bims-mepmim 2023-12-24 papers

bims-mepmim

Biomed News

on Metabolites in pathological microenvironments and immunometabolism

Issue of 2023–12–24
thirty-one papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism

Mtfp1 ablation enhances mitochondrial respiration and protects against hepatic steatosis.
Lactate helps in tissue repair by promoting efferocytosis-induced macrophage proliferation.
Muscle immune cells protect mitochondrial organelles during exercise.
Myeloid deletion of talin-1 reduces mucosal macrophages and protects mice from colonic inflammation.
Nutrient inputs and social metabolic control of T cell fate.
Myeloid cell-derived creatine in the hypoxic niche promotes glioblastoma growth.
Comparing in vitro nitric oxide blood uptake to its pulmonary diffusing capacity 20/12/2023.
Metabolic transitions regulate global protein fatty acylation.
Functional-metabolic coupling in distinct renal cell types coordinates organ-wide physiology and delays premature ageing.
ChREBP is activated by reductive stress and mediates GCKR-associated metabolic traits.
Complex II ambiguities-FADH2 in the electron transfer system.
Mitochondrial aldehyde dehydrogenase-2 coordinates the hydrogen sulfide - AMPK axis to attenuate high glucose-induced pancreatic β-cell dysfunction by glutathione antioxidant system.
Mitochondrial dysfunction abrogates dietary lipid processing in enterocytes.
CTRP6 promotes the macrophage inflammatory response, and its deficiency attenuates LPS-induced inflammation.
Apoptosis releases hydrogen sulfide to inhibit Th17 cell differentiation.
FAP expression in adipose tissue macrophages promotes obesity and metabolic inflammation.
Sensory neurons promote immune homeostasis in the lung.
Chemical modulation of cytosolic BAX homodimer potentiates BAX activation and apoptosis.
PPARγ agonist treatment reduces fibroadipose tissue in secondary lymphedema by exhausting fibroadipogenic PDGFRα+ mesenchymal cells.
Human serous cavity macrophages and dendritic cells possess counterparts in the mouse with a distinct distribution between species.
LncRNA H19 inhibition impairs endoplasmic reticulum-mitochondria contact in hepatic cells and augments gluconeogenesis by increasing VDAC1 levels.
Amino acid catabolite markers for early prognostication of pneumonia in patients with COVID-19.
Targeting AKT induced Ferroptosis through FTO/YTHDF2-dependent GPX4 m6A methylation up-regulating and degradating in colorectal cancer.
Merlin/NF2 regulates SLC7A11/xCT expression and cell viability under glucose deprivation at high cell density in glioblastoma cells.
TRIM21-mediated Sohlh2 ubiquitination suppresses M2 macrophage polarization and progression of triple-negative breast cancer.
ZAP-70 augments tonic B-cell receptor and CCR7 signaling in IGHV unmutated chronic lymphocytic leukemia.
Subcutaneous white adipose tissue independently regulates burn-induced hypermetabolism via immune-adipose crosstalk.
Rho GTPase activity crosstalk mediated by Arhgef11 and Arhgef12 coordinates cell protrusion-retraction cycles.
Pleural macrophages translocate to the lung during infection to promote improved influenza outcomes.
Mitochondrial fatty acid synthesis is an emergent central regulator of mammalian oxidative metabolism.
Synaptic plasticity via receptor tyrosine kinase/G-protein-coupled receptor crosstalk.

Nat Commun. 2023 Dec 20. 14(1): 8474

Mtfp1 ablation enhances mitochondrial respiration and protects against hepatic steatosis.

Cecilia Patitucci, Juan Diego Hernández-Camacho, Elodie Vimont, Sonny Yde, Thomas Cokelaer, Thibault Chaze, Quentin Giai Gianetto, Mariette Matondo, Anastasia Gazi, Ivan Nemazanyy, David A Stroud, Daniella H Hock, Erminia Donnarumma, Timothy Wai.

