bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2024‒05‒19
eighteen papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. Liver ACOX1 regulates levels of circulating lipids that promote metabolic health through adipose remodeling.
  2. Unraveling ETC complex I function in ferroptosis reveals a potential ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.
  3. IRE1α determines ferroptosis sensitivity through regulation of glutathione synthesis.
  4. Dysfunctional adipocytes promote tumor progression through YAP/TAZ-dependent cancer-associated adipocyte transformation.
  5. Glutamine promotes human CD8+ T cells and counteracts imiquimod-induced T cell hyporesponsiveness.
  6. Tuft cell-derived acetylcholine promotes epithelial chloride secretion and intestinal helminth clearance.
  7. CXCL16-dependent scavenging of oxidized lipids by islet macrophages promotes differentiation of pathogenic CD8+ T cells in diabetic autoimmunity.
  8. Classical monocyte ontogeny dictates their functions and fates as tissue macrophages.
  9. Serine synthesis controls mitochondrial biogenesis in macrophages.
  10. One-carbon unit supplementation fuels purine synthesis in tumor-infiltrating T cells and augments checkpoint blockade.
  11. Ironing out the role of ferroptosis in immunity.
  12. Cysteine substitutants emerge in lung cancer proteomes during arginine restriction.
  13. The aged tumor microenvironment limits T cell control of cancer.
  14. SIN-3 transcriptional coregulator maintains mitochondrial homeostasis and polyamine flux.
  15. Recruitment of plasma cells from IL-21-dependent and IL-21-independent immune reactions to the bone marrow.
  16. TREM2 deficiency reprograms intestinal macrophages and microbiota to enhance anti-PD-1 tumor immunotherapy.
  17. Cardiolipin oxidized by ROS from complex II acts as a target of gasdermin D to drive mitochondrial pore and heart dysfunction in endotoxemia.
  18. Spatially distinct epithelial and mesenchymal cell subsets along progressive lineage restriction in the branching embryonic mammary gland.
  1. Nat Commun. 2024 May 17. 15(1): 4214
    Liver ACOX1 regulates levels of circulating lipids that promote metabolic health through adipose remodeling.
    Dongliang Lu, Anyuan He, Min Tan, Marguerite Mrad, Amal El Daibani, Donghua Hu, Xuejing Liu, Brian Kleiboeker, Tao Che, Fong-Fu Hsu, Monika Bambouskova, Clay F Semenkovich, Irfan J Lodhi.
      The liver gene expression of the peroxisomal β-oxidation enzyme acyl-coenzyme A oxidase 1 (ACOX1), which catabolizes very long chain fatty acids (VLCFA), increases in the context of obesity, but how this pathway impacts systemic energy metabolism remains unknown. Here, we show that hepatic ACOX1-mediated β-oxidation regulates inter-organ communication involved in metabolic homeostasis. Liver-specific knockout of Acox1 (Acox1-LKO) protects mice from diet-induced obesity, adipose tissue inflammation, and systemic insulin resistance. Serum from Acox1-LKO mice promotes browning in cultured white adipocytes. Global serum lipidomics show increased circulating levels of several species of ω-3 VLCFAs (C24-C28) with previously uncharacterized physiological role that promote browning, mitochondrial biogenesis and Glut4 translocation through activation of the lipid sensor GPR120 in adipocytes. This work identifies hepatic peroxisomal β-oxidation as an important regulator of metabolic homeostasis and suggests that manipulation of ACOX1 or its substrates may treat obesity-associated metabolic disorders.
    DOI:  https://doi.org/10.1038/s41467-024-48471-2
  2. Mol Cell. 2024 May 16. pii: S1097-2765(24)00324-1. [Epub ahead of print]84(10): 1964-1979.e6
    Unraveling ETC complex I function in ferroptosis reveals a potential ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.
    Chao Mao, Guang Lei, Amber Horbath, Min Wang, Zhengze Lu, Yuelong Yan, Xiaoguang Liu, Lavanya Kondiparthi, Xiong Chen, Jun Cheng, Qidong Li, Zhihao Xu, Li Zhuang, Bingliang Fang, Joseph R Marszalek, Masha V Poyurovsky, Kellen Olszewski, Boyi Gan.
