bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2024–06–30
thirteen papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. Raman micro-spectroscopy reveals the spatial distribution of fumarate in cells and tissues.
  2. Myeloid-derived miR-6236 potentiates adipocyte insulin signaling and prevents hyperglycemia during obesity.
  3. Oxylipins and metabolites from pyroptotic cells act as promoters of tissue repair.
  4. Hepatocyte-macrophage crosstalk via the PGRN-EGFR axis modulates ADAR1-mediated immunity in the liver.
  5. Glycolysis in hepatic stellate cells coordinates fibrogenic extracellular vesicle release spatially to amplify liver fibrosis.
  6. NOS2-derived low levels of NO drive psoriasis pathogenesis.
  7. A metabolic redox relay supports ER proinsulin export in pancreatic islet β-cells.
  8. Protocol for the collection and analysis of the different immune cell subsets in the murine intestinal lamina propria.
  9. Human mitochondrial carriers of the SLC25 family function as monomers exchanging substrates with a ping-pong kinetic mechanism.
  10. Macrophage-derived chemokine CCL22 establishes local LN-mediated adaptive thermogenesis and energy expenditure.
  11. The extracellular matrix integrates mitochondrial homeostasis.
  12. Macrophages preserve endothelial cell specialization in the adrenal gland to modulate aldosterone secretion and blood pressure.
  13. Circulating KLRG1+ long-lived effector memory T cells retain the flexibility to become tissue resident.
  1. Nat Commun. 2024 Jun 25. 15(1): 5386
    Raman micro-spectroscopy reveals the spatial distribution of fumarate in cells and tissues.
    Marlous Kamp, Jakub Surmacki, Marc Segarra Mondejar, Tim Young, Karolina Chrabaszcz, Fadwa Joud, Vincent Zecchini, Alyson Speed, Christian Frezza, Sarah E Bohndiek.
      Aberrantly accumulated metabolites elicit intra- and inter-cellular pro-oncogenic cascades, yet current measurement methods require sample perturbation/disruption and lack spatio-temporal resolution, limiting our ability to fully characterize their function and distribution. Here, we show that Raman spectroscopy (RS) can directly detect fumarate in living cells in vivo and animal tissues ex vivo, and that RS can distinguish between Fumarate hydratase (Fh1)-deficient and Fh1-proficient cells based on fumarate concentration. Moreover, RS reveals the spatial compartmentalization of fumarate within cellular organelles in Fh1-deficient cells: consistent with disruptive methods, we observe the highest fumarate concentration (37 ± 19 mM) in mitochondria, where the TCA cycle operates, followed by the cytoplasm (24 ± 13 mM) and then the nucleus (9 ± 6 mM). Finally, we apply RS to tissues from an inducible mouse model of FH loss in the kidney, demonstrating RS can classify FH status. These results suggest RS could be adopted as a valuable tool for small molecule metabolic imaging, enabling in situ non-destructive evaluation of fumarate compartmentalization.
    DOI:  https://doi.org/10.1038/s41467-024-49403-w
  2. Nat Commun. 2024 Jun 25. 15(1): 5394
    Myeloid-derived miR-6236 potentiates adipocyte insulin signaling and prevents hyperglycemia during obesity.
    Bam D Paneru, Julia Chini, Sam J McCright, Nicole DeMarco, Jessica Miller, Leonel D Joannas, Jorge Henao-Mejia, Paul M Titchenell, David M Merrick, Hee-Woong Lim, Mitchell A Lazar, David A Hill.
      Adipose tissue macrophages (ATMs) influence obesity-associated metabolic dysfunction, but the mechanisms by which they do so are not well understood. We show that miR-6236 is a bona fide miRNA that is secreted by ATMs during obesity. Global or myeloid cell-specific deletion of miR-6236 aggravates obesity-associated adipose tissue insulin resistance, hyperglycemia, hyperinsulinemia, and hyperlipidemia. miR-6236 augments adipocyte insulin sensitivity by inhibiting translation of negative regulators of insulin signaling, including PTEN. The human genome harbors a miR-6236 homolog that is highly expressed in the serum and adipose tissue of obese people. hsa-MIR-6236 expression negatively correlates with hyperglycemia and glucose intolerance, and positively correlates with insulin sensitivity. Together, our findings establish miR-6236 as an ATM-secreted miRNA that potentiates adipocyte insulin signaling and protects against metabolic dysfunction during obesity.