Hepatic steatosis is the result of imbalanced nutrient delivery and metabolism in the liver and is the first hallmark of Metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD is the most common chronic liver disease and involves the accumulation of excess lipids in hepatocytes, inflammation, and cancer. Mitochondria play central roles in liver metabolism yet the specific mitochondrial functions causally linked to MASLD remain unclear. Here, we identify Mitochondrial Fission Process 1 protein (MTFP1) as a key regulator of mitochondrial and metabolic activity in the liver. Deletion of Mtfp1 in hepatocytes is physiologically benign in mice yet leads to the upregulation of oxidative phosphorylation (OXPHOS) activity and mitochondrial respiration, independently of mitochondrial biogenesis. Consequently, liver-specific knockout mice are protected against high fat diet-induced steatosis and metabolic dysregulation. Additionally, Mtfp1 deletion inhibits mitochondrial permeability transition pore opening in hepatocytes, conferring protection against apoptotic liver damage in vivo and ex vivo. Our work uncovers additional functions of MTFP1 in the liver, positioning this gene as an unexpected regulator of OXPHOS and a therapeutic candidate for MASLD.

DOI: https://doi.org/10.1038/s41467-023-44143-9
Nat Metab. 2023 Dec;5(12): 2045-2046

Lactate helps in tissue repair by promoting efferocytosis-induced macrophage proliferation.

DOI: https://doi.org/10.1038/s42255-023-00920-w
Nature. 2024 Jan;625(7993): 35-36

Muscle immune cells protect mitochondrial organelles during exercise.

Gerald Coulis, S Armando Villalta.



Keywords:  Cell biology; Immunology; Physiology

DOI:  https://doi.org/10.1038/d41586-023-03972-w
Sci Rep. 2023 Dec 15. 13(1): 22368

Myeloid deletion of talin-1 reduces mucosal macrophages and protects mice from colonic inflammation.

Yvonne L Latour, Kara M McNamara, Margaret M Allaman, Daniel P Barry, Thaddeus M Smith, Mohammad Asim, Kamery J Williams, Caroline V Hawkins, Justin Jacobse, Jeremy A Goettel, Alberto G Delgado, M Blanca Piazuelo, M Kay Washington, Alain P Gobert, Keith T Wilson.

The intestinal immune response is crucial in maintaining a healthy gut, but the enhanced migration of macrophages in response to pathogens is a major contributor to disease pathogenesis. Integrins are ubiquitously expressed cellular receptors that are highly involved in immune cell adhesion to endothelial cells while in the circulation and help facilitate extravasation into tissues. Here we show that specific deletion of the Tln1 gene encoding the protein talin-1, an integrin-activating scaffold protein, from cells of the myeloid lineage using the Lyz2-cre driver mouse reduces epithelial damage, attenuates colitis, downregulates the expression of macrophage markers, decreases the number of differentiated colonic mucosal macrophages, and diminishes the presence of CD68-positive cells in the colonic mucosa of mice infected with the enteric pathogen Citrobacter rodentium. Bone marrow-derived macrophages lacking expression of Tln1 did not exhibit a cell-autonomous phenotype; there was no impaired proinflammatory gene expression, nitric oxide production, phagocytic ability, or surface expression of CD11b, CD86, or major histocompatibility complex II in response to C. rodentium. Thus, we demonstrate that talin-1 plays a role in the manifestation of infectious colitis by increasing mucosal macrophages, with an effect that is independent of macrophage activation.

DOI: https://doi.org/10.1038/s41598-023-49614-z
Cell Metab. 2023 Dec 12. pii: S1550-4131(23)00460-6. [Epub ahead of print]

Nutrient inputs and social metabolic control of T cell fate.

Zachary A Bacigalupa, Madelyn D Landis, Jeffrey C Rathmell.