      The role of the mitochondrial electron transport chain (ETC) in regulating ferroptosis is not fully elucidated. Here, we reveal that pharmacological inhibition of the ETC complex I reduces ubiquinol levels while decreasing ATP levels and activating AMP-activated protein kinase (AMPK), the two effects known for their roles in promoting and suppressing ferroptosis, respectively. Consequently, the impact of complex I inhibitors on ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition is limited. The pharmacological inhibition of complex I in LKB1-AMPK-inactivated cells, or genetic ablation of complex I (which does not trigger apparent AMPK activation), abrogates the AMPK-mediated ferroptosis-suppressive effect and sensitizes cancer cells to GPX4-inactivation-induced ferroptosis. Furthermore, complex I inhibition synergizes with radiotherapy (RT) to selectively suppress the growth of LKB1-deficient tumors by inducing ferroptosis in mouse models. Our data demonstrate a multifaceted role of complex I in regulating ferroptosis and propose a ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.
    Keywords:  AMPK; ETC complex I; LKB1; cancer therapy; ferroptosis; lipid peroxidation; mitochondria
    DOI:  https://doi.org/10.1016/j.molcel.2024.04.009
  3. Nat Commun. 2024 May 15. 15(1): 4114
    IRE1α determines ferroptosis sensitivity through regulation of glutathione synthesis.
    Dadi Jiang, Youming Guo, Tianyu Wang, Liang Wang, Yuelong Yan, Ling Xia, Rakesh Bam, Zhifen Yang, Hyemin Lee, Takao Iwawaki, Boyi Gan, Albert C Koong.
      Cellular sensitivity to ferroptosis is primarily regulated by mechanisms mediating lipid hydroperoxide detoxification. We show that inositol-requiring enzyme 1 (IRE1α), an endoplasmic reticulum (ER) resident protein critical for the unfolded protein response (UPR), also determines cellular sensitivity to ferroptosis. Cancer and normal cells depleted of IRE1α gain resistance to ferroptosis, while enhanced IRE1α expression promotes sensitivity to ferroptosis. Mechanistically, IRE1α's endoribonuclease activity cleaves and down-regulates the mRNA of key glutathione biosynthesis regulators glutamate-cysteine ligase catalytic subunit (GCLC) and solute carrier family 7 member 11 (SLC7A11). This activity of IRE1α is independent of its role in regulating the UPR and is evolutionarily conserved. Genetic deficiency and pharmacological inhibition of IRE1α have similar effects in inhibiting ferroptosis and reducing renal ischemia-reperfusion injury in mice. Our findings reveal a previously unidentified role of IRE1α to regulate ferroptosis and suggests inhibition of IRE1α as a promising therapeutic strategy to mitigate ferroptosis-associated pathological conditions.
    DOI:  https://doi.org/10.1038/s41467-024-48330-0
  4. Nat Commun. 2024 May 14. 15(1): 4052
    Dysfunctional adipocytes promote tumor progression through YAP/TAZ-dependent cancer-associated adipocyte transformation.
    Yaechan Song, Heeju Na, Seung Eon Lee, You Min Kim, Jihyun Moon, Tae Wook Nam, Yul Ji, Young Jin, Jae Hyung Park, Seok Chan Cho, Jaehoon Lee, Daehee Hwang, Sang-Jun Ha, Hyun Woo Park, Jae Bum Kim, Han-Woong Lee.