    DOI:  https://doi.org/10.1038/s41467-024-49632-z
  3. Nature. 2024 Jun 26.
    Oxylipins and metabolites from pyroptotic cells act as promoters of tissue repair.
    Parul Mehrotra, Sophia Maschalidi, Laura Boeckaerts, Christian Maueröder, Rochelle Tixeira, Jonathan Pinney, Javier Burgoa Cardás, Vladimir Sukhov, Yunus Incik, Christopher J Anderson, Bing Hu, Burcu N Keçeli, Amanda Goncalves, Lieselotte Vande Walle, Nina Van Opdenbosch, Alexey Sergushichev, Esther Hoste, Umang Jain, Mohamed Lamkanfi, Kodi S Ravichandran.
      Pyroptosis is a lytic cell death mode that helps limit the spread of infections and is also linked to pathology in sterile inflammatory diseases and autoimmune diseases1-4. During pyroptosis, inflammasome activation and the engagement of caspase-1 lead to cell death, along with the maturation and secretion of the inflammatory cytokine interleukin-1β (IL-1β). The dominant effect of IL-1β in promoting tissue inflammation has clouded the potential influence of other factors released from pyroptotic cells. Here, using a system in which macrophages are induced to undergo pyroptosis without IL-1β or IL-1α release (denoted Pyro-1), we identify unexpected beneficial effects of the Pyro-1 secretome. First, we noted that the Pyro-1 supernatants upregulated gene signatures linked to migration, cellular proliferation and wound healing. Consistent with this gene signature, Pyro-1 supernatants boosted migration of primary fibroblasts and macrophages, and promoted faster wound closure in vitro and improved tissue repair in vivo. In mechanistic studies, lipidomics and metabolomics of the Pyro-1 supernatants identified the presence of both oxylipins and metabolites, linking them to pro-wound-healing effects. Focusing specifically on the oxylipin prostaglandin E2 (PGE2), we find that its synthesis is induced de novo during pyroptosis, downstream of caspase-1 activation and cyclooxygenase-2 activity; further, PGE2 synthesis occurs late in pyroptosis, with its release dependent on gasdermin D pores opened during pyroptosis. As for the pyroptotic metabolites, they link to immune cell infiltration into the wounds, and polarization to CD301+ macrophages. Collectively, these data advance the concept that the pyroptotic secretome possesses oxylipins and metabolites with tissue repair properties that may be harnessed therapeutically.
    DOI:  https://doi.org/10.1038/s41586-024-07585-9
  4. Cell Rep. 2024 Jun 26. pii: S2211-1247(24)00728-9. [Epub ahead of print]43(7): 114400
    Hepatocyte-macrophage crosstalk via the PGRN-EGFR axis modulates ADAR1-mediated immunity in the liver.
    Wei Liang Gan, Xi Ren, Vanessa Hui En Ng, Larry Ng, Yangyang Song, Vincent Tano, Jian Han, Omer An, Jinghe Xie, Bryan Y L Ng, Daryl Jin Tai Tay, Sze Jing Tang, Haoqing Shen, Shruti Khare, Kelvin Han Chung Chong, Dan Yock Young, Bin Wu, Ramanuj DasGupta, Leilei Chen.
