dadelahi, Charles R Moley, Mostafa F N Abushahba, Jerod A Skyberg.

Brucella is a gram negative, facultative, intracellular bacterial pathogen that constitutes a substantial threat to human and animal health. Brucella can replicate in a variety of tissues and can induce immune responses that alter host metabolite availability. Here, mice were infected with B. melitensis and murine spleens, livers, and female reproductive tracts were analyzed by GC-MS to determine tissue-specific metabolic changes at one-, two- and four-weeks post infection. The most remarkable changes were observed at two-weeks post-infection when relative to uninfected tissues, 42 of 329 detected metabolites in reproductive tracts were significantly altered by Brucella infection, while in spleens and livers, 68/205 and 139/330 metabolites were significantly changed, respectively. Several of the altered metabolites in host tissues were linked to the GABA shunt and glutaminolysis. Treatment of macrophages with GABA did not alter control of B. melitensis infection, and deletion of the putative GABA transporter BMEI0265 did not alter B. melitensis virulence. While glutaminolysis inhibition did not affect control of B. melitensis in macrophages, glutaminolysis was required for macrophage IL-1β production in response to B. melitensis . In sum, these results indicate that Brucella infection alters host tissue metabolism and that these changes could have effects on inflammation and the outcome of infection.

DOI: https://doi.org/10.1101/2024.11.16.623915
J Transl Med. 2024 Nov 29. 22(1): 1085

Cholesterol overload in macrophages drives metabolic dysfunction-associated steatohepatitis via inhibiting 7-dehydrocholesterol reductase in mice.

Xiaoxiao Li, Kai Wang, Yunhong Sun, Yirong Wang, Jiaxuan Wu, Yanqi Dang, Meng Li, Wenjun Zhou.

   BACKGROUND: Dietary cholesterol promotes metabolic dysfunction-associated steatohepatitis (MASH), with hepatic macrophages central to disease pathology. However, the mechanisms by which cholesterol-loaded macrophages influence MASH remain unclear.
METHODS: In this study, mice were fed a cholesterol-rich choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). Hepatic cholesterol levels, inflammatory markers, and pro-inflammatory macrophage polarization were assessed. In vitro studies examined the impact of cholesterol on macrophage polarization, identifying 7-dehydrocholesterol reductase (DHCR7) as a key cholesterol- and inflammation-responsive enzyme. DHCR7 expression in macrophages from MASH patients and model mice was evaluated. Functional studies involving in vitro knockdown and overexpression experiments, were complemented using myeloid-specific DHCR7 knockout mice. RNA sequencing was performed on liver tissues from wild-type and DHCR7 knockout mice to identify affected signaling pathways.
RESULTS: CDAHFD-fed mice exhibited local cholesterol accumulation and a pro-inflammatory macrophage phenotype in the liver. Cholesterol overload in vitro promoted M1 polarization and liver inflammation, reversible by simvastatin. DHCR7 expression, responded to cholesterol and polarization state, was downregulated in M1-polarized and hepatic macrophages from MASH patients and mice. DHCR7 suppression promoted pro-inflammatory phenotype, while its overexpression showed anti-inflammatory effects. Myeloid-specific DHCR7 deficiency in CDAHFD-fed mice worsened liver inflammation and pro-inflammatory macrophage infiltration. RNA sequencing identified the phosphoinositide 3-kinase (PI3K) pathway in DHCR7-regulated effects, with DHCR7-PI3K axis activation mitigating cholesterol-driven inflammation.
CONCLUSIONS: These findings unveil novel mechanistic insights into MASH pathogenesis, suggesting targeting macrophage-specific DHCR7 activation may offer a promising therapeutic strategy for MASH.

Keywords:  7-dehydrocholesterol reductase; Cholesterol overload; Hepatic macrophages; Inflammation; Metabolic dysfunction-associated steatohepatitis

DOI:  https://doi.org/10.1186/s12967-024-05905-1
Cell Rep Med. 2024 Nov 19. pii: S2666-3791(24)00601-3. [Epub ahead of print] 101830

Macrophages are activated toward phagocytic lymphoma cell clearance by pentose phosphate pathway inhibition.

Anna C Beielstein, Elena Izquierdo, Stuart Blakemore, Nadine Nickel, Michael Michalik, Samruddhi Chawan, Reinhild Brinker, Hans-Henrik Bartel, Daniela Vorholt, Lukas Albert, Janica L Nolte, Rebecca Linke, Carolina Raíssa Costa Picossi, Jorge Sáiz, Felix Picard, Alexandra Florin, Jörn Meinel, Reinhard Büttner, Paul Diefenhardt, Sebastian Brähler, Alma Villaseñor, Holger Winkels, Michael Hallek, Marcus Krüger, Coral Barbas, Christian P Pallasch.

  Macrophages in the B cell lymphoma microenvironment represent a functional node in progression and therapeutic response. We assessed metabolic regulation of macrophages in the context of therapeutic antibody-mediated phagocytosis. Pentose phosphate pathway (PPP) inhibition induces increased phagocytic lymphoma cell clearance by macrophages in vitro, in primary human chronic lymphocytic leukemia (CLL) patient co-cultures, and in mouse models. Addition of the PPP inhibitor S3 to antibody therapy achieves significantly prolonged overall survival in an aggressive B cell lymphoma mouse model. PPP inhibition induces metabolic activation and pro-inflammatory polarization of macrophages while it decreases macrophages' support for survival of lymphoma cells empowering anti-lymphoma function. As a mechanism of macrophage repolarization, the link between PPP and immune regulation was identified. PPP inhibition causes decreased glycogen level and subsequent modulation of the immune modulatory uridine diphosphate glucose (UDPG)-Stat1-Irg1-itaconate axis. Thus, we hypothesize the PPP as a key regulator and targetable modulator of macrophage activity in lymphoma to improve efficacy of immunotherapies and prolong survival.