      Obesity has emerged as a prominent risk factor for the development of malignant tumors. However, the existing literature on the role of adipocytes in the tumor microenvironment (TME) to elucidate the correlation between obesity and cancer remains insufficient. Here, we aim to investigate the formation of cancer-associated adipocytes (CAAs) and their contribution to tumor growth using mouse models harboring dysfunctional adipocytes. Specifically, we employ adipocyte-specific BECN1 KO (BaKO) mice, which exhibit lipodystrophy due to dysfunctional adipocytes. Our results reveal the activation of YAP/TAZ signaling in both CAAs and BECN1-deficient adipocytes, inducing adipocyte dedifferentiation and formation of a malignant TME. The additional deletion of YAP/TAZ from BaKO mice significantly restores the lipodystrophy and inflammatory phenotypes, leading to tumor regression. Furthermore, mice fed a high-fat diet (HFD) exhibit decreased BECN1 and increased YAP/TAZ expression in their adipose tissues. Treatment with the YAP/TAZ inhibitor, verteporfin, suppresses tumor progression in BaKO and HFD-fed mice, highlighting its efficacy against mice with metabolic dysregulation. Overall, our findings provide insights into the key mediators of CAA and their significance in developing a TME, thereby suggesting a viable approach targeting adipocyte homeostasis to suppress cancer growth.
    DOI:  https://doi.org/10.1038/s41467-024-48179-3
  5. iScience. 2024 May 17. 27(5): 109767
    Glutamine promotes human CD8+ T cells and counteracts imiquimod-induced T cell hyporesponsiveness.
    Luisa Bopp, Maria Lopéz Martinez, Clara Schumacher, Robert Seitz, Manuel Huerta Arana, Henning Klapproth, Dominika Lukas, Ju Hee Oh, Daniela Neumayer, Jan W Lackmann, Stefan Mueller, Esther von Stebut, Bent Brachvogel, Susanne Brodesser, Ramon I Klein Geltink, Mario Fabri.
      T cells protect tissues from cancer. Although investigations in mice showed that amino acids (AA) critically regulate T cell immunity, this remains poorly understood in humans. Here, we describe the AA composition of interstitial fluids in keratinocyte-derived skin cancers (KDSCs) and study the effect of AA on T cells using models of primary human cells and tissues. Gln contributed to ∼15% of interstitial AAs and promoted interferon gamma (IFN-γ), but not granzyme B (GzB) expression, in CD8+ T cells. Furthermore, the Toll-like receptor 7 agonist imiquimod (IMQ), a common treatment for KDSCs, down-regulated the metabolic gatekeepers c-MYC and mTORC1, as well as the AA transporter ASCT2 and intracellular Gln, Asn, Ala, and Asp in T cells. Reduced proliferation and IFN-γ expression, yet increased GzB, paralleled IMQ effects on AA. Finally, Gln was sufficient to promote IFN-γ-production in IMQ-treated T cells. Our findings indicate that Gln metabolism can be harnessed for treating KDSCs.
    Keywords:  Dermatology; Immunology
    DOI:  https://doi.org/10.1016/j.isci.2024.109767
  6. Immunity. 2024 May 06. pii: S1074-7613(24)00144-4. [Epub ahead of print]
    Tuft cell-derived acetylcholine promotes epithelial chloride secretion and intestinal helminth clearance.
    Tyler E Billipp, Connie Fung, Lily M Webeck, Derek B Sargent, Matthew B Gologorsky, Zuojia Chen, Margaret M McDaniel, Darshan N Kasal, John W McGinty, Kaitlyn A Barrow, Lucille M Rich, Alessio Barilli, Mark Sabat, Jason S Debley, Chuan Wu, Richard Myers, Michael R Howitt, Jakob von Moltke.
      Epithelial cells secrete chloride to regulate water release at mucosal barriers, supporting both homeostatic hydration and the "weep" response that is critical for type 2 immune defense against parasitic worms (helminths). Epithelial tuft cells in the small intestine sense helminths and release cytokines and lipids to activate type 2 immune cells, but whether they regulate epithelial secretion is unknown. Here, we found that tuft cell activation rapidly induced epithelial chloride secretion in the small intestine. This response required tuft cell sensory functions and tuft cell-derived acetylcholine (ACh), which acted directly on neighboring epithelial cells to stimulate chloride secretion, independent of neurons. Maximal tuft cell-induced chloride secretion coincided with immune restriction of helminths, and clearance was delayed in mice lacking tuft cell-derived ACh, despite normal type 2 inflammation. Thus, we have uncovered an epithelium-intrinsic response unit that uses ACh to couple tuft cell sensing to the secretory defenses of neighboring epithelial cells.
