bims-imicid 2023-08-06 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2023–08–06
28 papers selected by
Dylan Ryan, University of Cambridge

Ketolysis drives CD8+ T cell effector function through effects on histone acetylation.
Negative regulation of pro-apoptotic AMPK/JNK pathway by itaconate in mice with fulminant liver injury.
Extracellular vesicles in COVID-19 convalescence can regulate T cell metabolism and function.
Targeting abnormal lipid metabolism of T cells for systemic lupus erythematosus treatment.
1-Oleoyl-lysophosphatidylethanolamine stimulates RORγt activity in TH17 cells.
Enolase represents a metabolic checkpoint controlling the differential exhaustion programmes of hepatitis virus-specific CD8+ T cells.
Sulfur metabolic response in macrophage limits excessive inflammatory response by creating a negative feedback loop.
Apolipoprotein E deficiency potentiates macrophage against Staphylococcus aureus in mice with osteomyelitis via regulating cholesterol metabolism.
Ncoa2 promotes CD8+ T cell-mediated anti-tumor immunity by stimulating T-cell activation via upregulation of PGC-1α critical for mitochondrial function.
End-binding protein 1 regulates the metabolic fate of CD4+ T lymphoblasts and Jurkat T cells and the organization of the mitochondrial network.
SLC15A4 controls endolysosomal TLR7-9 responses by recruiting the innate immune adaptor TASL.
GSDMA3 deficiency reprograms cellular metabolism and modulates BCR signaling in murine B cells.
Macrophage metabolism reprogramming EGCG-Cu coordination capsules delivered in polyzwitterionic hydrogel for burn wound healing and regeneration.
Arginase 2 Promotes Cisplatin-Induced Acute Kidney Injury by the Inflammatory Response of Macrophages.
The immunosuppressive activity of myeloid-derived suppressor cells in murine Paracoccidioidomycosis relies on Indoleamine 2,3-dioxygenase activity and Dectin-1 and TLRs signaling.
Mycobacterium tuberculosis Rv2653 protein promotes inflammation response by enhancing glycolysis.
Discovery of a novel small molecule with efficacy in protecting against inflammation in vitro and in vivo by enhancing macrophages activation.
Transaldolase inhibits CD36 expression by modulating glutathione-p38 signaling, exerting protective effects against macrophage foam cell formation.
Lipocalin-2 promotes adipose-macrophage interactions to shape peripheral and central inflammatory responses in experimental autoimmune encephalomyelitis.
Mitochondrial Lon protease promotes CD4+ T cell activation by activating the cGAS-STING-TBK1 axis in systemic lupus erythematosus.
Monoacylglycerol lipase reprograms hepatocytes and macrophages to promote liver regeneration.
Targeting of SLC25A22 boosts the immunotherapeutic response in KRAS-mutant colorectal cancer.
Lysosome blockade induces divergent metabolic programs in macrophages and tumours for cancer immunotherapy.
Microbial energy metabolism fuels an intestinal macrophage niche in solitary isolated lymphoid tissues through purinergic signaling.
2-hydroxyglutarate rides the cancer-immunity cycle.
SLC38A5 aggravates DC-mediated psoriasiform skin inflammation via potentiating lysosomal acidification.
Artificial cells delivering itaconic acid induce anti-inflammatory memory-like macrophages to reverse acute liver failure and prevent reinjury.
Metabolomics acts as a powerful tool for comprehensively evaluating vaccines approved under emergency: a CoronaVac retrospective study.

Immunity. 2023 Jul 20. pii: S1074-7613(23)00314-X. [Epub ahead of print]

Ketolysis drives CD8+ T cell effector function through effects on histone acetylation.

Katarzyna M Luda, Joseph Longo, Susan M Kitchen-Goosen, Lauren R Duimstra, Eric H Ma, McLane J Watson, Brandon M Oswald, Zhen Fu, Zachary Madaj, Ariana Kupai, Bradley M Dickson, Lisa M DeCamp, Michael S Dahabieh, Shelby E Compton, Robert Teis, Irem Kaymak, Kin H Lau, Daniel P Kelly, Patrycja Puchalska, Kelsey S Williams, Connie M Krawczyk, Dominique Lévesque, François-Michel Boisvert, Ryan D Sheldon, Scott B Rothbart, Peter A Crawford, Russell G Jones.

  Environmental nutrient availability influences T cell metabolism, impacting T cell function and shaping immune outcomes. Here, we identified ketone bodies (KBs)-including β-hydroxybutyrate (βOHB) and acetoacetate (AcAc)-as essential fuels supporting CD8+ T cell metabolism and effector function. βOHB directly increased CD8+ T effector (Teff) cell cytokine production and cytolytic activity, and KB oxidation (ketolysis) was required for Teff cell responses to bacterial infection and tumor challenge. CD8+ Teff cells preferentially used KBs over glucose to fuel the tricarboxylic acid (TCA) cycle in vitro and in vivo. KBs directly boosted the respiratory capacity and TCA cycle-dependent metabolic pathways that fuel CD8+ T cell function. Mechanistically, βOHB was a major substrate for acetyl-CoA production in CD8+ T cells and regulated effector responses through effects on histone acetylation. Together, our results identify cell-intrinsic ketolysis as a metabolic and epigenetic driver of optimal CD8+ T cell effector responses.

Keywords:  CD8(+) T cells; TCA cycle; acetyl-CoA; cancer immunology; effector function; epigenetics; ketolysis; ketone bodies; metabolism

DOI:  https://doi.org/10.1016/j.immuni.2023.07.002
Cell Death Dis. 2023 07 31. 14(7): 486

Negative regulation of pro-apoptotic AMPK/JNK pathway by itaconate in mice with fulminant liver injury.

Kerui Fan, Kun Chen, Xinyan Zan, Ying Zhi, Xue Zhang, Xinyue Zhang, Jinghuan Qiu, Gang Liu, Longjiang Li, Li Tang, Kai Hu, Jingyuan Wan, Xianqiong Gong, Yongqiang Yang, Li Zhang.

Accumulating evidence indicates that metabolic responses are deeply integrated into signal transduction, which provides novel opportunities for the metabolic control of various disorders. Recent studies suggest that itaconate, a highly concerned bioactive metabolite catalyzed by immune responsive gene 1 (IRG1), is profoundly involved in the regulation of apoptosis, but the underlying mechanisms have not been fully understood. In the present study, the molecular mechanisms responsible for the apoptosis-modulatory activities of IRG1/itaconate have been investigated in mice with lipopolysaccharide (LPS)/D-galactosamine (D-Gal)-induced apoptotic liver injury. The results indicated that LPS/D-Gal exposure upregulated the level of IRG1 and itaconate. Deletion of IRG1 resulted in exacerbated hepatocytes apoptosis and liver injury. The phospho-antibody microarray analysis and immunoblot analysis indicated that IRG1 deletion enhanced the activation of AMP-activated protein kinase (AMPK)/c-jun-N-terminal kinase (JNK) pathway in LPS/D-Gal exposed mice. Mechanistically, IRG1 deficiency impaired the anti-oxidative nuclear factor erythroid-2 related factor 2 (Nrf2) signaling and then enhanced the activation of the redox-sensitive AMPK/JNK pathway that promotes hepatocytes apoptosis. Importantly, post-insult supplementation with 4-octyl itaconate (4-OI), a cell-permeable derivate of itaconate, resulted in beneficial outcomes in fulminant liver injury. Therefore, IRG1/itaconate might function as a negative regulator that controls AMPK-induced hepatocyte apoptosis in LPS/D-Gal-induced fulminant liver injury.