Keywords:  ADCP; Irg1; immunotherapy; itaconate; lymphoma; macrophage; metabolic modulation; pentose phosphate pathway; phagocytosis; polarization

DOI:  https://doi.org/10.1016/j.xcrm.2024.101830
Brain Sci. 2024 Oct 30. pii: 1098. [Epub ahead of print]14(11):

Inhibition of Glycolysis Alleviates Chronic Unpredictable Mild Stress Induced Neuroinflammation and Depression-like Behavior.

Bing Liu, Ke Dong, Xiaobing Chen, Huafeng Dong, Yun Zhao, Xue Wang, Zhaowei Sun, Fang Xie, Lingjia Qian.

   BACKGROUND: Growing evidence suggests that glucose metabolism plays a crucial role in activated immune cells, significantly contributing to the occurrence and development of neuroinflammation and depression-like behaviors. Chronic stress has been reported to induce microglia activation and disturbances in glucose metabolism in the hippocampus.
AIMS: This study aims to investigate how chronic stress-mediated glycolysis promotes neuroinflammation and to assess the therapeutic potential of the glycolysis inhibitor, 2-deoxy-D-glucose (2-DG), in a model of chronic stress-induced neuroinflammation and depression-like behavior.
METHODS: In in vitro studies, we first explored the effects of 2-DG on the inflammatory response of microglia cells. The results showed that corticosterone (Cort) induced reactive oxygen species (ROS) production, increased glycolysis, and promoted the release of inflammatory mediators. However, these effects were reversed by intervention with 2-DG. Subsequently, we examined changes in depression-like behavior and hippocampal glycolysis in mice during chronic stress. The results indicated that chronic stress led to prolonged escape latency in the Morris water maze, increased platform-crossing frequency, reduced sucrose preference index, and extended immobility time in the forced swim test, all of which are indicative of depression-like behavior in mice. Additionally, we found that the expression of the key glycolytic enzyme hexokinase 2 (HK2) was upregulated in the hippocampus of stressed mice, along with an increased release of inflammatory factors. Further in vivo experiments investigated the effects of 2-DG on glycolysis and pro-inflammatory mediator production, as well as the therapeutic effects of 2-DG on chronic stress-induced depression-like behavior in mice. The results showed that 2-DG alleviated chronic stress-induced depression-like behaviors, such as improving escape latency and platform-crossing frequency in the Morris water maze, and increasing the time spent in the center of the open field. Additionally, 2-DG intervention reduced the level of glycolysis in the hippocampus and decreased the release of pro-inflammatory mediators.
CONCLUSIONS: These findings suggest that 2-DG can mitigate neuroinflammation and depressive behaviors by inhibiting glycolysis and inflammatory responses. Overall, our results highlight the potential of 2-DG as a therapeutic agent for alleviating chronic stress-induced neuroinflammation through the regulation of glycolysis.

Keywords:  2-DG; CUMS; glycolysis; microglia; neuroinflammation

DOI:  https://doi.org/10.3390/brainsci14111098
Front Immunol. 2024 ;15 1469163

Branched-chain amino acid catabolism promotes M2 macrophage polarization.

Manxi Lu, Da Luo, Zixuan Zhang, Feng Ouyang, Yihong Shi, Changyong Hu, Hang Su, Yining Li, Jiayi Zhang, Qian Gui, Tian-Shu Yang.

   Introduction: During an immune response, macrophages undergo systematic metabolic rewiring tailored to support their functions. Branched-chain amino acid (BCAA) metabolism has been reported to modulate macrophage function; however, its role in macrophage alternative activation remain unclear. We aimed to investigate the role of BCAA metabolism in macrophage alternative activation.
Method: The metabolomics of BMDM-derived M0 and M2 macrophages were analyzed using LC-MS. BCAAs were supplemented and genes involved in BCAA catabolism were inhibited during M2 macrophage polarization. The expression of M2 marker genes was assessed through RT-qPCR, immunofluorescence, and flow cytometry.
Results and discussion: Metabolomic analysis identified increased BCAA metabolism as one of the most significantly rewired pathways upon alternative activation. M2 macrophages had significantly lower BCAA levels compared to controls. BCAA supplementation promoted M2 macrophage polarization both in vitro and in vivo and increased oxidative phosphorylation in M2 macrophages. Blocking BCAA entry into mitochondria by knockdown of SLC25A44 inhibited M2 macrophage polarization. Furthermore, M2 macrophages polarization was suppressed by knockdown of Branched-chain amino-acid transaminase 2 (BCAT2) and branched chain keto acid dehydrogenase E1 subunit alpha (BCKDHA), both of which are key enzymes involved in BCAA oxidation. Overall, our findings suggest that BCAA catabolism plays an important role in polarization toward M2 macrophages.

Keywords:  BCAA; BCAT2; BCKDHA; M2 macrophages; SLC25A44

DOI:  https://doi.org/10.3389/fimmu.2024.1469163
Front Immunol. 2024 ;15 1477776

Nutrient transporter pattern in CD56dim NK cells: CD16 (FcγRIIIA)-dependent modulation and association with memory NK cell functional profile.

Davide De Federicis, Cristina Capuano, Daniel Ciuti, Rosa Molfetta, Ricciarda Galandrini, Gabriella Palmieri.