    Keywords:  acetylcholine; chloride secretion; helminth infection; intestine; tuft cell; type 2 immunity
    DOI:  https://doi.org/10.1016/j.immuni.2024.03.023
  7. Immunity. 2024 May 06. pii: S1074-7613(24)00222-X. [Epub ahead of print]
    CXCL16-dependent scavenging of oxidized lipids by islet macrophages promotes differentiation of pathogenic CD8+ T cells in diabetic autoimmunity.
    Neetu Srivastava, Hao Hu, Orion J Peterson, Anthony N Vomund, Marta Stremska, Mohammad Zaman, Shilpi Giri, Tiandao Li, Cheryl F Lichti, Pavel N Zakharov, Bo Zhang, Nada A Abumrad, Yi-Guang Chen, Kodi S Ravichandran, Emil R Unanue, Xiaoxiao Wan.
      The pancreatic islet microenvironment is highly oxidative, rendering β cells vulnerable to autoinflammatory insults. Here, we examined the role of islet resident macrophages in the autoimmune attack that initiates type 1 diabetes. Islet macrophages highly expressed CXCL16, a chemokine and scavenger receptor for oxidized low-density lipoproteins (OxLDLs), regardless of autoimmune predisposition. Deletion of Cxcl16 in nonobese diabetic (NOD) mice suppressed the development of autoimmune diabetes. Mechanistically, Cxcl16 deficiency impaired clearance of OxLDL by islet macrophages, leading to OxLDL accumulation in pancreatic islets and a substantial reduction in intra-islet transitory (Texint) CD8+ T cells displaying proliferative and effector signatures. Texint cells were vulnerable to oxidative stress and diminished by ferroptosis; PD-1 blockade rescued this population and reversed diabetes resistance in NOD.Cxcl16-/- mice. Thus, OxLDL scavenging in pancreatic islets inadvertently promotes differentiation of pathogenic CD8+ T cells, presenting a paradigm wherein tissue homeostasis processes can facilitate autoimmune pathogenesis in predisposed individuals.
    Keywords:  CD8 T cell differentiation; CD8 T cell exhaustion; CD8 T cell ferroptosis; CXCL16; PD-1 checkpoint blockade; autoimmunity; oxidized LDL; pancreatic islets; tissue-resident macrophages; type 1 diabetes
    DOI:  https://doi.org/10.1016/j.immuni.2024.04.017
  8. Immunity. 2024 May 10. pii: S1074-7613(24)00224-3. [Epub ahead of print]
    Classical monocyte ontogeny dictates their functions and fates as tissue macrophages.
    Sébastien Trzebanski, Jung-Seok Kim, Niss Larossi, Ayala Raanan, Daliya Kancheva, Jonathan Bastos, Montaser Haddad, Aryeh Solomon, Ehud Sivan, Dan Aizik, Jarmila Sekeresova Kralova, Mor Gross-Vered, Sigalit Boura-Halfon, Tsvee Lapidot, Ronen Alon, Kiavash Movahedi, Steffen Jung.
      Classical monocytes (CMs) are ephemeral myeloid immune cells that circulate in the blood. Emerging evidence suggests that CMs can have distinct ontogeny and originate from either granulocyte-monocyte- or monocyte-dendritic-cell progenitors (GMPs or MDPs). Here, we report surface markers that allowed segregation of murine GMP- and MDP-derived CMs, i.e., GMP-Mo and MDP-Mo, as well as their functional characterization, including fate definition following adoptive cell transfer. GMP-Mo and MDP-Mo yielded an equal increase in homeostatic CM progeny, such as blood-resident non-classical monocytes and gut macrophages; however, these cells differentially seeded various other selected tissues, including the dura mater and lung. Specifically, GMP-Mo and MDP-Mo differentiated into distinct interstitial lung macrophages, linking CM dichotomy to previously reported pulmonary macrophage heterogeneity. Collectively, we provide evidence for the existence of two functionally distinct CM subsets in the mouse that differentially contribute to peripheral tissue macrophage populations in homeostasis and following challenge.