      ADAR1-mediated RNA editing establishes immune tolerance to endogenous double-stranded RNA (dsRNA) by preventing its sensing, primarily by MDA5. Although deleting Ifih1 (encoding MDA5) rescues embryonic lethality in ADAR1-deficient mice, they still experience early postnatal death, and removing other MDA5 signaling proteins does not yield the same rescue. Here, we show that ablation of MDA5 in a liver-specific Adar knockout (KO) murine model fails to rescue hepatic abnormalities caused by ADAR1 loss. Ifih1;Adar double KO (dKO) hepatocytes accumulate endogenous dsRNAs, leading to aberrant transition to a highly inflammatory state and recruitment of macrophages into dKO livers. Mechanistically, progranulin (PGRN) appears to mediate ADAR1 deficiency-induced liver pathology, promoting interferon signaling and attracting epidermal growth factor receptor (EGFR)+ macrophages into dKO liver, exacerbating hepatic inflammation. Notably, the PGRN-EGFR crosstalk communication and consequent immune responses are significantly repressed in ADAR1high tumors, revealing that pre-neoplastic or neoplastic cells can exploit ADAR1-dependent immune tolerance to facilitate immune evasion.
    Keywords:  ADAR1; CP: Cell biology; CP: Immunology; EGFR; HCC; PGRN; RNA editing; immunosuppression; innate immunity; liver inflammation; macrophage infiltration
    DOI:  https://doi.org/10.1016/j.celrep.2024.114400
  5. Sci Adv. 2024 Jun 28. 10(26): eadn5228
    Glycolysis in hepatic stellate cells coordinates fibrogenic extracellular vesicle release spatially to amplify liver fibrosis.
    Shalil Khanal, Yuanhang Liu, Adebowale O Bamidele, Alexander Q Wixom, Alexander M Washington, Nidhi Jalan-Sakrikar, Shawna A Cooper, Ivan Vuckovic, Song Zhang, Jun Zhong, Kenneth L Johnson, M Cristine Charlesworth, Iljung Kim, Yubin Yeon, Sangwoong Yoon, Yung-Kyun Noh, Chady Meroueh, Abdul Aziz Timbilla, Usman Yaqoob, Jinhang Gao, Yohan Kim, Fabrice Lucien, Robert C Huebert, Nissim Hay, Michael Simons, Vijay H Shah, Enis Kostallari.
      Liver fibrosis is characterized by the activation of perivascular hepatic stellate cells (HSCs), the release of fibrogenic nanosized extracellular vesicles (EVs), and increased HSC glycolysis. Nevertheless, how glycolysis in HSCs coordinates fibrosis amplification through tissue zone-specific pathways remains elusive. Here, we demonstrate that HSC-specific genetic inhibition of glycolysis reduced liver fibrosis. Moreover, spatial transcriptomics revealed a fibrosis-mediated up-regulation of EV-related pathways in the liver pericentral zone, which was abrogated by glycolysis genetic inhibition. Mechanistically, glycolysis in HSCs up-regulated the expression of EV-related genes such as Ras-related protein Rab-31 (RAB31) by enhancing histone 3 lysine 9 acetylation on the promoter region, which increased EV release. Functionally, these glycolysis-dependent EVs increased fibrotic gene expression in recipient HSC. Furthermore, EVs derived from glycolysis-deficient mice abrogated liver fibrosis amplification in contrast to glycolysis-competent mouse EVs. In summary, glycolysis in HSCs amplifies liver fibrosis by promoting fibrogenic EV release in the hepatic pericentral zone, which represents a potential therapeutic target.
    DOI:  https://doi.org/10.1126/sciadv.adn5228
  6. Cell Death Dis. 2024 Jun 26. 15(6): 449
    NOS2-derived low levels of NO drive psoriasis pathogenesis.
    Ines Köhler, Cecilia Bivik Eding, Nada-Katarina Kasic, Deepti Verma, Charlotta Enerbäck.