DOI: https://doi.org/10.1038/s41419-023-06001-w
iScience. 2023 Aug 18. 26(8): 107280

Extracellular vesicles in COVID-19 convalescence can regulate T cell metabolism and function.

Molly S George, Jenifer Sanchez, Christina Rollings, David Fear, Peter Irving, Linda V Sinclair, Anna Schurich.

  Long-term T cell dysregulation has been reported following COVID-19 disease. Prolonged T cell activation is associated with disease severity and may be implicated in producing long-covid symptoms. Here, we assess the role of extracellular vesicles (EV) in regulating T cell function over several weeks post COVID-19 disease. We find that alterations in cellular origin and protein content of EV in COVID-19 convalescence are linked to initial disease severity. We demonstrate that convalescent donor-derived EV can alter the function and metabolic rewiring of CD4 and CD8 T cells. Of note, EV following mild, but not severe disease, show distinctly immune-suppressive properties, reducing T cell effector cytokine production and glucose metabolism. Mechanistically our data indicate the involvement of EV-surface ICAM-1 in facilitating EV-T cell interaction. Our data demonstrate that circulatory EV are phenotypically and functionally altered several weeks following acute infection, suggesting a role for EV as long-term immune modulators.

Keywords:  Immunology; Virology

DOI:  https://doi.org/10.1016/j.isci.2023.107280
Biomed Pharmacother. 2023 Aug 01. pii: S0753-3322(23)00989-7. [Epub ahead of print]165 115198

Targeting abnormal lipid metabolism of T cells for systemic lupus erythematosus treatment.

Jia-Qin Hu, Yan-Hua Yan, Han Xie, Xue-Bing Feng, Wei-Hong Ge, Hua Zhou, Li-Li Yu, Ling-Yun Sun, Ying Xie.

  Systemic lupus erythematosus (SLE) is an autoimmune disease in which the immune system attacks its own tissues and organs. However, the causes of SLE remain unknown. Dyslipidemia is a common symptom observed in SLE patients and animal models and is closely correlated to disease activity. Lipid metabolic reprogramming has been considered as a hallmark of the dysfunction of T cells in patients with SLE, therefore, manipulating lipid metabolism provides a potential therapeutic target for treating SLE. A better understanding of the underlying mechanisms for the metabolic events of immune cells under pathological conditions is crucial for tuning immunometabolism to manage autoimmune diseases such as SLE. In this review, we aim to summarize the cross-link between lipid metabolism and the function of T cells as well as the underlying mechanisms, and provide light on the novel therapeutic strategies of active compounds from herbals for the treatment of SLE by targeting lipid metabolism in immune cells.

Keywords:  Dyslipidemia, systemic lupus erythematosus; Immune cells; Lipid metabolism; Potential therapeutic target

DOI:  https://doi.org/10.1016/j.biopha.2023.115198
Sci Immunol. 2023 Aug 04. 8(86): eadd4346

1-Oleoyl-lysophosphatidylethanolamine stimulates RORγt activity in TH17 cells.

Yusuke Endo, Toshio Kanno, Takahiro Nakajima, Kazutaka Ikeda, Yoshitaka Taketomi, Satoru Yokoyama, Shigemi Sasamoto, Hikari K Asou, Keisuke Miyako, Yoshinori Hasegawa, Yusuke Kawashima, Osamu Ohara, Makoto Murakami, Toshinori Nakayama.

Metabolic fluxes involving fatty acid biosynthesis play essential roles in controlling the differentiation of T helper 17 (TH17) cells. However, the exact enzymes and lipid metabolites involved, as well as their link to promoting the core gene transcriptional signature required for the differentiation of TH17 cells, remain largely unknown. From a pooled CRISPR-based screen and unbiased lipidomics analyses, we identified that 1-oleoyl-lysophosphatidylethanolamine could act as a lipid modulator of retinoid-related orphan receptor gamma t (RORγt) activity in TH17 cells. In addition, we specified five enzymes, including Gpam, Gpat3, Lplat1, Pla2g12a, and Scd2, suggestive of the requirement of glycerophospholipids with monounsaturated fatty acids being required for the transcription of Il17a. 1-Oleoyl-lysophosphatidylethanolamine was reduced in Pla2g12a-deficient TH17 cells, leading to the abolition of interleukin-17 (IL-17) production and disruption to the core transcriptional program required for the differentiation of TH17 cells. Furthermore, mice with T cell-specific deficiency of Pla2g12a failed to develop disease in an experimental autoimmune encephalomyelitis model of multiple sclerosis. Thus, our data indicate that 1-oleoyl-lysophosphatidylethanolamine is a lipid metabolite that promotes RORγt-induced TH17 cell differentiation and the pathogenicity of TH17 cells.

DOI: https://doi.org/10.1126/sciimmunol.add4346
Gut. 2023 Aug 04. pii: gutjnl-2022-328734. [Epub ahead of print]

Enolase represents a metabolic checkpoint controlling the differential exhaustion programmes of hepatitis virus-specific CD8+ T cells.

Frances Winkler, Anna V Hipp, Carlos Ramirez, Bianca Martin, Matteo Villa, Emilia Neuwirt, Oliver Gorka, Jeroen Aerssens, Susanne E Johansson, Nisha Rana, Sian Llewellyn-Lacey, David A Price, Marcus Panning, Olaf Groß, Erika L Pearce, Carl M Hermann, Kathrin Schumann, Luciana Hannibal, Christoph Neumann-Haefelin, Tobias Boettler, Percy Knolle, Maike Hofmann, Dirk Wohlleber, Robert Thimme, Bertram Bengsch.

   OBJECTIVE: Exhausted T cells with limited effector function are enriched in chronic hepatitis B and C virus (HBV and HCV) infection. Metabolic regulation contributes to exhaustion, but it remains unclear how metabolism relates to different exhaustion states, is impacted by antiviral therapy, and if metabolic checkpoints regulate dysfunction.
DESIGN: Metabolic state, exhaustion and transcriptome of virus-specific CD8+ T cells from chronic HBV-infected (n=31) and HCV-infected patients (n=52) were determined ex vivo and during direct-acting antiviral (DAA) therapy. Metabolic flux and metabolic checkpoints were tested in vitro. Intrahepatic virus-specific CD8+ T cells were analysed by scRNA-Seq in a HBV-replicating murine in vivo model of acute and chronic infection.
RESULTS: HBV-specific (core18-27, polymerase455-463) and HCV-specific (NS31073-1081, NS31406-1415, NS5B2594-2602) CD8+ T cell responses exhibit heterogeneous metabolic profiles connected to their exhaustion states. The metabolic state was connected to the exhaustion profile rather than the aetiology of infection. Mitochondrial impairment despite intact glucose uptake was prominent in severely exhausted T cells linked to elevated liver inflammation in chronic HCV infection and in HBV polymerase455-463 -specific CD8+ T cell responses. In contrast, relative metabolic fitness was observed in HBeAg-negative HBV infection in HBV core18-27-specific responses. DAA therapy partially improved mitochondrial programmes in severely exhausted HCV-specific T cells and enriched metabolically fit precursors. We identified enolase as a metabolic checkpoint in exhausted T cells. Metabolic bypassing improved glycolysis and T cell effector function. Similarly, enolase deficiency was observed in intrahepatic HBV-specific CD8+ T cells in a murine model of chronic infection.
CONCLUSION: Metabolism of HBV-specific and HCV-specific T cells is strongly connected to their exhaustion severity. Our results highlight enolase as metabolic regulator of severely exhausted T cells. They connect differential bioenergetic fitness with distinct exhaustion subtypes and varying liver disease, with implications for therapeutic strategies.