    Keywords:  CM; GMP-Mo; MDP-Mo; dura mater; influenza; lung; macrophages; monocytes; monopoiesis
    DOI:  https://doi.org/10.1016/j.immuni.2024.04.019
  9. Sci Adv. 2024 May 17. 10(20): eadn2867
    Serine synthesis controls mitochondrial biogenesis in macrophages.
    Chuanlong Wang, Muyang Zhao, Peng Bin, Yuyi Ye, Qingyi Chen, Zhiru Tang, Wenkai Ren.
      Mitochondrial dysfunction is the pivotal driving factor of multiple inflammatory diseases, and targeting mitochondrial biogenesis represents an efficacious approach to ameliorate such dysfunction in inflammatory diseases. Here, we demonstrated that phosphoglycerate dehydrogenase (PHGDH) deficiency promotes mitochondrial biogenesis in inflammatory macrophages. Mechanistically, PHGDH deficiency boosts mitochondrial reactive oxygen species (mtROS) by suppressing cytoplasmic glutathione synthesis. mtROS provokes hypoxia-inducible factor-1α signaling to direct nuclear specificity protein 1 and nuclear respiratory factor 1 transcription. Moreover, myeloid Phgdh deficiency reverses diet-induced obesity. Collectively, this study reveals that a mechanism involving de novo serine synthesis orchestrates mitochondrial biogenesis via mitochondrial-to-nuclear communication, and provides a potential therapeutic target for tackling inflammatory diseases and mitochondria-mediated diseases.
    DOI:  https://doi.org/10.1126/sciadv.adn2867
  10. Cell Chem Biol. 2024 May 16. pii: S2451-9456(24)00169-7. [Epub ahead of print]31(5): 932-943.e8
    One-carbon unit supplementation fuels purine synthesis in tumor-infiltrating T cells and augments checkpoint blockade.
    Xincheng Xu, Zihong Chen, Caroline R Bartman, Xi Xing, Kellen Olszewski, Joshua D Rabinowitz.
      Nucleotides perform important metabolic functions, carrying energy and feeding nucleic acid synthesis. Here, we use isotope tracing-mass spectrometry to quantitate contributions to purine nucleotides from salvage versus de novo synthesis. We further explore the impact of augmenting a key precursor for purine synthesis, one-carbon (1C) units. We show that tumors and tumor-infiltrating T cells (relative to splenic or lymph node T cells) synthesize purines de novo. Shortage of 1C units for T cell purine synthesis is accordingly a potential bottleneck for anti-tumor immunity. Supplementing 1C units by infusing formate drives formate assimilation into purines in tumor-infiltrating T cells. Orally administered methanol functions as a formate pro-drug, with deuteration enabling kinetic control of formate production. Safe doses of methanol raise formate levels and augment anti-PD-1 checkpoint blockade in MC38 tumors, tripling durable regressions. Thus, 1C deficiency can gate antitumor immunity and this metabolic checkpoint can be overcome with pharmacological 1C supplementation.
    DOI:  https://doi.org/10.1016/j.chembiol.2024.04.007
  11. Immunity. 2024 May 14. pii: S1074-7613(24)00140-7. [Epub ahead of print]57(5): 941-956
    Ironing out the role of ferroptosis in immunity.
    Hannah N Bell, Brent R Stockwell, Weiping Zou.
      Ferroptosis is a type of regulated cell death that drives the pathophysiology of many diseases. Oxidative stress is detectable in many types of regulated cell death, but only ferroptosis involves lipid peroxidation and iron dependency. Ferroptosis originates and propagates from several organelles, including the mitochondria, endoplasmic reticulum, Golgi, and lysosomes. Recent data have revealed that immune cells can both induce and undergo ferroptosis. A mechanistic understanding of how ferroptosis regulates immunity is critical to understanding how ferroptosis controls immune responses and how this is dysregulated in disease. Translationally, more work is needed to produce ferroptosis-modulating immunotherapeutics. This review focuses on the role of ferroptosis in immune-related diseases, including infection, autoimmune diseases, and cancer. We discuss how ferroptosis is regulated in immunity, how this regulation contributes to disease pathogenesis, and how targeting ferroptosis may lead to novel therapies.