  Cells in multicellular organisms experience diverse neighbors, signals, and evolving physical environments that drive functional and metabolic demands. To maintain proper development and homeostasis while avoiding inappropriate cell proliferation or death, individual cells interact with their neighbors via "social" cues to share and partition available nutrients. Metabolic signals also contribute to cell fate by providing biochemical links between cell-extrinsic signals and available resources. In addition to metabolic checkpoints that sense nutrients and directly supply molecular intermediates for biosynthetic pathways, many metabolites directly signal or provide the basis for post-translational modifications of target proteins and chromatin. In this review, we survey the landscape of T cell nutrient sensing and metabolic signaling that supports proper immunity while avoiding immunodeficiency or autoimmunity. The integration of cell-extrinsic microenvironmental cues with cell-intrinsic metabolic signaling provides a social metabolic control model to integrate cell signaling, metabolism, and fate.

Keywords:  T cells; epigenetics; immunometabolism; metabolic signaling; social control model

DOI:  https://doi.org/10.1016/j.cmet.2023.12.009
Cell Metab. 2023 Dec 14. pii: S1550-4131(23)00445-X. [Epub ahead of print]

Myeloid cell-derived creatine in the hypoxic niche promotes glioblastoma growth.

Aida Rashidi, Leah K Billingham, Andrew Zolp, Tzu-Yi Chia, Caylee Silvers, Joshua L Katz, Cheol H Park, Suzi Delay, Lauren Boland, Yuheng Geng, Steven M Markwell, Crismita Dmello, Victor A Arrieta, Kaylee Zilinger, Irene M Jacob, Aurora Lopez-Rosas, David Hou, Brandyn Castro, Alicia M Steffens, Kathleen McCortney, Jordain P Walshon, Mariah S Flowers, Hanchen Lin, Hanxiang Wang, Junfei Zhao, Adam Sonabend, Peng Zhang, Atique U Ahmed, Daniel J Brat, Dieter H Heiland, Catalina Lee-Chang, Maciej S Lesniak, Navdeep S Chandel, Jason Miska.

  Glioblastoma (GBM) is a malignancy dominated by the infiltration of tumor-associated myeloid cells (TAMCs). Examination of TAMC metabolic phenotypes in mouse models and patients with GBM identified the de novo creatine metabolic pathway as a hallmark of TAMCs. Multi-omics analyses revealed that TAMCs surround the hypoxic peri-necrotic regions of GBM and express the creatine metabolic enzyme glycine amidinotransferase (GATM). Conversely, GBM cells located within these same regions are uniquely specific in expressing the creatine transporter (SLC6A8). We hypothesized that TAMCs provide creatine to tumors, promoting GBM progression. Isotopic tracing demonstrated that TAMC-secreted creatine is taken up by tumor cells. Creatine supplementation protected tumors from hypoxia-induced stress, which was abrogated with genetic ablation or pharmacologic inhibition of SLC6A8. Lastly, inhibition of creatine transport using the clinically relevant compound, RGX-202-01, blunted tumor growth and enhanced radiation therapy in vivo. This work highlights that myeloid-to-tumor transfer of creatine promotes tumor growth in the hypoxic niche.

Keywords:  creatine metabolism; glioblastoma; myeloid cells; pseudopalisading necrosis

DOI:  https://doi.org/10.1016/j.cmet.2023.11.013
Nitric Oxide. 2023 Dec 20. pii: S1089-8603(23)00104-0. [Epub ahead of print]

Comparing in vitro nitric oxide blood uptake to its pulmonary diffusing capacity 20/12/2023.

Colin Borland, Ruhi Patel.

  Whether endothelium derived Nitric Oxide (NO) uptake by the blood is limited by a boundary layer, the red cell membrane or its interior is the subject of continued debate. Whether lung uptake of NO in the single-breath DLNO test is limited by blood or not is also debated. To understand which processes are limiting blood NO uptake we have modelled NO chemical kinetics and we have derived a shrinking core model, Thiele Modulus and FTCS (Euler) numerical solution. In a rapid reaction apparatus, NO uptake appears limited by a boundary layer, and throughout the red cell, by diffusion. In the single breath situation, and arguably with endogenous NO in vivo, NO uptake appears limited by a boundary layer and a pseudo first order chemical reaction in the outer molecular layers of the red cell. We have not found evidence to support red cell membrane limitation.