Keywords:  alpha beta T cells; chronic viral hepatitis; hepatitis B; hepatitis C; immunology in hepatology

DOI:  https://doi.org/10.1136/gutjnl-2022-328734
Redox Biol. 2023 Jul 29. pii: S2213-2317(23)00235-5. [Epub ahead of print]65 102834

Sulfur metabolic response in macrophage limits excessive inflammatory response by creating a negative feedback loop.

Haruna Takeda, Shohei Murakami, Zun Liu, Tomohiro Sawa, Masatomo Takahashi, Yoshihiro Izumi, Takeshi Bamba, Hideyo Sato, Takaaki Akaike, Hiroki Sekine, Hozumi Motohashi.

  The excessive inflammatory response of macrophages plays a vital role in the pathogenesis of various diseases. The dynamic metabolic alterations in macrophages, including amino acid metabolism, are known to orchestrate their inflammatory phenotype. To explore a new metabolic pathway that regulates the inflammatory response, we examined metabolome changes in mouse peritoneal macrophages (PMs) in response to lipopolysaccharide (LPS) and found a coordinated increase of cysteine and its related metabolites, suggesting an enhanced demand for cysteine during the inflammatory response. Because Slc7a11, which encodes a cystine transporter xCT, was remarkably upregulated upon the pro-inflammatory challenge and found to serve as a major channel of cysteine supply, we examined the inflammatory behavior of Slc7a11 knockout PMs (xCT-KO PMs) to clarify an impact of the increased cysteine demand on inflammation. The xCT-KO PMs exhibited a prolonged upregulation of pro-inflammatory genes, which was recapitulated by cystine depletion in the culture media of wild-type PMs, suggesting that cysteine facilitates the resolution of inflammation. Detailed analysis of the sulfur metabolome revealed that supersulfides, such as cysteine persulfide, were increased in PMs in response to LPS, which was abolished in xCT-KO PMs. Supplementation of N-acetylcysteine tetrasulfide (NAC-S2), a supersulfide donor, attenuated the pro-inflammatory gene expression in xCT-KO PMs. Thus, activated macrophages increase cystine uptake via xCT and produce supersulfides, creating a negative feedback loop to limit excessive inflammation. Our study highlights the finely tuned regulation of macrophage inflammatory response by sulfur metabolism.

Keywords:  Cysteine; Inflammation; LPS; Macrophage; Persulfide; xCT

DOI:  https://doi.org/10.1016/j.redox.2023.102834
Front Cell Infect Microbiol. 2023 ;13 1187543

Apolipoprotein E deficiency potentiates macrophage against Staphylococcus aureus in mice with osteomyelitis via regulating cholesterol metabolism.

Mincheng Lu, Ruiyi He, Chao Li, Zixian Liu, Yuhui Chen, Bingsheng Yang, Xianrong Zhang, Bin Yu.

   Introduction: Staphylococcus aureus (S. aureus) osteomyelitis causes a variety of metabolism disorders in microenvironment and cells. Defining the changes in cholesterol metabolism and identifying key factors involved in cholesterol metabolism disorders during S. aureus osteomyelitis is crucial to understanding the mechanisms of S. aureus osteomyelitis and is important in designing host-directed therapeutic strategies.
Methods: In this study, we conducted in vitro and in vivo experiments to define the effects of S. aureus osteomyelitis on cholesterol metabolism, as well as the role of Apolipoprotein E (ApoE) in regulating cholesterol metabolism by macrophages during S. aureus osteomyelitis.
Results: The data from GSE166522 showed that cholesterol metabolism disorder was induced by S. aureus osteomyelitis. Loss of cholesterol from macrophage obtained from mice with S. aureus osteomyelitis was detected by liquid chromatography-tandem mass spectrometry(LC-MS/MS), which is consistent with Filipin III staining results. Changes in intracellular cholesterol content influenced bactericidal capacity of macrophage. Subsequently, it was proven by gene set enrichment analysis and qPCR, that ApoE played a key role in developing cholesterol metabolism disorder in S. aureus osteomyelitis. ApoE deficiency in macrophages resulted in increased resistance to S. aureus. ApoE-deficient mice manifested abated bone destruction and decreased bacteria load. Moreover, the combination of transcriptional analysis, qPCR, and killing assay showed that ApoE deficiency led to enhanced cholesterol biosynthesis in macrophage, ameliorating anti-infection ability.
Conclusion: We identified a previously unrecognized role of ApoE in S. aureus osteomyelitis from the perspective of metabolic reprogramming. Hence, during treating S. aureus osteomyelitis, considering cholesterol metabolism as a potential therapeutic target presents a new research direction.

Keywords:  Apolipoprotein E; Staphylococcus aureus; cholesterol metabolism; infection; macrophages; osteomyelitis

DOI:  https://doi.org/10.3389/fcimb.2023.1187543
Cancer Immunol Res. 2023 Aug 04. pii: CIR-23-0092. [Epub ahead of print]

Ncoa2 promotes CD8+ T cell-mediated anti-tumor immunity by stimulating T-cell activation via upregulation of PGC-1α critical for mitochondrial function.

Xiancai Zhong, Hongmin Wu, Ching Ouyang, Wencan Zhang, Yun Shi, Yi-Chang Wang, David K Ann, Yousang Gwack, Weirong Shang, Zuoming Sun.

Nuclear receptor coactivator 2 (Ncoa2) is a member of the Ncoa family of co-activators, and we previously showed that Ncoa2 regulates the differentiation of induced regulatory T cells. However, it remains unknown if Ncoa2 plays a role in CD8+ T-cell function. Here, we show that Ncoa2 promotes CD8+ T cell-mediated immune responses against tumors by stimulating T-cell activation via upregulating PGC-1α expression to enhance mitochondrial function. Mice deficient in Ncoa2 in T cells (Ncoa2fl/fl/CD4Cre) displayed defective immune responses against implanted MC38 tumors, which associated with significantly reduced tumor-infiltrating CD8+ T cells and decreased IFNγ production. Consistently, CD8+ T cells from Ncoa2fl/fl/CD4Cre mice failed to reject tumors after adoptive transfer into Rag1-/- mice. Further, in response to TCR stimulation, Ncoa2fl/fl/CD4Cre CD8+ T cells failed to increase mitochondrial mass, showed impaired oxidative phosphorylation, and had lower expression of PGC-1α, a master regulator of mitochondrial biogenesis and function. Mechanically, T cell activation-induced phosphorylation of CREB triggered the recruitment of Ncoa2 to bind to enhancers, thus, stimulating PGC-1α expression. Forced expression of PGC-1α in Ncoa2fl/fl/CD4Cre CD8+ T cells restored mitochondrial function, T-cell activation, IFNγ production, and anti-tumor immunity. This work informs the development of Ncoa2-based therapies that modulate CD8+ T cell-mediated anti-tumor immune responses.

DOI: https://doi.org/10.1158/2326-6066.CIR-23-0092
Front Immunol. 2023 ;14 1197289

End-binding protein 1 regulates the metabolic fate of CD4+ T lymphoblasts and Jurkat T cells and the organization of the mitochondrial network.

Álvaro Gómez-Morón, Silvia Requena, Clara Pertusa, Marta Lozano-Prieto, Diego Calzada-Fraile, Camila Scagnetti, Inés Sánchez-García, Ana Adela Calero-García, Manuel Izquierdo, Noa B Martín-Cófreces.