    Keywords:  ACSL4; FSP1; SLC7A11; T cell; apoptosis; cancer therapy; ferroptosis; glutathione; immune checkpoint blockade; interferon; pyroptosis; system xc(-)
    DOI:  https://doi.org/10.1016/j.immuni.2024.03.019
  12. Mol Cell. 2024 May 16. pii: S1097-2765(24)00384-8. [Epub ahead of print]84(10): 1819-1821
    Cysteine substitutants emerge in lung cancer proteomes during arginine restriction.
    Dennis J Hsu, Sohail F Tavazoie.
      In this issue of Molecular Cell, Yang et al.1 find that arginine-to-cysteine substitutants are enriched in a subset of lung cancer proteomes, potentiated by arginine deprivation, and promote resistance to chemotherapy.
    DOI:  https://doi.org/10.1016/j.molcel.2024.04.019
  13. Nat Immunol. 2024 May 14.
    The aged tumor microenvironment limits T cell control of cancer.
    Alex C Y Chen, Sneha Jaiswal, Daniela Martinez, Cansu Yerinde, Keely Ji, Velita Miranda, Megan E Fung, Sarah A Weiss, Maria Zschummel, Kazuhiro Taguchi, Christopher S Garris, Thorsten R Mempel, Nir Hacohen, Debattama R Sen.
      The etiology and effect of age-related immune dysfunction in cancer is not completely understood. Here we show that limited priming of CD8+ T cells in the aged tumor microenvironment (TME) outweighs cell-intrinsic defects in limiting tumor control. Increased tumor growth in aging is associated with reduced CD8+ T cell infiltration and function. Transfer of T cells from young mice does not restore tumor control in aged mice owing to rapid induction of T cell dysfunction. Cell-extrinsic signals in the aged TME drive a tumor-infiltrating age-associated dysfunctional (TTAD) cell state that is functionally, transcriptionally and epigenetically distinct from canonical T cell exhaustion. Altered natural killer cell-dendritic cell-CD8+ T cell cross-talk in aged tumors impairs T cell priming by conventional type 1 dendritic cells and promotes TTAD cell formation. Aged mice are thereby unable to benefit from therapeutic tumor vaccination. Critically, myeloid-targeted therapy to reinvigorate conventional type 1 dendritic cells can improve tumor control and restore CD8+ T cell immunity in aging.
    DOI:  https://doi.org/10.1038/s41590-024-01828-7
  14. iScience. 2024 May 17. 27(5): 109789
    SIN-3 transcriptional coregulator maintains mitochondrial homeostasis and polyamine flux.
    Giovannetti Marina, Rodríguez-Palero María-Jesús, Fabrizio Paola, Nicolle Ophélie, Bedet Cécile, Michaux Grégoire, Witting Michael, Artal-Sanz Marta, Palladino Francesca.
      Mitochondrial function relies on the coordinated transcription of mitochondrial and nuclear genomes to assemble respiratory chain complexes. Across species, the SIN3 coregulator influences mitochondrial functions, but how its loss impacts mitochondrial homeostasis and metabolism in the context of a whole organism is unknown. Exploring this link is important because SIN3 haploinsufficiency causes intellectual disability/autism syndromes and SIN3 plays a role in tumor biology. Here we show that loss of C. elegans SIN-3 results in transcriptional deregulation of mitochondrial- and nuclear-encoded mitochondrial genes, potentially leading to mito-nuclear imbalance. Consistent with impaired mitochondrial function, sin-3 mutants show extensive mitochondrial fragmentation by transmission electron microscopy (TEM) and in vivo imaging, and altered oxygen consumption. Metabolomic analysis of sin-3 mutant animals revealed a mitochondria stress signature and deregulation of methionine flux, resulting in decreased S-adenosyl methionine (SAM) and increased polyamine levels. Our results identify SIN3 as a key regulator of mitochondrial dynamics and metabolic flux, with important implications for human pathologies.