Keywords:  Diffusing capacity; Nitric oxide; Plasma boundary layer; Red blood cell; Red cell membrane red cell interior

DOI:  https://doi.org/10.1016/j.niox.2023.11.006
J Biol Chem. 2023 Dec 13. pii: S0021-9258(23)02591-7. [Epub ahead of print] 105563

Metabolic transitions regulate global protein fatty acylation.

Manasi Talwadekar, Subhash Khatri, Chinthapalli Balaji, Arnab Chakraborty, Nandini-Pal Basak, Siddhesh Kamat, Ullas Kolthur-Seetharam.

  Intermediary metabolites and flux through various pathways have emerged as key determinants of post-translational modifications. Independently, dynamic fluctuations in their concentrations are known to drive cellular energetics in a bi-directional manner. Notably, intracellular fatty acid pools that drastically change during fed and fasted states act as precursors for both ATP production and fatty acylation of proteins. Protein fatty acylation is well regarded for its role in regulating structure and functions of diverse proteins, however the effect of intracellular concentrations of fatty acids on protein modification is less understood. In this regard, we unequivocally demonstrate that metabolic contexts, viz. fed and fasted states, dictate the extent of global fatty acylation. Moreover, we show that presence or absence of glucose, that influences cellular and mitochondrial uptake/utilization of fatty acids, affects palmitoylation and oleoylation, which is consistent with their intracellular abundance in fed and fasted states. Employing complementary approaches including click-chemistry, lipidomics and imaging, we show the top-down control of cellular metabolic state. Importantly, our results establish the crucial role of mitochondria and retrograde signaling components like SIRT4, AMPK and mTOR in orchestrating protein fatty acylation at a whole cell level. Specifically, pharmacogenetic perturbations that alter either mitochondrial functions and/or retrograde signaling affect protein fatty acylation. Besides illustrating the cross-talk between carbohydrate and lipid metabolism in mediating bulk post-translational modification, our findings also highlight the involvement of mitochondrial energetics.

Keywords:  Acylation; acyl exchange; free fatty acids; oleate; palmitate; sirtuins

DOI:  https://doi.org/10.1016/j.jbc.2023.105563
Nat Commun. 2023 Dec 18. 14(1): 8405

Functional-metabolic coupling in distinct renal cell types coordinates organ-wide physiology and delays premature ageing.

Jack Holcombe, Helen Weavers.

Precise coupling between cellular physiology and metabolism is emerging as a vital relationship underpinning tissue health and longevity. Nevertheless, functional-metabolic coupling within heterogenous microenvironments in vivo remains poorly understood due to tissue complexity and metabolic plasticity. Here, we establish the Drosophila renal system as a paradigm for linking mechanistic analysis of metabolism, at single-cell resolution, to organ-wide physiology. Kidneys are amongst the most energetically-demanding organs, yet exactly how individual cell types fine-tune metabolism to meet their diverse, unique physiologies over the life-course remains unclear. Integrating live-imaging of metabolite and organelle dynamics with spatio-temporal genetic perturbation within intact functional tissue, we uncover distinct cellular metabolic signatures essential to support renal physiology and healthy ageing. Cell type-specific programming of glucose handling, PPP-mediated glutathione regeneration and FA β-oxidation via dynamic lipid-peroxisomal networks, downstream of differential ERR receptor activity, precisely match cellular energetic demands whilst limiting damage and premature senescence; however, their dramatic dysregulation may underlie age-related renal dysfunction.

DOI: https://doi.org/10.1038/s41467-023-44098-x
Cell Metab. 2023 Dec 08. pii: S1550-4131(23)00421-7. [Epub ahead of print]

ChREBP is activated by reductive stress and mediates GCKR-associated metabolic traits.