   Background: Human memory NK cells represent a heterogeneous CD56dim population that expands and persists in human cytomegalovirus (HCMV)-seropositive healthy individuals. They are characterized by the preferential, not fully overlapping, expression of NKG2C (activating receptor for HLA-E) and CD57 maturation marker, and by the lack of FcεRIγ adaptor chain. Hyperresponsiveness to Fcγ receptor IIIA (CD16) engagement represents the distinctive functional signature of memory NK cells. Although CD16 engagement was shown to acutely enhance glycolytic and oxidative pathways, its capability to induce a persisting metabolic reprogramming of human NK cells is poorly understood yet.
Results: Here, we describe the peculiar nutrient transporter expression pattern of FcεRIγ- memory NK cells, characterized by higher levels of CD98 neutral amino acid antiporter and CD71 transferrin receptor, and lower expression of GLUT1 glucose transporter, with respect to FcεRIγ+ conventional NK cells. Although CD16 engagement acutely enhances glycolytic and oxidative pathways, its capability to induce a persisting metabolic reprogramming of human NK cells is poorly understood yet. Our results firstly show that sustained CD16 engagement by contact with IgG-opsonized target cells induces the mTORC1-dependent upregulation of CD98 and CD71 nutrient receptors on CD56dim NK cells, in a transporter-specific fashion, that is finely tuned by cell-dependent (grade of functional maturation, and memory or conventional lineage) and stimulus-dependent (time length and cooperation with cytokines) factors. We also demonstrate that CD98 antiporter function is required for CD16-dependent IFN-γ production, and that enhanced CD98-mediated neutral amino acid uptake associates with heightened memory NK cell functional response.
Conclusion: Collectively, our work documents that CD16 engagement leads to a metabolic rewiring of human NK cells and suggests that a distinct nutrient transporter expression pattern may contribute to memory NK cell peculiar functional features.

Keywords:  CD16; IFN-γ; mTORC1; memory natural killer cells; nutrient transporters

DOI:  https://doi.org/10.3389/fimmu.2024.1477776
bioRxiv. 2024 Nov 13. pii: 2024.11.12.623198. [Epub ahead of print]

Dynamic metabolic modeling of ATP allocation during viral infection.

Alvin Lu, Ilija Dukovski, Daniel Segrè.

Viral pathogens, like SARS-CoV-2, hijack the host's macromolecular production machinery, imposing an energetic burden that is distributed across cellular metabolism. To explore the dynamic metabolic tension between the host's survival and viral replication, we developed a computational framework that uses genome-scale models to perform dynamic Flux Balance Analysis of human cell metabolism during virus infections. Relative to previous models, our framework addresses the physiology of viral infections of non-proliferating host cells through two new features. First, by incorporating the lipid content of SARS-CoV-2 biomass, we discovered activation of previously overlooked pathways giving rise to new predictions of possible drug targets. Furthermore, we introduce a dynamic model that simulates the partitioning of resources between the virus and the host cell, capturing the extent to which the competition depletes the human cells from essential ATP. By incorporating viral dynamics into our COMETS framework for spatio-temporal modeling of metabolism, we provide a mechanistic, dynamic and generalizable starting point for bridging systems biology modeling with viral pathogenesis. This framework could be extended to broadly incorporate phage dynamics in microbial systems and ecosystems.

DOI: https://doi.org/10.1101/2024.11.12.623198
Cell Commun Signal. 2024 Nov 25. 22(1): 564

N-acetylaspartate mitigates pro-inflammatory responses in microglial cells by intersecting lipid metabolism and acetylation processes.

Federica Felice, Pamela De Falco, Martina Milani, Serena Castelli, Antonella Ragnini-Wilson, Giacomo Lazzarino, Nadia D'Ambrosi, Fabio Ciccarone, Maria Rosa Ciriolo.

   BACKGROUND: Microglia play a crucial role in brain development and repair by facilitating processes such as synaptic pruning and debris clearance. They can be activated in response to various stimuli, leading to either pro-inflammatory or anti-inflammatory responses associated with specific metabolic alterations. The imbalances between microglia activation states contribute to chronic neuroinflammation, a hallmark of neurodegenerative diseases. N-acetylaspartate (NAA) is a brain metabolite predominantly produced by neurons and is crucial for central nervous system health. Alterations in NAA metabolism are observed in disorders such as Multiple Sclerosis and Canavan disease. While NAA's role in oligodendrocytes and astrocytes has been investigated, its impact on microglial function remains less understood.
METHODS: The murine BV2 microglial cell line and primary microglia were used as experimental models. Cells were treated with exogenous NAA and stimulated with LPS/IFN-γ to reproduce the pro-inflammatory phenomenon. HPLC and immunofluorescence analysis were used to study lipid metabolism following NAA treatment. Automated fluorescence microscopy was used to analyze phagocytic activity. The effects on the pro-inflammatory response were evaluated by analysis of protein/mRNA expression and ChIP assay of typical inflammatory markers.
RESULTS: NAA treatment promotes an increase in both lipid synthesis and degradation, and enhances the phagocytic activity of BV2 cells, thus fostering surveillant microglia characteristics. Importantly, NAA decreases the pro-inflammatory state induced by LPS/IFN-γ via the activation of histone deacetylases (HDACs). These findings were validated in primary microglial cells, highlighting the impact on cellular metabolism and inflammatory responses.
CONCLUSIONS: The study highlighted the role of NAA in reinforcing the oxidative metabolism of surveillant microglial cells and, most importantly, in buffering the inflammatory processes characterizing reactive microglia. These results suggest that the decreased levels of NAA observed in neurodegenerative disorders can contribute to chronic neuroinflammation.