      Psoriasis is an IL-23/Th17-mediated skin disorder with a strong genetic predisposition. The impact of its susceptibility gene nitric oxide synthase 2 (NOS2) remains unknown. Here, we demonstrate strong NOS2 mRNA expression in psoriatic epidermis, an effect that is IL-17 dependent. However, its complete translation to protein is prevented by the IL-17-induced miR-31 implying marginally upregulated NO levels in psoriatic skin. We demonstrate that lower levels of NO, as opposed to higher levels, increase keratinocyte proliferation and mediate IL-17 downstream effects. We hypothesized that the psoriatic phenotype may be alleviated by either eliminating or increasing cellular NO levels. In fact, using the imiquimod psoriasis mouse model, we found a profound impact on the psoriatic inflammation in both IMQ-treated NOS2 KO mice and wild-type mice treated with IMQ and the NO-releasing berdazimer gel. In conclusion, we demonstrate that IL-17 induces NOS2 and fine-tunes its translation towards a window of proinflammatory and hyperproliferative effects and identify NO donor therapy as a new treatment modality for psoriasis.
    DOI:  https://doi.org/10.1038/s41419-024-06842-z
  7. JCI Insight. 2024 Jun 27. pii: e178725. [Epub ahead of print]
    A metabolic redox relay supports ER proinsulin export in pancreatic islet β-cells.
    Kristen E Rohli, Nicole J Stubbe, Emily M Walker, Gemma L Pearson, Scott A Soleimanpour, Samuel B Stephens.
      Endoplasmic reticulum (ER) stress and proinsulin misfolding are heralded as contributing factors to β-cell dysfunction in Type 2 diabetes (T2D), yet how ER function becomes compromised is not well understood. Recent data identifies altered ER redox homeostasis as a critical mechanism that contributes to insulin granule loss in diabetes. Hyperoxidation of the ER delays proinsulin export and limits the proinsulin supply available for insulin granule formation. In this report, we identified glucose metabolism as a critical determinant in the redox homeostasis of the ER. Using multiple β-cell models, we showed that loss of mitochondrial function or inhibition of cellular metabolism elicited ER hyperoxidation and delayed ER proinsulin export. Our data further demonstrated that β-cell ER redox homeostasis was supported by the metabolic supply of reductive redox donors. We showed that limiting NADPH and thioredoxin flux delayed ER proinsulin export, whereas Txnip suppression restored ER redox and proinsulin trafficking. Taken together, we propose that β-cell ER redox homeostasis is buffered by cellular redox donor cycles, which are maintained through active glucose metabolism.
    Keywords:  Beta cells; Cell biology; Endocrinology; Insulin; Protein traffic
    DOI:  https://doi.org/10.1172/jci.insight.178725
  8. STAR Protoc. 2024 Jun 26. pii: S2666-1667(24)00319-8. [Epub ahead of print]5(3): 103154
    Protocol for the collection and analysis of the different immune cell subsets in the murine intestinal lamina propria.
    Arthi Shanmugavadivu, Katlynn Carter, Aysan Poursadegh Zonouzi, Ari Waisman, Tommy Regen.
      The intestinal lamina propria (LP) is a leukocyte-rich cornerstone of the immune system owing to its vital role in immune surveillance and barrier defense against external pathogens. Here, we present a protocol for isolating and analyzing immune cell subsets from the mouse intestinal LP for further downstream applications. Starting from tissue collection and cleaning, epithelium removal, and enzymatic digestion to collection of single cells, we explain each step in detail to maximize the yield of immune cells from the intestinal LP.
    Keywords:  Cell isolation; Flow Cytometry; Immunology
    DOI:  https://doi.org/10.1016/j.xpro.2024.103154
  9. EMBO J. 2024 Jun 27.
    Human mitochondrial carriers of the SLC25 family function as monomers exchanging substrates with a ping-pong kinetic mechanism.
    Camila Cimadamore-Werthein, Martin S King, Denis Lacabanne, Eva Pyrihová, Stephany Jaiquel Baron, Edmund Rs Kunji.