  The organization of the mitochondrial network is relevant for the metabolic fate of T cells and their ability to respond to TCR stimulation. This arrangement depends on cytoskeleton dynamics in response to TCR and CD28 activation, which allows the polarization of the mitochondria through their change in shape, and their movement along the microtubules towards the immune synapse. This work focus on the role of End-binding protein 1 (EB1), a protein that regulates tubulin polymerization and has been previously identified as a regulator of intracellular transport of CD3-enriched vesicles. EB1-interferred cells showed defective intracellular organization and metabolic strength in activated T cells, pointing to a relevant connection of the cytoskeleton and metabolism in response to TCR stimulation, which leads to increased AICD. By unifying the organization of the tubulin cytoskeleton and mitochondria during CD4+ T cell activation, this work highlights the importance of this connection for critical cell asymmetry together with metabolic functions such as glycolysis, mitochondria respiration, and cell viability.

Keywords:  EB1; T cell receptor; cell asymmetry; cytoskeleton; glycolysis; mitochondria

DOI:  https://doi.org/10.3389/fimmu.2023.1197289
Cell Rep. 2023 Jul 31. pii: S2211-1247(23)00927-0. [Epub ahead of print]42(8): 112916

SLC15A4 controls endolysosomal TLR7-9 responses by recruiting the innate immune adaptor TASL.

Haobo Zhang, Léa Bernaleau, Maeva Delacrétaz, Ed Hasanovic, Ales Drobek, Hermann Eibel, Manuele Rebsamen.

  Endolysosomal Toll-like receptors (TLRs) play crucial roles in immune responses to pathogens, while aberrant activation of these pathways is associated with autoimmune diseases, including systemic lupus erythematosus (SLE). The endolysosomal solute carrier family 15 member 4 (SLC15A4) is required for TLR7/8/9-induced responses and disease development in SLE models. SLC15A4 has been proposed to affect TLR7-9 activation through its transport activity, as well as by assembling an IRF5-activating complex with TASL, but the relative contribution of these functions remains unclear. Here, we show that the essential role of SLC15A4 is to recruit TASL to endolysosomes, while its transport activity is dispensable when TASL is tethered to this compartment. Endolysosomal-localized TASL rescues TLR7-9-induced IRF5 activation as well as interferon β and cytokine production in SLC15A4-deficient cells. SLC15A4 acts as signaling scaffold, and this function is essential to control TLR7-9-mediated inflammatory responses. These findings support targeting the SLC15A4-TASL complex as a potential therapeutic strategy for SLE and related diseases.

Keywords:  CP: Immunology; IRF5; SLC15A4; SLE; TASL; Toll-like receptors; autoimmunity; lysosome

DOI:  https://doi.org/10.1016/j.celrep.2023.112916
iScience. 2023 Aug 18. 26(8): 107341

GSDMA3 deficiency reprograms cellular metabolism and modulates BCR signaling in murine B cells.

Fei Guan, Xi Luo, Ju Liu, Yanmei Huang, Qi Liu, Jiang Chang, Guofeng Fang, Danqing Kang, Heng Gu, Li Luo, Lu Yang, Zhaoyu Lin, Xiang Gao, Chaohong Liu, Jiahui Lei.

  Metabolism plays a crucial role in B cell differentiation and function. GSDMA3 is related to mitochondrial metabolism and is involved in immune responses. Here, we used Gsdma3 KO mice to examine the effect of GSDMA3 on B cells. The results demonstrated that GSDMA3 deficiency reprogrammed B cell metabolism, evidenced by upregulating PI3K-Akt-mTOR signaling, along with elevated ROS reproduction and reduced maximal oxygen consumption rate in mitochondria. Moreover, the BCR signaling in the KO B cells was impaired. The reduced BCR signaling was associated with decreased BCR clustering, caused by inhibited activation of WASP. However, GSDMA3 deficiency had no effects on B cell development and functions in humoral immunity, which might be associated with the compensation of upregulated GSDMA2 expression and the fine balance between PI3K signaling and BCR signals interaction. Our observations reveal a previously unknown influence of GSDMA3 on B cells under physiological and immunized states.

Keywords:  Biological sciences; Immunology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2023.107341
Bioact Mater. 2023 Nov;29 251-264

Macrophage metabolism reprogramming EGCG-Cu coordination capsules delivered in polyzwitterionic hydrogel for burn wound healing and regeneration.

Qinghua Li, Huijuan Song, Shuangyang Li, Pengbo Hu, Chuangnian Zhang, Ju Zhang, Zujian Feng, Deling Kong, Weiwei Wang, Pingsheng Huang.

  Excessive reactive oxygen species (ROS) at severe burn injury sites may promote metabolic reprogramming of macrophages to induce a deteriorative and uncontrolled inflammation cycle, leading to delayed wound healing and regeneration. Here, a novel bioactive, anti-fouling, flexible polyzwitterionic hydrogel encapsulated with epigallocatechin gallate (EGCG)-copper (Cu) capsules (termed as EGCG-Cu@CBgel) is engineered for burn wound management, which is dedicated to synergistically exerting ROS-scavenging, immune metabolic regulation and pro-angiogenic effects. EGCG-Cu@CBgel can scavenge ROS to normalize intracellular redox homeostasis, effectively relieving oxidative damages and blocking proinflammatory signal transduction. Importantly, EGCG-Cu can inhibit the activity of hexokinase and phosphofructokinase, alleviate accumulation of pyruvate and convert it to acetyl coenzyme A (CoA), whereby inhibits glycolysis and normalizes tricarboxylic acid (TCA) cycle. Additionally, metabolic reprogramming of macrophages by EGCG-Cu downregulates M1-type polarization and the expression of proinflammatory cytokines both in vitro and in vivo. Meanwhile, copper ions (Cu2+) released from the hydrogel facilitate angiogenesis. EGCG-Cu@CBgel significantly accelerates the healing of severe burn wound via promoting wound closure, weakening tissue-damaging inflammatory responses and enhancing the remodeling of pathological structure. Overall, this study demonstrates the great potential of bioactive hydrogel dressing in treating burn wounds without unnecessary secondary damage to newly formed skin, and highlights the importance of immunometabolism modulation in tissue repair and regeneration.

Keywords:  Burn wound healing; EGCG-Cu capsule; Hydrogel dressing; Metabolic reprogramming; ROS scavenging

DOI:  https://doi.org/10.1016/j.bioactmat.2023.07.011
Lab Invest. 2023 Aug 02. pii: S0023-6837(23)00170-8. [Epub ahead of print] 100227

Arginase 2 Promotes Cisplatin-Induced Acute Kidney Injury by the Inflammatory Response of Macrophages.

Yushi Uchida, Kumiko Torisu, Seishi Aihara, Noriyuki Imazu, Hiroaki Ooboshi, Takanari Kitazono, Toshiaki Nakano.