Keywords:  Anti-inflammatory response; Histone deacetylases; Lipid turnover; Microglial polarization; NAA; Oxidative metabolism

DOI:  https://doi.org/10.1186/s12964-024-01947-6
ACS Nano. 2024 Nov 28.

Rewiring Tryptophan Metabolism via Programmable Probiotic Integrated by Dual-Layered Microcapsule Protects against Inflammatory Bowel Disease in Mice.

Wen Li, Yichen Liu, Xiaoming Zheng, Jing Han, Anchen Shi, Chi Chun Wong, Ruochen Wang, Xunan Jing, Yan Li, Shu Fan, Cuiyu Zhang, Yinnan Chen, Gang Guo, Jun Yu, Junjun She.

  Intestinal dysbiosis and the associated l-tryptophan metabolic disorder are pivotal in inflammatory bowel disease progression, leading to a compromised intestinal barrier integrity. Remedying the dysfunction in tryptophan metabolism has emerged as a promising therapeutic strategy. Herein, we reprogram the tryptophan metabolism in situ by EcN-TRP@A/G, encapsulating the engineered probiotic, EcN-TRP, with enhanced tryptophan synthesis capacity, for sustained modulation, thereby restoring intestinal barrier function and microbial homeostasis. The pH-responsive dual-layered EcN-TRP@A/G microcapsule developed via high-voltage electrospraying and liquid interface self-assembly, preserved probiotic viability in the harsh gastrointestinal milieu, and facilitated targeted colon release. Bioluminescent tracking in mice reveals a 22.84-fold increase in EcN-TRP@A/G viability and distribution compared to naked EcN-TRP. Targeted metabolomics highlights EcN-TRP@A/G's modulation of the tryptophan-indole pathway. Oral administration of EcN-TRP@A/G sustained elevates indole metabolites, particularly indole-3-acetic acid and indole-3-propionic acid, in colon tissue for up to 7 days. In IBD mice, EcN-TRP@A/G improves intestinal permeability, reduces inflammation, and recovers the gut microbiome by enhancing beneficial bacteria abundance like Prevotellaceae_UCG-001 and Anaerostipes while suppressing pathogenic strains like Escherichia-Shigella. Our findings offer a cost-effective approach, harnessing the probiotic metabolic potential in situ through engineered modifications for effective IBD treatment.

Keywords:  genetically engineered probiotics; gut barrier; gut microbiota; inflammatory bowel disease; tryptophan metabolism

DOI:  https://doi.org/10.1021/acsnano.4c12801
J Cell Mol Med. 2024 Nov;28(22): e70088

The interplay of EBV virus and cell metabolism in lung cancer.

Hongwei Wang.

  Epstein-Barr virus infection has been implicated in various cancers, including lung cancer, where it influences cellular metabolism to promote tumorigenesis. This review examines the complex interplay between Epstein-Barr virus and cell metabolism in lung cancer, highlighting viral mechanisms of metabolic reprogramming and their implications for therapeutic strategies. Key viral proteins such as LMP1 and LMP2A manipulate glycolysis, glutaminolysis and lipid metabolism to support viral replication and immune evasion within the tumour microenvironment. Understanding these interactions provides insights into novel therapeutic approaches targeting viral-induced metabolic vulnerabilities in Epstein-Barr virus-associated lung cancer.

Keywords:  Epstein–Barr virus; cell metabolism; glycolysis; immune evasion; lung cancer

DOI:  https://doi.org/10.1111/jcmm.70088
Elife. 2024 Nov 26. pii: e99162. [Epub ahead of print]13

Adipocyte microRNA-802 promotes adipose tissue inflammation and insulin resistance by modulating macrophages in obesity.

Yue Yang, Bin Huang, Yimeng Qin, Danwei Wang, Yinuo Jin, Linmin Su, Qingxin Wang, Yi Pan, Yanfeng Zhang, Yumeng Shen, Wenjun Hu, Zhengyu Cao, Liang Jin, Fangfang Zhang.

  Adipose tissue inflammation is now considered to be a key process underlying metabolic diseases in obese individuals. However, it remains unclear how adipose inflammation is initiated and maintained or the mechanism by which inflammation develops. We found that microRNA-802 (Mir802) expression in adipose tissue is progressively increased with the development of dietary obesity in obese mice and humans. The increasing trend of Mir802 preceded the accumulation of macrophages. Adipose tissue-specific knockout of Mir802 lowered macrophage infiltration and ameliorated systemic insulin resistance. Conversely, the specific overexpression of Mir802 in adipose tissue aggravated adipose inflammation in mice fed a high-fat diet. Mechanistically, Mir802 activates noncanonical and canonical NF-κB pathways by targeting its negative regulator, TRAF3. Next, NF-κB orchestrated the expression of chemokines and SREBP1, leading to strong recruitment and M1-like polarization of macrophages. Our findings indicate that Mir802 endows adipose tissue with the ability to recruit and polarize macrophages, which underscores Mir802 as an innovative and attractive candidate for miRNA-based immune therapy for adipose inflammation.

Keywords:  immunology; inflammation; mouse

DOI:  https://doi.org/10.7554/eLife.99162
Metabolites. 2024 Nov 17. pii: 634. [Epub ahead of print]14(11):

Modulation of Urea Transport Attenuates TLR2-Mediated Microglial Activation and Upregulates Microglial Metabolism In Vitro.

Najlaa A Al-Thani, Dylan Zinck, Gavin S Stewart, Derek A Costello.