Charandeep Singh, Byungchang Jin, Nirajan Shrestha, Andrew L Markhard, Apekshya Panda, Sarah E Calvo, Amy Deik, Xingxiu Pan, Austin L Zuckerman, Amel Ben Saad, Kathleen E Corey, Julia Sjoquist, Stephanie Osganian, Roya AminiTabrizi, Eugene P Rhee, Hardik Shah, Olga Goldberger, Alan C Mullen, Valentin Cracan, Clary B Clish, Vamsi K Mootha, Russell P Goodman.

  Common genetic variants in glucokinase regulator (GCKR), which encodes GKRP, a regulator of hepatic glucokinase (GCK), influence multiple metabolic traits in genome-wide association studies (GWASs), making GCKR one of the most pleiotropic GWAS loci in the genome. It is unclear why. Prior work has demonstrated that GCKR influences the hepatic cytosolic NADH/NAD+ ratio, also referred to as reductive stress. Here, we demonstrate that reductive stress is sufficient to activate the transcription factor ChREBP and necessary for its activation by the GKRP-GCK interaction, glucose, and ethanol. We show that hepatic reductive stress induces GCKR GWAS traits such as increased hepatic fat, circulating FGF21, and circulating acylglycerol species, which are also influenced by ChREBP. We define the transcriptional signature of hepatic reductive stress and show its upregulation in fatty liver disease and downregulation after bariatric surgery in humans. These findings highlight how a GCKR-reductive stress-ChREBP axis influences multiple human metabolic traits.

Keywords:  ChREBP; FGF21; GCK; GCKR; MLIXPL; NAD(+); NADH; fatty liver disease; gastric bypass surgery; metabolism; reductive stress; trigylcerides

DOI:  https://doi.org/10.1016/j.cmet.2023.11.010
J Biol Chem. 2023 Nov 22. pii: S0021-9258(23)02498-5. [Epub ahead of print]300(1): 105470

Complex II ambiguities-FADH2 in the electron transfer system.

Erich Gnaiger.

  The prevailing notion that reduced cofactors NADH and FADH2 transfer electrons from the tricarboxylic acid cycle to the mitochondrial electron transfer system creates ambiguities regarding respiratory Complex II (CII). CII is the only membrane-bound enzyme in the tricarboxylic acid cycle and is part of the electron transfer system of the mitochondrial inner membrane feeding electrons into the coenzyme Q-junction. The succinate dehydrogenase subunit SDHA of CII oxidizes succinate and reduces the covalently bound prosthetic group FAD to FADH2 in the canonical forward tricarboxylic acid cycle. However, several graphical representations of the electron transfer system depict FADH2 in the mitochondrial matrix as a substrate to be oxidized by CII. This leads to the false conclusion that FADH2 from the β-oxidation cycle in fatty acid oxidation feeds electrons into CII. In reality, dehydrogenases of fatty acid oxidation channel electrons to the Q-junction but not through CII. The ambiguities surrounding Complex II in the literature and educational resources call for quality control, to secure scientific standards in current communications of bioenergetics, and ultimately support adequate clinical applications. This review aims to raise awareness of the inherent ambiguity crisis, complementing efforts to address the well-acknowledged issues of credibility and reproducibility.

Keywords:  Complex II; coenzyme Q; electron transfer system; fatty acid oxidation; flavin adenine dinucleotide; succinate dehydrogenase; tricarboxylic acid cycle

DOI:  https://doi.org/10.1016/j.jbc.2023.105470
Redox Biol. 2023 Dec 18. pii: S2213-2317(23)00395-6. [Epub ahead of print]69 102994

Mitochondrial aldehyde dehydrogenase-2 coordinates the hydrogen sulfide - AMPK axis to attenuate high glucose-induced pancreatic β-cell dysfunction by glutathione antioxidant system.

Udayakumar Karunakaran, Suma Elumalai, Seung Min Chung, Kathrin Maedler, Kyu Chang Won, Jun Sung Moon.