  Acute kidney injury (AKI) is a complex clinical syndrome with a rapid decrease in renal function caused by several different etiologies, including sepsis, ischemia, and the administration of nephrotoxic drugs. Tubular arginase 2 (ARG2), an arginine-metabolic enzyme, is a potential therapeutic target for AKI, but it has not been confirmed under various AKI conditions. The aim of this study was to investigate ARG2 as a therapeutic target for cisplatin-induced AKI. Cisplatin-treated mice with a genetic deficiency in Arg2 had a significant amelioration of renal dysfunction, characterized by decreased acute tubular damage and apoptosis. In contrast, cisplatin-induced tubular toxicity was not ameliorated in proximal tubule cells derived from Arg2-deficient mice. Immunohistochemical analysis demonstrated the increased infiltration of ARG2-positive macrophages in kidneys damaged by cisplatin. Importantly, cisplatin-treated Arg2 knockout mice exhibited a significant reduction in kidney inflammation, characterized by the decreased infiltration of inflammatory macrophages and reduced gene expression of interleukin-6 (IL-6) and interleukin-1β (IL-1β). The secretion of IL-6 and IL-1β induced by lipopolysaccharide was decreased in bone marrow-derived macrophages isolated from Arg2-deficient mice. Furthermore, the lipopolysaccharide-induced elevation of mitochondrial membrane potential and production of reactive oxygen species were reduced in bone marrow-derived macrophages lacking Arg2. These findings indicate that ARG2 promotes the inflammatory responses of macrophages through mitochondrial reactive oxygen species, resulting in the exacerbation of AKI. Therefore, targeting ARG2 in macrophages may constitute a promising therapeutic approach for AKI.

Keywords:  acute kidney injury; arginase 2; cisplatin; macrophage

DOI:  https://doi.org/10.1016/j.labinv.2023.100227
Sci Rep. 2023 07 31. 13(1): 12391

The immunosuppressive activity of myeloid-derived suppressor cells in murine Paracoccidioidomycosis relies on Indoleamine 2,3-dioxygenase activity and Dectin-1 and TLRs signaling.

Valéria de Lima Kaminski, Nycolas Willian Preite, Bruno Montanari Borges, Bianca Vieira Dos Santos, Vera Lucia Garcia Calich, Flávio Vieira Loures.

Paracoccidioidomycosis (PCM) is a systemic mycosis with a high incidence in Latin America. Prior studies have demonstrated the significance of the enzyme Indoleamine 2,3-dioxygenase (IDO-1) in the immune regulation of PCM as well as the vital role of myeloid-derived suppressor cells (MDSCs) in moderating PCM severity. Additionally, Dectin-1 and Toll-Like Receptors (TLRs) signaling in cancer, infection, and autoimmune diseases have been shown to impact MDSC-IDO-1+ activity. To expand our understanding of MDSCs and the role of IDO-1 and pattern recognition receptors (PRRs) signaling in PCM, we generated MDSCs in vitro and administered an IDO-1 inhibitor before challenging the cells with Paracoccidioides brasiliensis yeasts. By co-culturing MDSCs with lymphocytes, we assessed T-cell proliferation to examine the influence of IDO-1 on MDSC activity. Moreover, we utilized specific antibodies and MDSCs from Dectin-1, TLR4, and TLR2 knockout mice to evaluate the effect of these PRRs on IDO-1 production by MDSCs. We confirmed the importance of these in vitro findings by assessing MDSC-IDO-1+ in the lungs of mice following the fungal infection. Taken together, our data show that IDO-1 expression by MDSCs is crucial for the control of T-cell proliferation, and the production of this enzyme is partially dependent on Dectin-1, TLR2, and TLR4 signaling during murine PCM.

DOI: https://doi.org/10.1038/s41598-023-39262-8
Jpn J Infect Dis. 2023 Jul 31.

Mycobacterium tuberculosis Rv2653 protein promotes inflammation response by enhancing glycolysis.

Yaman Du, Rui Zheng, Hongli Yin, Li Ma, Jingfang Li, Yun Chen, Xi Zhang, Pengzuo Tao, Lili Gao, Li Yang, Liang He.

  Mycobacterium tuberculosis (M.tb) infection caused communicable disease tuberculosis (TB) is a major cause of ill health and one of the leading causes of death worldwide. Protein encoded by region of deletion (RD) of M.tb mediated the pathogenic properties of M.tb through inducing inflammation response or disrupting host cell metabolism. We cloned and purified Rv2653 protein from RD13 to explore its regulatory effect on host macrophages. We found Rv2653 protein promoted the glycolysis level and upregulated the expression of glycolytic key enzymes HK2 and LDHA of THP1 cells. Furthermore, Rv2653 induced glycolysis contributes to the activation of NLRP3 inflammasome. Rv2653 activated the mTORC1 signaling pathway, and the mTORC1 inhibitor NR1 blocked Rv2653-induced HK2, LDHA and NLRP3 expression. siRNA interfering HK2 or LDHA significantly inhibited the activation of NLRP3 inflammasome by Rv2653, blocked Rv2653 triggered inflammatory factors IL-1β, IL-6, TNF-α, ROS and NO, and promoted the survival of BCG in THP1 cells. Altogether, Rv2653 promotes the glycolysis process by activating mTORC1 signaling pathway, activates NLRP3 inflammasome and the release of inflammatory factors, ultimately inhibits the intracellular survival of BCG in THP1 cells. Therefore, we revealed Rv2653-induced anti-M.tb immune mechanisms which contributes to the development of new anti-TB strategy.

Keywords:  HK2; LDHA; Mycobacterium tuberculosis; NLRP3; Rv2653

DOI:  https://doi.org/10.7883/yoken.JJID.2022.647
Biomed Pharmacother. 2023 Aug 01. pii: S0753-3322(23)01064-8. [Epub ahead of print]165 115273

Discovery of a novel small molecule with efficacy in protecting against inflammation in vitro and in vivo by enhancing macrophages activation.

Cui Zhang, Zheng Cao, Hehua Lei, Chuan Chen, Ruichen Du, Yuchen Song, Ce Zhang, Jinlin Zhou, Yujing Lu, Luodong Huang, Peihong Shen, Limin Zhang.

  Immune response and inflammation highly contribute to many metabolic syndromes such as inflammatory bowel disease (IBD), ageing and cancer with disruption of host metabolic homeostasis and the gut microbiome. Icariin-1 (GH01), a small-molecule flavonoid derived from Epimedium, has been shown to protect against systemic inflammation. However, the molecular mechanisms by which GH01 ameliorates ulcerative colitis via regulation of microbiota-mediated macrophages polarization remain elusive. In this study, we found that GH01 effectively ameliorated dextran sulfate sodium (DSS)-induced colitis symptoms in mice. Disruption of intestinal barrier function, commensal microbiota and its metabolites were also significantly restored by GH01 in a dose-dependent manner. Of note, we also found that GH01 enhanced phagocytic ability of macrophages and switched macrophage phenotype from M1 to M2 both in vitro and in vivo. Such macrophage polarization was highly associated with intestinal barrier integrity and the gut microbial community. Consequently, GH01 exhibited strong anti-inflammatory capacity by inhibiting TLR4 and NF-κB pathways and proinflammatory factors (IL-6). These findings suggested that GH01 might be a potential nutritional intervention strategy for IBD treatment with the gut microbial community-meditated macrophage as the therapeutic targets.

Keywords:  Gut microbial community; Icariin-1; Intestinal inflammation; Macrophage phenotype; Ulcerative colitis

DOI:  https://doi.org/10.1016/j.biopha.2023.115273
Acta Biochim Biophys Sin (Shanghai). 2023 Aug 01.

Transaldolase inhibits CD36 expression by modulating glutathione-p38 signaling, exerting protective effects against macrophage foam cell formation.

Chengyi Li, Zihao Song, Pengyue Gao, Wei Duan, Xiu Liu, Sijia Liang, Quan Gong, Jiawei Guo.