  Background: Alzheimer's disease (AD) is a neurodegenerative disorder traditionally characterised by the presence of amyloid beta (Aβ) plaques and neurofibrillary tau tangles in the brain. However, emerging research has highlighted additional metabolic hallmarks of AD pathology. These include the metabolic reprogramming of microglia in favour of glycolysis over oxidative phosphorylation. This shift is attributed to an 'M1'-like pro-inflammatory phenotype, which exacerbates neuroinflammation and contributes to neuronal damage. The urea cycle also presents as an altered metabolic pathway in AD, due to elevated urea levels and altered expression of urea cycle enzymes, metabolites, and transporters in the brain. However, to date, these changes remain largely unexplored. Methods: This study focuses on understanding the effects of extracellular urea and urea transporter-B (UT-B) inhibition on inflammatory changes in lipoteichoic acid (LTA)-stimulated BV2 microglia and on the viability of SH-SY5Y neuronal cells under oxidative stress and neurotoxic conditions. Results: In BV2 microglia, UT-B inhibition demonstrated a notable anti-inflammatory effect by reducing the formation of nitric oxide (NO) and the expression of tumour necrosis factor α (TNFα) and CCL2 in response to stimulation with the toll-like receptor (TLR)2 agonist, lipoteichoic acid (LTA). This was accompanied by a reduction in extracellular urea and upregulation of UT-B expression. The application of exogenous urea was also shown to mediate the inflammatory profile of BV2 cells in a similar manner but had only a modest impact on UT-B expression. While exposure to LTA alone did not alter the microglial metabolic profile, inhibition of UT-B upregulated the expression of genes associated with both glycolysis and fatty acid oxidation. Conversely, neither increased extracellular urea nor UT-B inhibition had a significant impact on cell viability or cytotoxicity in SH-SY5Y neurones exposed to oxidative stressors tert-butyl hydroperoxide (t-BHP) and 6-hydroxydopamine (6-OHDA). Conclusions: This study further highlights the involvement of urea transport in regulating the neuroinflammation associated with AD. Moreover, we reveal a novel role for UT-B in maintaining microglial metabolic homeostasis. Taken together, these findings contribute supporting evidence to the regulation of UT-B as a therapeutic target for intervention into neuroinflammatory and neurodegenerative disease.

Keywords:  6-OHDA; UT-B; lipoteichoic acid; neuroinflammation; nitric oxide; oxidative stress; tBHP; urea

DOI:  https://doi.org/10.3390/metabo14110634
Adv Sci (Weinh). 2024 Nov 25. e2409310

Calcium Channel Blocker Lacidipine Promotes Antitumor Immunity by Reprogramming Tryptophan Metabolism.

Yuwen Sheng, Chong Qiao, Zhonghui Zhang, Xiaoke Shi, Linhan Yang, Ruiying Xi, Jialing Yu, Wanli Liu, Guolin Zhang, Fei Wang.

  Dysfunction of calcium channels is involved in the development and progression of some cancers. However, it remains unclear the role of calcium channel inhibitors in tumor immunomodulation. Here, calcium channel blocker lacidipine is identified to potently inhibit the enzymatic activity and expression of indoleamine 2,3-dioxygenase 1 (IDO1), a rate-limiting enzyme in tryptophan metabolism. Lacidipine activates effector T cells and incapacitates regulatory T cells (Tregs) to augment the anti-tumor effect of chemotherapeutic agents in breast cancer by converting immunologically "cold" into "hot" tumors. Mechanistically, lacidipine targets calcium channels (CaV1.2/1.3) to inhibit Pyk2-JAK1-calmodulin complex-mediated IDO1 transcription suppression, which suppresses the kynurenine pathway and maintains the total nicotinamide adenine dinucleotide (NAD) pool by regulating NAD biosynthesis. These results reveal a new function of calcium channels in IDO1-mediated tryptophan metabolism in tumor immunity and warrant further development of lacidipine for the metabolic immunotherapy in breast cancer.

Keywords:  breast cancer; calcium channel; immunotherapy; indoleamine 2, 3‐dioxygenase; lacidipine

DOI:  https://doi.org/10.1002/advs.202409310
Mol Biol Cell. 2024 Nov 27. mbcE24060283

Salmonella-induced cholesterol accumulation in infected macrophages suppresses autophagy via mTORC1 activation.

Holly M Torsilieri, Clint M Upchurch, Norbert Leitinger, James E Casanova.

Salmonella enterica serovar Typhimurium is a Gram-negative bacillus that infects the host intestinal epithelium and resident macrophages. Many intracellular pathogens induce an autophagic response in host cells but have evolved mechanisms to subvert that response. Autophagy is closely linked to cellular cholesterol levels; mTORC1 senses increased cholesterol in lysosomal membranes, leading to its hyperactivity and suppression of autophagy. Previous studies indicate that Salmonella infection induces dramatic accumulation of cholesterol in macrophages, a fraction of which localizes to Salmonella containing vacuoles (SCVs). We previously reported that the bacterial effector protein SseJ triggers cholesterol accumulation through a signaling cascade involving Focal Adhesion Kinase (FAK) and Akt. Here we show that mTORC1 is recruited to SCVs and is hyperactivated in a cholesterol-dependent manner. If cholesterol accumulation is prevented pharmacologically or through mutation of sseJ, autophagy is induced and bacterial survival is attenuated. Notably, the host lipid transfer protein OSBP is also recruited to SCVs and its activity is necessary for both cholesterol transfer to SCVs and mTORC1 activation during infection. Finally, lipidomic analysis of Salmonella-infected macrophages revealed new insights into how Salmonella may manipulate lipid homeostasis to benefit its survival. We propose that S. Typhimurium induces cholesterol accumulation through SseJ to activate mTORC1, preventing autophagic clearance of bacteria. [Media: see text].