    Keywords:  Cell biology; Omics; Systems biology
    DOI:  https://doi.org/10.1016/j.isci.2024.109789
  15. Nat Commun. 2024 May 17. 15(1): 4182
    Recruitment of plasma cells from IL-21-dependent and IL-21-independent immune reactions to the bone marrow.
    Marta Ferreira-Gomes, Yidan Chen, Pawel Durek, Hector Rincon-Arevalo, Frederik Heinrich, Laura Bauer, Franziska Szelinski, Gabriela Maria Guerra, Ana-Luisa Stefanski, Antonia Niedobitek, Annika Wiedemann, Marina Bondareva, Jacob Ritter, Katrin Lehmann, Sebastian Hardt, Christian Hipfl, Sascha Hein, Eberhard Hildt, Mareen Matz, Henrik E Mei, Qingyu Cheng, Van Duc Dang, Mario Witkowski, Andreia C Lino, Andrey Kruglov, Fritz Melchers, Carsten Perka, Eva V Schrezenmeier, Andreas Hutloff, Andreas Radbruch, Thomas Dörner, Mir-Farzin Mashreghi.
      Bone marrow plasma cells (BMPC) are the correlate of humoral immunity, consistently releasing antibodies into the bloodstream. It remains unclear if BMPC reflect different activation environments or maturation of their precursors. Here we define human BMPC heterogeneity and track the recruitment of antibody-secreting cells (ASC) from SARS-CoV-2 vaccine immune reactions to the bone marrow (BM). Trajectories based on single-cell transcriptomes and repertoires of peripheral and BM ASC reveal sequential colonisation of BMPC compartments. In activated B cells, IL-21 suppresses CD19 expression, indicating that CD19low-BMPC are derived from follicular, while CD19high-BMPC originate from extrafollicular immune reactions. In primary immune reactions, both CD19low- and CD19high-BMPC compartments are populated. In secondary immune reactions, most BMPC are recruited to CD19high-BMPC compartments, reflecting their origin from extrafollicular reactivations of memory B cells. A pattern also observable in vaccinated-convalescent individuals and upon diphtheria/tetanus/pertussis recall-vaccination. Thus, BMPC diversity reflects the evolution of a given humoral immune response.
    DOI:  https://doi.org/10.1038/s41467-024-48570-0
  16. Sci Immunol. 2024 May 17. 9(95): eadi5374
    TREM2 deficiency reprograms intestinal macrophages and microbiota to enhance anti-PD-1 tumor immunotherapy.
    Blanda Di Luccia, Martina Molgora, Darya Khantakova, Natalia Jaeger, Hao-Wei Chang, Rafael S Czepielewski, Beth A Helmink, Emily J Onufer, José L Fachi, Bishan Bhattarai, Tihana Trsan, Patrick F Rodrigues, JinChao Hou, Jennifer K Bando, Cristiane Sécca da Silva, Marina Cella, Susan Gilfillan, Robert D Schreiber, Jeffrey I Gordon, Marco Colonna.
      The gut microbiota and tumor-associated macrophages (TAMs) affect tumor responses to anti-programmed cell death protein 1 (PD-1) immune checkpoint blockade. Reprogramming TAM by either blocking or deleting the macrophage receptor triggering receptor on myeloid cells 2 (TREM2) attenuates tumor growth, and lack of functional TREM2 enhances tumor elimination by anti-PD-1. Here, we found that anti-PD-1 treatment combined with TREM2 deficiency in mice induces proinflammatory programs in intestinal macrophages and a concomitant expansion of Ruminococcus gnavus in the gut microbiota. Gavage of wild-type mice with R. gnavus enhanced anti-PD-1-mediated tumor elimination, recapitulating the effect occurring in the absence of TREM2. A proinflammatory intestinal environment coincided with expansion, increased circulation, and migration of TNF-producing CD4+ T cells to the tumor bed. Thus, TREM2 remotely controls anti-PD-1 immune checkpoint blockade through modulation of the intestinal immune environment and microbiota, with R. gnavus emerging as a potential probiotic agent for increasing responsiveness to anti-PD-1.