  In atherosclerosis, macrophage-derived foam cell formation is considered to be a hallmark of the pathological process; this occurs via the uptake of modified lipoproteins. In the present study, we aim to determine the role of transaldolase in foam cell formation and atherogenesis and reveal the mechanisms underlying its role. Bone marrow-derived macrophages (BMDMs) isolated from mice successfully form foam cells after treatment with oxidized low-density lipoprotein (80 μg/mL). Elevated transaldolase levels in the foam cell model are assessed by quantitative polymerase chain reaction and western blot analysis. Transaldolase overexpression and knockdown in BMDMs are achieved via plasmid transfection and small interfering RNA technology, respectively. We find that transaldolase overexpression effectively attenuates, whereas transaldolase knockdown accelerates, macrophage-derived foam cell formation through the inhibition or activation of cholesterol uptake mediated by the scavenger receptor cluster of differentiation 36 (CD36) in a p38 mitogen-activated protein kinase (MAPK) signaling-dependent manner. Transaldolase-mediated glutathione (GSH) homeostasis is identified as the upstream regulator of p38 MAPK-mediated CD36-dependent cholesterol uptake in BMDMs. Transaldolase upregulates GSH production, thereby suppressing p38 activity and reducing the CD36 level, ultimately preventing foam cell formation and atherosclerosis. Thus, our findings indicate that the transaldolase-GSH-p38-CD36 axis may represent a promising therapeutic target for atherosclerosis.

Keywords:  CD36; GSH; foam cell formation; p38 MAPK; transaldolase

DOI:  https://doi.org/10.3724/abbs.2023146
Mol Metab. 2023 Jul 28. pii: S2212-8778(23)00117-5. [Epub ahead of print] 101783

Lipocalin-2 promotes adipose-macrophage interactions to shape peripheral and central inflammatory responses in experimental autoimmune encephalomyelitis.

Francesca Sciarretta, Veronica Ceci, Marta Tiberi, Fabio Zaccaria, Haoyun Li, Zhong-Yan Zhou, Qiyang Sun, Daniels Konja, Alessandro Matteocci, Anup Bhusal, Martina Verri, Diego Fresegna, Sara Balletta, Andrea Ninni, Marco Rosina, Kyoungho Suk, Diego Centonze, Yu Wang, Valerio Chiurchiù, Katia Aquilano, Daniele Lettieri-Barbato.

  Accumulating evidence suggests that dysfunctional adipose tissue (AT) plays a major role in the risk of developing multiple sclerosis (MS), the most common immune-mediated and demyelinating disease of the central nervous system. However, the contribution of adipose tissue to the etiology and progression of MS is still obscure. This study aimed at deciphering the responses of AT in experimental autoimmune encephalomyelitis (EAE), the best characterized animal model of MS. We observed a significant AT loss in EAE mice at the onset of disease, with a significant infiltration of M1-like macrophages and fibrosis in the AT, resembling a cachectic phenotype. Through an integrative and multilayered approach, we identified lipocalin2 (LCN2) as the key molecule released by dysfunctional adipocytes through redox-dependent mechanism. Adipose-derived LCN2 shapes the pro-inflammatory macrophage phenotype, and the genetic deficiency of LCN2 specifically in AT reduced weight loss as well as inflammatory macrophage infiltration in spinal cord in EAE mice. Mature adipocytes downregulating LCN2 reduced lipolytic response to inflammatory stimuli (e.g. TNFα) through an ATGL-mediated mechanism. Overall data highlighted a role LCN2 in exacerbating inflammatory phenotype in EAE model, suggesting a pathogenic role of dysfunctional AT in MS.

Keywords:  adipocyte; adipose tissue; cachexia; immune cells; lipid metabolism; macrophages; mitochondria

DOI:  https://doi.org/10.1016/j.molmet.2023.101783
Int Immunopharmacol. 2023 Jul 31. pii: S1567-5769(23)00842-1. [Epub ahead of print]123 110519

Mitochondrial Lon protease promotes CD4+ T cell activation by activating the cGAS-STING-TBK1 axis in systemic lupus erythematosus.

Xiangyang Huang, Yi Liu, Guanghui Ling, Xin Cao.

  Systemic lupus erythematosus (SLE) is an autoimmune disease in which autoreactive CD4+ T cells play an essential role. We extracted CD4+ T cells from SLE-prone Fcgr2b-/- mice to elaborate the mechanism of mitochondrial Lon protease in CD4+ T cell activation in SLE. Transcriptome sequencing was performed in SLE-prone Fcgr2b-/- mice, and the stimulator of interferon gene (STING) related to SLE was obtained. It was demonstrated that STING expression was elevated in CD4+ T cells in SLE-prone Fcgr2b-/- mice. The downstream genes and pathways of STING were predicted by GO and KEGG approaches. The data indicated that STING regulated IFN signaling to promote CD4+ T cell activation in SLE-prone Fcgr2b-/- mice. Next, the interaction of cGAS, STING, TBK1, and IFN-I was verified by Co-IP assay. Moreover, the roles of cGAS, STING, and TBK1 in activating CD4+ T cells from SLE-prone Fcgr2b-/- mice were evaluated using gain- or loss-of-function experiments. Mechanistically, cGAS upregulated the IFN-I signaling pathway by directly interacting with STING and TBK1, contributing to CD4+ T cell activation. Besides, cytosolic mtDNA could activate CD4+ T cell activation in SLE-prone Fcgr2b-/- mice by upregulating the cGAS-STING-TBK1 axis. The function of mitochondrial Lon protease in oxidative damage and mtDNA release in CD4+ T cells of SLE-prone Fcgr2b-/- mice were explored. Mitochondrial Lon protease enhanced mtDNA release into the cytoplasm under oxidative stress. Collectively, our work indicates that mitochondrial Lon protease enhances CD4+ T cell activation by inducing mtDNA leakage and offers new candidate targets for developing diagnostic and therapeutic strategies.

Keywords:  CD4(+) T cells; Mitochondrial Lon protease; Systemic lupus erythematosus; Type I interferon; cGAS-STING-TBK1; mtDNA

DOI:  https://doi.org/10.1016/j.intimp.2023.110519
JHEP Rep. 2023 Aug;5(8): 100794

Monoacylglycerol lipase reprograms hepatocytes and macrophages to promote liver regeneration.

Manon Allaire, Rola Al Sayegh, Morgane Mabire, Adel Hammoutene, Matthieu Siebert, Charles Caër, Mathilde Cadoux, JingHong Wan, Aida Habib, Maude Le Gall, Pierre de la Grange, Hervé Guillou, Catherine Postic, Valérie Paradis, Sophie Lotersztajn, Hélène Gilgenkrantz.