DOI: https://doi.org/10.1091/mbc.E24-06-0283
Virulence. 2024 Dec;15(1): 2435381

Xylose utilization promotes Salmonella replication within macrophages and systemic infection in mice.

Xinyue Wang, Yuyang Sun, Houliang Guo, Xiaolin Yan, Shuai Ma, Bin Yang, Lingyan Jiang.

  The intracellular pathogen Salmonella can cause systemic diseases via its survival and replication in host macrophages. Xylose is the second most abundant sugar in nature and Salmonella can use xylose as its sole carbon source for growth. However, whether xylose utilization contributes to the pathogenicity and intracellular growth of Salmonella has not yet been determined. In this study, we observed that the xylose concentration in macrophages increased during Salmonella infection. Moreover, there was an increase in expression of Salmonella xylose catabolic genes (xylA and xylB) and the transcriptional regulatory gene of xylose metabolism (xylR) in macrophages, revealing the possibility of using host-accumulated xylose by Salmonella for intracellular growth. Mutation of either xylAB or xylR reduced Salmonella replication in macrophages and attenuated the colonization of mouse systemic loci (e.g. the liver and spleen), indicating that xylose utilization promotes Salmonella replication within macrophages and systemic infection in mice. Moreover, we found that xylose utilization by intracellular Salmonella was activated by the cAMP-CRP complex upon detection of low glucose levels in the infected macrophages. Collectively, these findings reveal that although the available glucose decreases during infection, Salmonella can use xylose, which accumulates in infected macrophages, as an alternative carbon source to promote intracellular replication and virulence.

Keywords:  Salmonella; intracellular replication; macrophages; virulence; xylose utilization

DOI:  https://doi.org/10.1080/21505594.2024.2435381
Cytotherapy. 2024 Oct 31. pii: S1465-3249(24)00905-8. [Epub ahead of print]

Mesenchymal stromal cells can block palmitate training of macrophages via cyclooxygenase-2 and interleukin-1 receptor antagonist.

Laura M Bitterlich, Courteney Tunstead, Andrew E Hogan, James A Ankrum, Karen English.

  Innate training of macrophages can be beneficial for the clearance of pathogens. However, for certain chronic conditions, innate training can have detrimental effects due to an excessive production of pro-inflammatory cytokines. Obesity is a condition that is associated with a range of increased pro-inflammatory training stimuli including the free fatty acid palmitate. Mesenchymal stromal cells (MSCs) are powerful immunomodulators and known to suppress inflammatory macrophages via a range of soluble factors. We show that palmitate training of murine bone-marrow-derived macrophages and human monocyte-derived macrophages (MDMs) results in an increased production of TNFα and IL-6 upon stimulation with lipopolysaccharide and is associated with epigenetic remodeling. Palmitate training led to metabolic changes, however, MSCs did not alter the metabolic profile of human MDMs. Using a transwell system, we demonstrated that human bone marrow MSCs block palmitate training in both murine and human macrophages suggesting the involvement of secreted factors. MSC disruption of the training process occurs through more than one pathway. Suppression of palmitate-enhanced TNFα production is associated with cyclooxygenase-2 activity in MSCs, while secretion of interleukin-1 receptor antagonist by MSCs is required to suppress palmitate-enhanced IL-6 production in MDMs.

Keywords:  innate training; macrophages; mesenchymal stromal cells; obesity; palmitate

DOI:  https://doi.org/10.1016/j.jcyt.2024.10.011
bioRxiv. 2024 Nov 11. pii: 2024.11.10.622811. [Epub ahead of print]

Cholesterol metabolism and intrabacterial potassium homeostasis are intrinsically related in Mycobacterium tuberculosis.

Yue Chen, Berge Hagopian, Shumin Tan.

Potassium (K + ) is the most abundant intracellular cation, but much remains unknown regarding how K + homeostasis is integrated with other key bacterial biology aspects. Here, we show that K + homeostasis disruption (CeoBC K + uptake system deletion) impedes Mycobacterium tuberculosis (Mtb) response to, and growth in, cholesterol, a critical carbon source during infection, with K + augmenting activity of the Mtb ATPase MceG that is vital for bacterial cholesterol import. Reciprocally, cholesterol directly binds to CeoB, modulating its function, with a residue critical for this interaction identified. Finally, cholesterol binding-deficient CeoB mutant Mtb are attenuated for growth in lipid-rich foamy macrophages and in vivo colonization. Our findings raise the concept of a role for cholesterol as a key co-factor, beyond its role as a carbon source, and illuminate how changes in bacterial intrabacterial K + levels can act as part of the metabolic adaptation critical for bacterial survival and growth in the host.

DOI: https://doi.org/10.1101/2024.11.10.622811
Trends Endocrinol Metab. 2024 Nov 27. pii: S1043-2760(24)00294-7. [Epub ahead of print]

Host metabolic inflammation fueled by bacterial DNA.

Ke Wang, Karina Cunha E Rocha, Houji Qin, Zixuan Zeng, Wei Ying.