  Progression of β-cell loss in diabetes mellitus is significantly influenced by persistent hyperglycemia. At the cellular level, a number of signaling cascades affect the expression of apoptotic genes, ultimately resulting in β-cell failure; these cascades have not been elucidated. Mitochondrial aldehyde dehydrogenase-2 (ALDH2) plays a central role in the detoxification of reactive aldehydes generated from endogenous and exogenous sources and protects against mitochondrial deterioration in cells. Here we report that under diabetogenic conditions, ALDH2 is strongly inactivated in β-cells through CDK5-dependent glutathione antioxidant imbalance by glucose-6-phosphate dehydrogenase (G6PD) degradation. Intriguingly, CDK5 inhibition strengthens mitochondrial antioxidant defense through ALDH2 activation. Mitochondrial ALDH2 activation selectively preserves β-cells against high-glucose-induced dysfunction by activating AMPK and Hydrogen Sulfide (H2S) signaling. This is associated with the stabilization and enhancement of the activity of G6PD by SIRT2, a cytoplasmic NAD+-dependent deacetylase, and is thereby linked to an elevation in the GSH/GSSG ratio, which leads to the inhibition of mitochondrial dysfunction under high-glucose conditions. Furthermore, treatment with NaHS, an H2S donor, selectively preserves β-cell function by promoting ALDH2 activity, leading to the inhibition of lipid peroxidation by high-glucose concentrations. Collectively, our results provide the first direct evidence that ALDH2 activation enhances H2S-AMPK-G6PD signaling, leading to improved β-cell function and survival under high-glucose conditions via the glutathione redox balance.

Keywords:  CDK5/AMPK pathway; Diabetes; Glucotoxicity; Glutathione; Hydrogen sulfide; Oxidative stress; Pancreatic β-cells

DOI:  https://doi.org/10.1016/j.redox.2023.102994
Nature. 2023 Dec 20.

Mitochondrial dysfunction abrogates dietary lipid processing in enterocytes.

Chrysanthi Moschandrea, Vangelis Kondylis, Ioannis Evangelakos, Marija Herholz, Farina Schneider, Christina Schmidt, Ming Yang, Sandra Ehret, Markus Heine, Michelle Y Jaeckstein, Karolina Szczepanowska, Robin Schwarzer, Linda Baumann, Theresa Bock, Efterpi Nikitopoulou, Susanne Brodesser, Marcus Krüger, Christian Frezza, Joerg Heeren, Aleksandra Trifunovic, Manolis Pasparakis.

Digested dietary fats are taken up by enterocytes where they are assembled into pre-chylomicrons in the endoplasmic reticulum followed by transport to the Golgi for maturation and subsequent secretion to the circulation1. The role of mitochondria in dietary lipid processing is unclear. Here we show that mitochondrial dysfunction in enterocytes inhibits chylomicron production and the transport of dietary lipids to peripheral organs. Mice with specific ablation of the mitochondrial aspartyl-tRNA synthetase DARS2 (ref. 2), the respiratory chain subunit SDHA3 or the assembly factor COX10 (ref. 4) in intestinal epithelial cells showed accumulation of large lipid droplets (LDs) in enterocytes of the proximal small intestine and failed to thrive. Feeding a fat-free diet suppressed the build-up of LDs in DARS2-deficient enterocytes, which shows that the accumulating lipids derive mostly from digested fat. Furthermore, metabolic tracing studies revealed an impaired transport of dietary lipids to peripheral organs in mice lacking DARS2 in intestinal epithelial cells. DARS2 deficiency caused a distinct lack of mature chylomicrons concomitant with a progressive dispersal of the Golgi apparatus in proximal enterocytes. This finding suggests that mitochondrial dysfunction results in impaired trafficking of chylomicrons from the endoplasmic reticulum to the Golgi, which in turn leads to storage of dietary lipids in large cytoplasmic LDs. Taken together, these results reveal a role for mitochondria in dietary lipid transport in enterocytes, which might be relevant for understanding the intestinal defects observed in patients with mitochondrial disorders5.