   Background & Aims: Liver regeneration is a repair process in which metabolic reprogramming of parenchymal and inflammatory cells plays a major role. Monoacylglycerol lipase (MAGL) is an ubiquitous enzyme at the crossroad between lipid metabolism and inflammation. It converts monoacylglycerols into free fatty acids and metabolises 2-arachidonoylglycerol into arachidonic acid, being thus the major source of pro-inflammatory prostaglandins in the liver. In this study, we investigated the role of MAGL in liver regeneration.
Methods: Hepatocyte proliferation was studied in vitro in hepatoma cell lines and ex vivo in precision-cut human liver slices. Liver regeneration was investigated in mice treated with a pharmacological MAGL inhibitor, MJN110, as well as in animals globally invalidated for MAGL (MAGL-/-) and specifically invalidated in hepatocytes (MAGLHep-/-) or myeloid cells (MAGLMye-/-). Two models of liver regeneration were used: acute toxic carbon tetrachloride injection and two-thirds partial hepatectomy. MAGLMye-/- liver macrophages profiling was analysed by RNA sequencing. A rescue experiment was performed by in vivo administration of interferon receptor antibody in MAGLMye-/- mice.
Results: Precision-cut human liver slices from patients with chronic liver disease and human hepatocyte cell lines exposed to MJN110 showed reduced hepatocyte proliferation. Mice with global invalidation or mice treated with MJN110 showed blunted liver regeneration. Moreover, mice with specific deletion of MAGL in either hepatocytes or myeloid cells displayed delayed liver regeneration. Mechanistically, MAGLHep-/- mice showed reduced liver eicosanoid production, in particular prostaglandin E2 that negatively impacts on hepatocyte proliferation. MAGL inhibition in macrophages resulted in the induction of the type I interferon pathway. Importantly, neutralising the type I interferon pathway restored liver regeneration of MAGLMye-/- mice.
Conclusions: Our data demonstrate that MAGL promotes liver regeneration by hepatocyte and macrophage reprogramming.
Impact and Implications: By using human liver samples and mouse models of global or specific cell type invalidation, we show that the monoacylglycerol pathway plays an essential role in liver regeneration. We unveil the mechanisms by which MAGL expressed in both hepatocytes and macrophages impacts the liver regeneration process, via eicosanoid production by hepatocytes and the modulation of the macrophage interferon pathway profile that restrains hepatocyte proliferation.

Keywords:  Injury; MAGL; Proliferation; Wound healing

DOI:  https://doi.org/10.1016/j.jhepr.2023.100794
Nat Commun. 2023 Aug 04. 14(1): 4677

Targeting of SLC25A22 boosts the immunotherapeutic response in KRAS-mutant colorectal cancer.

Qiming Zhou, Yao Peng, Fenfen Ji, Huarong Chen, Wei Kang, Lam-Shing Chan, Hongyan Gou, Yufeng Lin, Pingmei Huang, Danyu Chen, Qinyao Wei, Hao Su, Cong Liang, Xiang Zhang, Jun Yu, Chi Chun Wong.

KRAS is an important tumor intrinsic factor driving immune suppression in colorectal cancer (CRC). In this study, we demonstrate that SLC25A22 underlies mutant KRAS-induced immune suppression in CRC. In immunocompetent male mice and humanized male mice models, SLC25A22 knockout inhibits KRAS-mutant CRC tumor growth with reduced myeloid derived suppressor cells (MDSC) but increased CD8+ T-cells, implying the reversion of mutant KRAS-driven immunosuppression. Mechanistically, we find that SLC25A22 plays a central role in promoting asparagine, which binds and activates SRC phosphorylation. Asparagine-mediated SRC promotes ERK/ETS2 signaling, which drives CXCL1 transcription. Secreted CXCL1 functions as a chemoattractant for MDSC via CXCR2, leading to an immunosuppressive microenvironment. Targeting SLC25A22 or asparagine impairs KRAS-induced MDSC infiltration in CRC. Finally, we demonstrate that the targeting of SLC25A22 in combination with anti-PD1 therapy synergizes to inhibit MDSC and activate CD8+ T cells to suppress KRAS-mutant CRC growth in vivo. We thus identify a metabolic pathway that drives immunosuppression in KRAS-mutant CRC.

DOI: https://doi.org/10.1038/s41467-023-39571-6
J Exp Clin Cancer Res. 2023 Aug 04. 42(1): 192

Lysosome blockade induces divergent metabolic programs in macrophages and tumours for cancer immunotherapy.

Jing Ma, Ruijuan Ma, Xueke Zeng, Liming Zhang, Jianing Liu, Wei Zhang, Tao Li, Hanjing Niu, Guochen Bao, Chaojie Wang, Peng George Wang, Jiajia Wang, Xia Li, Taotao Zou, Songqiang Xie.

BACKGROUND: Platinum-drugs based chemotherapy in clinic increases the potency of tumor cells to produce M2 macrophages, thus leading to poor anti-metastatic activity and immunosuppression. Lysosome metabolism is critical for cancer cell migration and invasion, but how it promotes antitumor immunity in tumours and macrophages is poorly understood and the underlying mechanisms are elusive. The present study aimed to explore a synergistic strategy to dismantle the immunosuppressive microenvironment of tumours and metallodrugs discovery by using the herent metabolic plasticity.
METHODS: Naphplatin was prepared by coordinating an active alkaline moiety to cisplatin, which can regulate the lysosomal functions. Colorectal carcinoma cells were selected to perform the in vivo biological assays. Blood, tumour and spleen tissues were collected and analyzed by flow cytometry to further explore the relationship between anti-tumour activity and immune cells. Transformations of bone marrow derived macrophage (BMDM) and M2-BMDM to the M1 phenotype was confirmed after treatment with naphplatin. The key mechanisms of lysosome-mediated mucolipin-1(Mcoln1) and mitogen-activated protein kinase (MAPK) activation in M2 macrophage polarization have been unveiled. RNA sequencing (RNA-seq) was used to further explore the key mechanism underlying high-mobility group box 1(HMGB1)-mediated Cathepsin L(CTSL)-lysosome function blockade.
RESULTS: We demonstrated that naphplatin induces divergent lysosomal metabolic programs and reprograms macrophages in tumor cells to terminate the vicious tumour-associated macrophages (TAMs)-MDSCs-Treg triangle. Mechanistically, macrophages treated with naphplatin cause lysosome metabolic activation by triggering Ca2+ release via Mcoln1, which induces the activation of p38 and nuclear factor-κB (NF-κB) and finally results in polarizing M2 macrophages. In contrast, HMGB1-mediated lysosome metabolic blockade in cancer cells is strongly linked to antitumor effects by promoting cytoplasmic translocation of HMGB1.
CONCLUSIONS: This study reveals the crucial strategies of macrophage-based metallodrugs discovery that are able to treat both immunologically "hot" and "cold" cancers. Different from traditional platinum-based antitumour drugs by inhibition of DNAs, we also deliver a strong antitumour strategy by targeting lysosome to induce divergent metabolic programs in macrophages and tumours for cancer immunotherapy.

DOI: https://doi.org/10.1186/s13046-023-02768-0
Sci Immunol. 2023 Aug 04. 8(86): eabq4573

Microbial energy metabolism fuels an intestinal macrophage niche in solitary isolated lymphoid tissues through purinergic signaling.

Pailin Chiaranunt, Kyle Burrows, Louis Ngai, Siu Ling Tai, Eric Y Cao, Helen Liang, Homaira Hamidzada, Anthony Wong, Julia Gschwend, Pascal Flüchter, Meggie Kuypers, Tijana Despot, Abdul Momen, Sung Min Lim, Thierry Mallevaey, Christoph Schneider, Tyrrell Conway, Hiromi Imamura, Slava Epelman, Arthur Mortha.

Maintaining macrophage (MΦ) heterogeneity is critical to ensure intestinal tissue homeostasis and host defense. The gut microbiota and host factors are thought to synergistically guide intestinal MΦ development, although the exact nature, regulation, and location of such collaboration remain unclear. Here, we report that microbial biochemical energy metabolism promotes colony-stimulating factor 2 (CSF2) production by group 3 innate lymphoid cells (ILC3s) within solitary isolated lymphoid tissues (SILTs) in a cell-extrinsic, NLRP3/P2X7R-dependent fashion in the steady state. Tissue-infiltrating monocytes accumulating around SILTs followed a spatially constrained, distinct developmental trajectory into SILT-associated MΦs (SAMs). CSF2 regulated the mitochondrial membrane potential and reactive oxygen species production of SAMs and contributed to the antimicrobial defense against enteric bacterial infections. Collectively, these findings identify SILTs and CSF2-producing ILC3s as a microanatomic niche for intestinal MΦ development and functional programming fueled by the integration of commensal microbial energy metabolism.