  Metabolic diseases, characterized by chronic low-grade inflammation, exhibit a compromised gut barrier allowing the translocation of bacteria-derived products to bloodstream and distant metabolic organs. Bacterial DNA can be detected in metabolic tissues during the onset of these diseases, highlighting its role in the development of metabolic diseases. Extracellular vesicles (EVs) are involved in the delivery of bacterial DNA to the local tissues, and its sensing by the host triggers local and system inflammation. Understanding bacterial DNA translocation and its induced inflammation is crucial in deciphering metabolic disease pathways. Here, we delve into the mechanisms dictating the interaction between host physiology and bacterial DNA, focusing on its origin and delivery, host immune responses against it, and its roles in metabolic disorders.

Keywords:  bacterial DNA; complement immunity; extracellular vesicles; immune response; metabolic diseases; tissue inflammation

DOI:  https://doi.org/10.1016/j.tem.2024.11.003
Viruses. 2024 Nov 13. pii: 1769. [Epub ahead of print]16(11):

Longitudinal 1H NMR-Based Metabolomics in Saliva Unveils Signatures of Transition from Acute to Post-Acute Phase of SARS-CoV-2 Infection.

Luiza Tomé Mendes, Marcos C Gama-Almeida, Desirée Lopes Reis, Ana Carolina Pires E Silva, Rômulo Leão Silva Neris, Rafael Mello Galliez, Terezinha Marta Pereira Pinto Castiñeiras, On Behalf Of The Ufrj Covid-Working Group, Christian Ludwig, Ana Paula Valente, Gilson Costa Dos Santos Junior, Tatiana El-Bacha, Iranaia Assunção-Miranda.

  COVID-19 can range from a mild to severe acute respiratory syndrome and also could result in multisystemic damage. Additionally, many people develop post-acute symptoms associated with immune and metabolic disturbances in response to viral infection, requiring longitudinal and multisystem studies to understand the complexity of COVID-19 pathophysiology. Here, we conducted a 1H Nuclear Magnetic Resonance metabolomics in saliva of symptomatic subjects presenting mild and moderate respiratory symptoms to investigate prospective changes in the metabolism induced after acute-phase SARS-CoV-2 infection. Saliva from 119 donors presenting non-COVID and COVID-19 respiratory symptoms were evaluated in the acute phase (T1) and the post-acute phase (T2). We found two clusters of metabolite fluctuation in the COVID-19 group. Cluster 1, metabolites such as glucose, (CH3)3 choline-related metabolites, 2-hydroxybutyrate, BCAA, and taurine increased in T2 relative to T1, and in cluster 2, acetate, creatine/creatinine, phenylalanine, histidine, and lysine decreased in T2 relative to T1. Metabolic fluctuations in the COVID-19 group were associated with overweight/obesity, vaccination status, higher viral load, and viral clearance of the respiratory tract. Our data unveil metabolic signatures associated with the transition to the post-acute phase of SARS-CoV-2 infection that may reflect tissue damage, inflammatory process, and activation of tissue repair cascade. Thus, they contribute to describing alterations in host metabolism that may be associated with prolonged symptoms of COVID-19.

Keywords:  SARS-CoV-2 infection; long COVID; metabolic fluctuation; metabolome; saliva

DOI:  https://doi.org/10.3390/v16111769
Front Immunol. 2024 ;15 1465448

Longitudinal mitochondrial bioenergetic signatures of blood monocytes and lymphocytes improve during treatment of drug-susceptible pulmonary tuberculosis patients Monocyte/lymphocyte bioenergetic signatures post-TB treatment.

Bridgette M Cumming, Kelvin W Addicott, Fernanda Maruri, Vanessa Pillay, Rukaya Asmal, Sashen Moodley, Beatriz Barreto-Durate, Mariana Araújo-Pereira, Matilda Mazibuko, Zoey Mhlane, Nikiwe Mbatha, Khadija Khan, Senamile Makhari, Farina Karim, Lauren Peetluk, Alexander S Pym, Mahomed Yunus S Moosa, Yuri F van der Heijden, Timothy S Sterling, Bruno B Andrade, Alasdair Leslie, Adrie J C Steyn.

  The impact of human pulmonary tuberculosis (TB) on the bioenergetic metabolism of circulating immune cells remains elusive, as does the resolution of these effects with TB treatment. In this study, the rates of oxidative phosphorylation (OXPHOS) and glycolysis in circulating lymphocytes and monocytes of patients with drug-susceptible TB at diagnosis, 2 months, and 6 months during treatment, and 12 months after diagnosis were investigated using extracellular flux analysis. At diagnosis, the bioenergetic parameters of both blood lymphocytes and monocytes of TB patients were severely impaired in comparison to non-TB and non-HIV-infected controls. However, most bioenergetic parameters were not affected by HIV status or glycemic index. Treatment of TB patients restored the % spare respiratory capacity (%SRC) of the circulating lymphocytes to that observed in non-TB and non-HIV infected controls by 12 months. Treatment also improved the maximal respiration of circulating lymphocytes and the %SRC of circulating monocytes of the TB patients. Notably, the differential correlation of the clinical and bioenergetic parameters of the monocytes and lymphocytes from the controls and TB patients at baseline and month 12 was consistent with improved metabolic health and resolution of inflammation following successful TB treatment. Network analysis of the bioenergetic parameters of circulating immune cells with serum cytokine levels indicated a highly coordinated immune response at month 6. These findings underscore the importance of metabolic health in combating TB, supporting the need for further investigation of the bioenergetic immunometabolism associated with TB infection for novel therapeutic approaches aimed at bolstering cellular energetics to enhance immune responses and expedite recovery in TB patients.