    DOI:  https://doi.org/10.1126/sciimmunol.adi5374
  17. Cell Rep. 2024 May 15. pii: S2211-1247(24)00565-5. [Epub ahead of print]43(5): 114237
    Cardiolipin oxidized by ROS from complex II acts as a target of gasdermin D to drive mitochondrial pore and heart dysfunction in endotoxemia.
    Yan Tang, Junru Wu, Xuejing Sun, Shasha Tan, Wenbo Li, Siyu Yin, Lun Liu, Yuanyuan Chen, Yuanyuan Liu, Qian Tan, Youxiang Jiang, Wenjing Yang, Wei Huang, Chunyan Weng, Qing Wu, Yao Lu, Hong Yuan, Qingzhong Xiao, Alex F Chen, Qingbo Xu, Timothy R Billiar, Jingjing Cai.
      Cardiac dysfunction, an early complication of endotoxemia, is the major cause of death in intensive care units. No specific therapy is available at present for this cardiac dysfunction. Here, we show that the N-terminal gasdermin D (GSDMD-N) initiates mitochondrial apoptotic pore and cardiac dysfunction by directly interacting with cardiolipin oxidized by complex II-generated reactive oxygen species (ROS) during endotoxemia. Caspase-4/11 initiates GSDMD-N pores that are subsequently amplified by the upregulation and activation of NLRP3 inflammation through further generation of ROS. GSDMD-N pores form prior to BAX and VDAC1 apoptotic pores and further incorporate into BAX and VDAC1 oligomers within mitochondria membranes to exacerbate the apoptotic process. Our findings identify oxidized cardiolipin as the definitive target of GSDMD-N in mitochondria of cardiomyocytes during endotoxin-induced myocardial dysfunction (EIMD), and modulation of cardiolipin oxidation could be a therapeutic target early in the disease process to prevent EIMD.
    Keywords:  CP: Immunology; cardiolipin; complex II; endotoxin-induced myocardial dysfunction; gasdermin D; mitochondria
    DOI:  https://doi.org/10.1016/j.celrep.2024.114237
  18. EMBO J. 2024 May 17.
    Spatially distinct epithelial and mesenchymal cell subsets along progressive lineage restriction in the branching embryonic mammary gland.
    Claudia Carabaña, Wenjie Sun, Camila Veludo Ramos, Mathilde Huyghe, Meghan Perkins, Aurélien Maillot, Robin Journot, Fatima Hartani, Marisa M Faraldo, Bethan Lloyd-Lewis, Silvia Fre.
      How cells coordinate morphogenetic cues and fate specification during development remains a fundamental question in organogenesis. The mammary gland arises from multipotent stem cells (MaSCs), which are progressively replaced by unipotent progenitors by birth. However, the lack of specific markers for early fate specification has prevented the delineation of the features and spatial localization of MaSC-derived lineage-committed progenitors. Here, using single-cell RNA sequencing from E13.5 to birth, we produced an atlas of matched mouse mammary epithelium and mesenchyme and reconstructed the differentiation trajectories of MaSCs toward basal and luminal fate. We show that murine MaSCs exhibit lineage commitment just prior to the first sprouting events of mammary branching morphogenesis at E15.5. We identify early molecular markers for committed and multipotent MaSCs and define their spatial distribution within the developing tissue. Furthermore, we show that the mammary embryonic mesenchyme is composed of two spatially restricted cell populations, and that dermal mesenchyme-produced FGF10 is essential for embryonic mammary branching morphogenesis. Altogether, our data elucidate the spatiotemporal signals underlying lineage specification of multipotent MaSCs, and uncover the signals from mesenchymal cells that guide mammary branching morphogenesis.
    Keywords:  Branching Morphogenesis; Embryonic Explants; Fate Specification; Mammary Stem Cells; scRNA-seq
    DOI:  https://doi.org/10.1038/s44318-024-00115-3
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