DOI: https://doi.org/10.1038/s41586-023-06857-0
J Biol Chem. 2023 Dec 14. pii: S0021-9258(23)02594-2. [Epub ahead of print] 105566

CTRP6 promotes the macrophage inflammatory response, and its deficiency attenuates LPS-induced inflammation.

Cheng Xu, Dylan C Sarver, Xia Lei, Ageline Sahagun, Jun Zhong, Chan Hyun Na, Assaf Rudich, G William Wong.

  Macrophages play critical roles in inflammation and tissue homeostasis, and their functions are regulated by various autocrine, paracrine, and endocrine factors. We have previously shown that CTRP6, a secreted protein of the C1q family, targets both adipocytes and macrophages to promote obesity-linked inflammation. However, the gene programs and signaling pathways directly regulated by CTRP6 in macrophages remain unknown. Here, we combine transcriptomic and phosphoproteomic analyses to show that CTRP6 activates inflammatory gene programs and signaling pathways in mouse bone marrow-derived macrophages (BMDMs). Treatment of BMDMs with CTRP6 upregulated proinflammatory, and suppressed the anti-inflammatory, gene expression. We also showed that CTRP6 activates p44/42-MAPK, p38-MAPK, and NF-κB signaling pathways to promote inflammatory cytokine secretion from BMDMs, and that pharmacologic inhibition of these signaling pathways markedly attenuated the effects of CTRP6. Pretreatment of BMDMs with CTRP6 also sensitized and potentiated the BMDMs response to LPS-induced inflammatory signaling and cytokine secretion. Consistent with the metabolic phenotype of proinflammatory macrophages, CTRP6 treatment induced a shift toward aerobic glycolysis and lactate production, reduced oxidative metabolism, and elevated mitochondrial ROS production in BMDMs. Importantly, in accordance with our in vitro findings, BMDMs from CTRP6-deficient mice were less inflammatory at baseline and showed a marked suppression of LPS-induced inflammatory gene expression and cytokine secretion. Finally, loss of CTRP6 in mice also dampened LPS-induced inflammation and hypothermia. Collectively, our findings suggest that CTRP6 regulates and primes the macrophage response to inflammatory stimuli and thus may have a role in modulating tissue inflammatory tone in different physiological and disease contexts.

Keywords:  CTRP; LPS; inflammation; macrophage; phosphoproteomics; signaling; transcriptomics

DOI:  https://doi.org/10.1016/j.jbc.2023.105566
Cell Metab. 2023 Dec 13. pii: S1550-4131(23)00444-8. [Epub ahead of print]

Apoptosis releases hydrogen sulfide to inhibit Th17 cell differentiation.

Qianmin Ou, Xinhua Qiao, Zhengshi Li, Luhan Niu, Fangcao Lei, Ruifeng Cheng, Ting Xie, Ning Yang, Yao Liu, Ling Fu, Jing Yang, Xueli Mao, Xiaoxing Kou, Chang Chen, Songtao Shi.

  Over 50 billion cells undergo apoptosis each day in an adult human to maintain immune homeostasis. Hydrogen sulfide (H2S) is also required to safeguard the function of immune response. However, it is unknown whether apoptosis regulates H2S production. Here, we show that apoptosis-deficient MRL/lpr (B6.MRL-Faslpr/J) and Bim-/- (B6.129S1-Bcl2l11tm1.1Ast/J) mice exhibit significantly reduced H2S levels along with aberrant differentiation of Th17 cells, which can be rescued by the additional H2S. Moreover, apoptotic cells and vesicles (apoVs) express key H2S-generating enzymes and generate a significant amount of H2S, indicating that apoptotic metabolism is an important source of H2S. Mechanistically, H2S sulfhydrates selenoprotein F (Sep15) to promote signal transducer and activator of transcription 1 (STAT1) phosphorylation and suppress STAT3 phosphorylation, leading to the inhibition of Th17 cell differentiation. Taken together, this study reveals a previously unknown role of apoptosis in maintaining H2S homeostasis and the unique role of H2S in regulating Th17 cell differentiation via sulfhydration of Sep15C38.