      Members of the SLC25 mitochondrial carrier family link cytosolic and mitochondrial metabolism and support cellular maintenance and growth by transporting compounds across the mitochondrial inner membrane. Their monomeric or dimeric state and kinetic mechanism have been a matter of long-standing debate. It is believed by some that they exist as homodimers and transport substrates with a sequential kinetic mechanism, forming a ternary complex where both exchanged substrates are bound simultaneously. Some studies, in contrast, have provided evidence indicating that the mitochondrial ADP/ATP carrier (SLC25A4) functions as a monomer, has a single substrate binding site, and operates with a ping-pong kinetic mechanism, whereby ADP is imported before ATP is exported. Here we reanalyze the oligomeric state and kinetic properties of the human mitochondrial citrate carrier (SLC25A1), dicarboxylate carrier (SLC25A10), oxoglutarate carrier (SLC25A11), and aspartate/glutamate carrier (SLC25A13), all previously reported to be dimers with a sequential kinetic mechanism. We demonstrate that they are monomers, except for dimeric SLC25A13, and operate with a ping-pong kinetic mechanism in which the substrate import and export steps occur consecutively. These observations are consistent with a common transport mechanism, based on a functional monomer, in which a single central substrate-binding site is alternately accessible.
    Keywords:  Bioenergetics; Kinetic Analysis; Mitochondria; SLC25 Mitochondrial Carrier Family; Transport
    DOI:  https://doi.org/10.1038/s44318-024-00150-0
  10. Sci Adv. 2024 Jun 28. 10(26): eadn5229
    Macrophage-derived chemokine CCL22 establishes local LN-mediated adaptive thermogenesis and energy expenditure.
    Yexian Yuan, Ruoci Hu, Jooman Park, Shaolei Xiong, Zilai Wang, Yanyu Qian, Zuoxiao Shi, Ruifan Wu, Zhenbo Han, Sang-Ging Ong, Shuhao Lin, Krista A Varady, Pingwen Xu, Daniel C Berry, Gang Shu, Yuwei Jiang.
      There is a regional preference around lymph nodes (LNs) for adipose beiging. Here, we show that local LN removal within inguinal white adipose tissue (iWAT) greatly impairs cold-induced beiging, and this impairment can be restored by injecting M2 macrophages or macrophage-derived C-C motif chemokine (CCL22) into iWAT. CCL22 injection into iWAT effectively promotes iWAT beiging, while blocking CCL22 with antibodies can prevent it. Mechanistically, the CCL22 receptor, C-C motif chemokine receptor 4 (CCR4), within eosinophils and its downstream focal adhesion kinase/p65/interleukin-4 signaling are essential for CCL22-mediated beige adipocyte formation. Moreover, CCL22 levels are inversely correlated with body weight and fat mass in mice and humans. Acute elevation of CCL22 levels effectively prevents diet-induced body weight and fat gain by enhancing adipose beiging. Together, our data identify the CCL22-CCR4 axis as an essential mediator for LN-controlled adaptive thermogenesis and highlight its potential to combat obesity and its associated complications.
    DOI:  https://doi.org/10.1126/sciadv.adn5229
  11. Cell. 2024 Jun 24. pii: S0092-8674(24)00638-X. [Epub ahead of print]
    The extracellular matrix integrates mitochondrial homeostasis.
    Hanlin Zhang, C Kimberly Tsui, Gilberto Garcia, Larry K Joe, Haolun Wu, Ayane Maruichi, Wudi Fan, Sentibel Pandovski, Peter H Yoon, Brant M Webster, Jenni Durieux, Phillip A Frankino, Ryo Higuchi-Sanabria, Andrew Dillin.
      Cellular homeostasis is intricately influenced by stimuli from the microenvironment, including signaling molecules, metabolites, and pathogens. Functioning as a signaling hub within the cell, mitochondria integrate information from various intracellular compartments to regulate cellular signaling and metabolism. Multiple studies have shown that mitochondria may respond to various extracellular signaling events. However, it is less clear how changes in the extracellular matrix (ECM) can impact mitochondrial homeostasis to regulate animal physiology. We find that ECM remodeling alters mitochondrial homeostasis in an evolutionarily conserved manner. Mechanistically, ECM remodeling triggers a TGF-β response to induce mitochondrial fission and the unfolded protein response of the mitochondria (UPRMT). At the organismal level, ECM remodeling promotes defense of animals against pathogens through enhanced mitochondrial stress responses. We postulate that this ECM-mitochondria crosstalk represents an ancient immune pathway, which detects infection- or mechanical-stress-induced ECM damage, thereby initiating adaptive mitochondria-based immune and metabolic responses.