Keywords:  Seahorse XF96; TB treatment; bioenergetic metabolism; cytokines; lymphocytes; monocytes; tuberculosis

DOI:  https://doi.org/10.3389/fimmu.2024.1465448
Nutrients. 2024 Nov 07. pii: 3826. [Epub ahead of print]16(22):

Adipocyte FGF21 Signaling Defect Aggravated Adipose Tissue Inflammation in Gestational Diabetes Mellitus.

Lun Hua, Yi Yang, Haoqi Zhang, Xuemei Jiang, Chao Jin, Bin Feng, Lianqiang Che, Shengyu Xu, Yan Lin, De Wu, Yong Zhuo.

  Gestational diabetes mellitus (GDM) is associated with increased inflammation in adipose tissues. Fibroblast growth factor 21 (FGF21) is an endocrine hormone which signals to multiple tissues to regulate metabolism. However, its role in GDM remains largely unknown. In this study, we found that impaired FGF21 signaling in GDM correlates with worsened inflammation and insulin resistance in white adipose tissues in mice. Mechanistically, the pregnancy-related upregulation of FGF21 signaling in adipocytes promotes the differentiation of regulatory T cells (Tregs), which are critical for reducing pregnancy-induced adipose tissue inflammation. The anti-inflammatory effects of FGF21 may involve linolenic acid-mediated PGE2 synthesis in adipocytes. These findings underscore FGF21's role in mediating crosstalk between mature adipocytes and immune cells in white adipose tissue and suggest that targeting FGF21 signaling and its downstream metabolites could offer a potential therapeutic approach for GDM in humans.

Keywords:  FGF21; PGE2; Tregs; adipose tissues inflammation; gestational diabetes mellitus

DOI:  https://doi.org/10.3390/nu16223826
Drug Resist Updat. 2024 Nov 23. pii: S1368-7646(24)00133-X. [Epub ahead of print]78 101175

Blockade of purine metabolism reverses macrophage immunosuppression and enhances anti-tumor immunity in non-small cell lung cancer.

Li Yang, Aitian Li, Weina Yu, Huishang Wang, Lei Zhang, Dan Wang, Ying Wang, Ru Zhang, Qingyang Lei, Zhangnan Liu, Shanshan Zhen, Haiming Qin, Yaqing Liu, Yang Yang, Xian-Lu Song, Yi Zhang.

   AIMS: Immune checkpoint blockade therapy is not effective in most patients with non-small cell lung cancer (NSCLC) due to the immunosuppressive tumor microenvironment. Macrophages are key components of tumor-infiltrating immune cells and play a critical role in immunosuppression, which can be mediated by cell-intrinsic metabolism. This study aimed to evaluate whether macrophages regulate NSCLC progression through metabolic crosstalk with cancer cells and affect immunotherapy efficacy.
METHODS: The macrophage landscape of NSCLC tissues were analyzed by single-cell sequencing and verified through flow cytometry and immunofluorescence. Multiplex assay, single-cell sequencing data, ELISA, immunofluorescence, and RNA-seq et al. were used to investigate and verify the mechanism of macrophage-mediated metabolic regulation on immunosuppression. The tumor-bearing model was established in C57BL/6 J mice to explore in vivo efficacy.
RESULTS: We found that tumor tissue-derived macrophages exhibited an anti-inflammatory phenotype and had a prognostic value for NSCLC. NSCLC cell-secreted CXCL8 recruited macrophages from peritumor tissues to tumor sites and promoted programmed death-ligand 1 (PD-L1) expression by activating purine metabolism with increasing xanthine dehydrogenase and uric acid production. Moreover, purine metabolism-mediated macrophage immunosuppression was dependent on NLRP3/caspase-1/IL-1β signaling. Blockade of purine metabolism signaling enhanced anti-tumor immunity and the efficacy of anti-PD-L1 therapy.
CONCLUSIONS: Collectively, our findings reveal a key role of purine metabolism in macrophage immunosuppression and suggest that blockade of purine metabolism combined with immune checkpoint blockade could provide synergistic effects in NSCLC treatment.

Keywords:  CXCL8; Immune checkpoint; NSCLC; Purine metabolism; TAMs

DOI:  https://doi.org/10.1016/j.drup.2024.101175
J Exp Med. 2025 Jan 06. pii: e20232055. [Epub ahead of print]222(1):

Succinate-producing microbiota drives tuft cell hyperplasia to protect against Clostridioides difficile.

Tasia D Kellogg, Simona Ceglia, Benedikt M Mortzfeld, Tanvi M Tanna, Abigail L Zeamer, Matthew R Mancini, Sage E Foley, Doyle V Ward, Shakti K Bhattarai, Beth A McCormick, Andrea Reboldi, Vanni Bucci.

The role of microbes and their metabolites in modulating tuft cell (TC) dynamics in the large intestine and the relevance of this pathway to infections is unknown. Here, we uncover that microbiome-driven colonic TC hyperplasia protects against Clostridioides difficile infection. Using selective antibiotics, we demonstrate increased type 2 cytokines and TC hyperplasia in the colon but not in the ileum. We demonstrate the causal role of the microbiome in modulating this phenotype using fecal matter transplantation and administration of consortia of succinate-producing bacteria. Administration of succinate production-deficient microbes shows a reduced response in a Pou2f3-dependent manner despite similar intestinal colonization. Finally, antibiotic-treated mice prophylactically administered with succinate-producing bacteria show increased protection against C. difficile-induced morbidity and mortality. This effect is nullified in Pou2f3-/- mice, confirming that the protection occurs via the TC pathway. We propose that activation of TCs by the microbiota in the colon is a mechanism evolved by the host to counterbalance microbiome-derived cues that facilitate invasion by pathogens.

DOI: https://doi.org/10.1084/jem.20232055