DOI: https://doi.org/10.1126/sciimmunol.abq4573
Curr Opin Biotechnol. 2023 Jul 27. pii: S0958-1669(23)00086-1. [Epub ahead of print]83 102976

2-hydroxyglutarate rides the cancer-immunity cycle.

Iosifina P Foskolou, Lukas Bunse, Jan Van den Bossche.

2-hydroxyglutarate (2HG) is a biproduct of the Krebs cycle, which exists in a D- and L- enantiomer and is structurally similar to α-ketoglutarate. Both 2HG enantiomers have been described to accumulate in diverse cancer and immune cells and can influence cell fate and function. While D-2HG was originally considered as an 'oncometabolite' that aberrantly builds up in certain cancers, it is becoming clear that it also physiologically accumulates in immune cells and regulates immune function. Conversely, L-2HG is considered as an 'immunometabolite' due to its induction and regulatory function in T cells, but it can also be induced in certain cancers. Here, the authors review the effects of both 2HG enantiomers on immune cells within the tumor microenvironment.

DOI: https://doi.org/10.1016/j.copbio.2023.102976
Cell Rep. 2023 Aug 01. pii: S2211-1247(23)00921-X. [Epub ahead of print]42(8): 112910

SLC38A5 aggravates DC-mediated psoriasiform skin inflammation via potentiating lysosomal acidification.

Leqing Zhu, Xichun Xia, Guangqiang Li, Chuyun Zhu, Qingqing Li, Baocheng Wang, Nan-Xi Shi, Zhiwei Lei, Shuxian Yang, Zhanpeng Zhang, Haishan Li, Jingyi Tan, Zonghua Liu, Qiong Wen, Hui Zhong, Xue-Jia Lin, Guodong Sun, Xiucong Bao, Qian Wang, Liehua Deng, Lianghua Bin, Guangchao Cao, Zhinan Yin.

  Amino acid (aa) metabolism is closely correlated with the pathogenesis of psoriasis; however, details on aa transportation during this process are barely known. Here, we find that SLC38A5, a sodium-dependent neutral aa transporter that counter-transports protons, is markedly upregulated in the psoriatic skin of both human patients and mouse models. SLC38A5 deficiency significantly ameliorates the pathogenesis of psoriasis, indicating a pathogenic role of SLC38A5. Surprisingly, SLC38A5 is almost exclusively expressed in dendritic cells (DCs) when analyzing the psoriatic lesion and mainly locates on the lysosome. Mechanistically, SLC38A5 potentiates lysosomal acidification, which dictates the cleavage and activation of TLR7 with ensuing production of pro-inflammatory cytokines such as interleukin-23 (IL-23) and IL-1β from DCs and eventually aggravates psoriatic inflammation. In summary, this work uncovers an auxiliary mechanism in driving lysosomal acidification, provides inspiring insights for DC biology and psoriasis etiology, and reveals SLC38A5 as a promising therapeutic target for treating psoriasis.

Keywords:  CP: Immunology; SLC38A5; dendritic cells; inflammation; lysosomal acidification; psoriasis

DOI:  https://doi.org/10.1016/j.celrep.2023.112910
Cell Rep Med. 2023 Jul 26. pii: S2666-3791(23)00260-4. [Epub ahead of print] 101132

Artificial cells delivering itaconic acid induce anti-inflammatory memory-like macrophages to reverse acute liver failure and prevent reinjury.

Na Yin, Wenjun Zhang, Xiao-Xin Sun, Runxiu Wei, Qiang Yang, Fengming He, Changrui Li, Ling Guo, Min Feng.

  Hepatic macrophages represent a key cellular component of the liver and are essential for the progression of acute liver failure (ALF). We construct artificial apoptotic cells loaded with itaconic acid (AI-Cells), wherein the compositions of the synthetic plasma membrane and surface topology are rationally engineered. AI-Cells are predominantly localized to the liver and further transport to hepatic macrophages. Intravenous administration of AI-Cells modulates macrophage inflammation to protect the liver from acetaminophen-induced ALF. Mechanistically, AI-Cells act on caspase-1 to suppress NLRP3 inflammasome-mediated cleavage of pro-IL-1β into its active form in macrophages. Notably, AI-Cells specifically induce anti-inflammatory memory-like hepatic macrophages in ALF mice, which prevent constitutive overproduction of IL-1β when liver reinjury occurs. In light of AI-Cells' precise delivery and training of memory-like hepatic macrophages, they offer promising therapeutic potential in reversing ALF by finely controlling inflammatory responses and orchestrating liver homeostasis, which potentially affect the treatment of various types of liver failure.

Keywords:  IL-1β; acute liver failure; artificial cells; itaconic acid; memory-like hepatic macrophages

DOI:  https://doi.org/10.1016/j.xcrm.2023.101132
Front Immunol. 2023 ;14 1168308

Metabolomics acts as a powerful tool for comprehensively evaluating vaccines approved under emergency: a CoronaVac retrospective study.

Xinyu Liu, Congshu Xiao, Pengwei Guan, Qianqian Chen, Lei You, Hongwei Kong, Wangshu Qin, Peng Dou, Qi Li, Yanju Li, Ying Jiao, Zhiwei Zhong, Jun Yang, Xiaolin Wang, Qingqing Wang, Jinhui Zhao, Zhiliang Xu, Hong Zhang, Rongkuan Li, Peng Gao, Guowang Xu.

   Introduction: To control the COVID-19 pandemic, great efforts have been made to realize herd immunity by vaccination since 2020. Unfortunately, most of the vaccines against COVID-19 were approved in emergency without a full-cycle and comprehensive evaluation process as recommended to the previous vaccines. Metabolome has a close tie with the phenotype and can sensitively reflect the responses to stimuli, rendering metabolomic analysis have the potential to appraise and monitor vaccine effects authentically.
Methods: In this study, a retrospective study was carried out for 330 Chinese volunteers receiving recommended two-dose CoronaVac, a vaccine approved in emergency in 2020. Venous blood was sampled before and after vaccination at 5 separate time points for all the recipients. Routine clinical laboratory analysis, metabolomic and lipidomic analysis data were collected.
Results and discussion: It was found that the serum antibody-positive rate of this population was around 81.82%. Most of the laboratory parameters were slightly perturbated within the relevant reference intervals after vaccination. The metabolomic and lipidomic analyses showed that the metabolic shift after inoculation was mainly in the glycolysis, tricarboxylic acid cycle, amino acid metabolism, urea cycle, as well as microbe-related metabolism (bile acid metabolism, tryptophan metabolism and phenylalanine metabolism). Time-course metabolome changes were found in parallel with the progress of immunity establishment and peripheral immune cell counting fluctuation, proving metabolomics analysis was an applicable solution to evaluate immune effects complementary to traditional antibody detection. Taurocholic acid, lysophosphatidylcholine 16:0 sn-1, glutamic acid, and phenylalanine were defined as valuable metabolite markers to indicate the establishment of immunity after vaccination. Integrated with the traditional laboratory analysis, this study provided a feasible metabolomics-based solution to relatively comprehensively evaluate vaccines approved under emergency.

Keywords:  COVID-19; CoronaVac; immune response; lipidomics; metabolomics; vaccine

DOI:  https://doi.org/10.3389/fimmu.2023.1168308