    Keywords:  TGF-β; TMEM2; extracellular matrix; hyaluronan; immunity; mitochondria
    DOI:  https://doi.org/10.1016/j.cell.2024.05.057
  12. Cell Rep. 2024 Jun 26. pii: S2211-1247(24)00723-X. [Epub ahead of print]43(7): 114395
    Macrophages preserve endothelial cell specialization in the adrenal gland to modulate aldosterone secretion and blood pressure.
    Zheng Fan, Mara Karakone, Shunmugam Nagarajan, Nadine Nagy, Wiebke Mildenberger, Ekaterina Petrova, Laura Catharina Hinte, Mitchell Bijnen, Philipp Häne, Eric Nelius, Jing Chen, Irina Ferapontova, Ferdinand von Meyenn, Francesco Trepiccione, Mesut Berber, David Penton Ribas, Anne Eichmann, Maria-Christina Zennaro, Norihiko Takeda, Jens W Fischer, Ariadni Spyroglou, Martin Reincke, Felix Beuschlein, Johannes Loffing, Melanie Greter, Christian Stockmann.
      Macrophages play crucial roles in organ-specific functions and homeostasis. In the adrenal gland, macrophages closely associate with sinusoidal capillaries in the aldosterone-producing zona glomerulosa. We demonstrate that macrophages preserve capillary specialization and modulate aldosterone secretion. Using macrophage-specific deletion of VEGF-A, single-cell transcriptomics, and functional phenotyping, we found that the loss of VEGF-A depletes PLVAP+ fenestrated endothelial cells in the zona glomerulosa, leading to increased basement membrane collagen IV deposition and subendothelial fibrosis. This results in increased aldosterone secretion, called "haptosecretagogue" signaling. Human aldosterone-producing adenomas also show capillary rarefaction and basement membrane thickening. Mice with myeloid cell-specific VEGF-A deletion exhibit elevated serum aldosterone, hypokalemia, and hypertension, mimicking primary aldosteronism. These findings underscore macrophage-to-endothelial cell signaling as essential for endothelial cell specialization, adrenal gland function, and blood pressure regulation, with broader implications for other endocrine organs.
    Keywords:  CP: Cell biology; CP: Immunology; aldosterone; capillary homeostasis; endothelial cell heterogeneity; haptocrine secretion; hypertension; macrophages; subendothelial fibrosis; vascular endothelial growth factor
    DOI:  https://doi.org/10.1016/j.celrep.2024.114395
  13. Sci Immunol. 2024 Jun 28. 9(96): eadj8356
    Circulating KLRG1+ long-lived effector memory T cells retain the flexibility to become tissue resident.
    Erin D Lucas, Matthew A Huggins, Changwei Peng, Christine O'Connor, Abigail R Gress, Claire E Thefaine, Emma M Dehm, Yoshiaki Kubota, Stephen C Jameson, Sara E Hamilton.
      KLRG1+ CD8 T cells persist for months after clearance of acute infections and maintain high levels of effector molecules, contributing protective immunity against systemic pathogens. Upon secondary infection, these long-lived effector cells (LLECs) are incapable of forming other circulating KLRG1- memory subsets such as central and effector memory T cells. Thus, KLRG1+ memory T cells are frequently referred to as a terminally differentiated population that is relatively short lived. Here, we show that after viral infection of mice, effector cells derived from LLECs rapidly enter nonlymphoid tissues and reduce pathogen burden but are largely dependent on receiving antigen cues from vascular endothelial cells. Single-cell RNA sequencing reveals that secondary memory cells in nonlymphoid tissues arising from either KLRG1+ or KLRG1- memory precursors develop a similar resident memory transcriptional signature. Thus, although LLECs cannot differentiate into other circulating memory populations, they still retain the flexibility to enter tissues and establish residency.
    DOI:  https://doi.org/10.1126/sciimmunol.adj8356
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