Keywords:  SLE; Th17 cells; apoVs; apoptosis; apoptotic vesicles; hydrogen sulfide; systemic lupus erythematosus

DOI:  https://doi.org/10.1016/j.cmet.2023.11.012
Proc Natl Acad Sci U S A. 2023 Dec 19. 120(51): e2303075120

FAP expression in adipose tissue macrophages promotes obesity and metabolic inflammation.

Yunyun Wu, Chao Wu, Tiancong Shi, Qian Cai, Tianyao Wang, Yingluo Xiong, Yubin Zhang, Wei Jiang, Mingfang Lu, Zhengrong Chen, Jing Chen, Jiqiu Wang, Rui He.

  Adipose tissue macrophages (ATM) are key players in the development of obesity and associated metabolic inflammation which contributes to systemic metabolic dysfunction. We here found that fibroblast activation protein α (FAP), a well-known marker of cancer-associated fibroblast, is selectively expressed in murine and human ATM among adipose tissue-infiltrating leukocytes. Macrophage FAP deficiency protects mice against diet-induced obesity and proinflammatory macrophage infiltration in obese adipose tissues, thereby alleviating hepatic steatosis and insulin resistance. Mechanistically, FAP specifically mediates monocyte chemokine protein CCL8 expression by ATM, which is further upregulated upon high-fat-diet (HFD) feeding, contributing to the recruitment of monocyte-derived proinflammatory macrophages with no effect on their classical inflammatory activation. CCL8 overexpression restores HFD-induced metabolic phenotypes in the absence of FAP. Moreover, macrophage FAP deficiency enhances energy expenditure and oxygen consumption preceding differential body weight after HFD feeding. Such enhanced energy expenditure is associated with increased levels of norepinephrine (NE) and lipolysis in white adipose tissues, likely due to decreased expression of monoamine oxidase, a NE degradation enzyme, by Fap-/- ATM. Collectively, our study identifies FAP as a previously unrecognized regulator of ATM function contributing to diet-induced obesity and metabolic inflammation and suggests FAP as a potential immunotherapeutic target against metabolic disorders.

Keywords:  CCL8; fibroblast activation protein (FAP); inflammation; macrophage; obesity

DOI:  https://doi.org/10.1073/pnas.2303075120
Cell. 2023 Dec 13. pii: S0092-8674(23)01313-2. [Epub ahead of print]

Sensory neurons promote immune homeostasis in the lung.

Masato Tamari, Kate L Del Bel, Aaron M Ver Heul, Lydia Zamidar, Keisuke Orimo, Masato Hoshi, Anna M Trier, Hiroshi Yano, Ting-Lin Yang, Catherine M Biggs, Kenichiro Motomura, Rintaro Shibuya, Chuyue D Yu, Zili Xie, Hisato Iriki, Zhen Wang, Kelsey Auyeung, Gargi Damle, Deniz Demircioglu, Jill K Gregory, Dan Hasson, Jinye Dai, Rui B Chang, Hideaki Morita, Kenji Matsumoto, Sanjay Jain, Steven Van Dyken, Joshua D Milner, Dusan Bogunovic, Hongzhen Hu, David Artis, Stuart E Turvey, Brian S Kim.

  Cytokines employ downstream Janus kinases (JAKs) to promote chronic inflammatory diseases. JAK1-dependent type 2 cytokines drive allergic inflammation, and patients with JAK1 gain-of-function (GoF) variants develop atopic dermatitis (AD) and asthma. To explore tissue-specific functions, we inserted a human JAK1 GoF variant (JAK1GoF) into mice and observed the development of spontaneous AD-like skin disease but unexpected resistance to lung inflammation when JAK1GoF expression was restricted to the stroma. We identified a previously unrecognized role for JAK1 in vagal sensory neurons in suppressing airway inflammation. Additionally, expression of Calcb/CGRPβ was dependent on JAK1 in the vagus nerve, and CGRPβ suppressed group 2 innate lymphoid cell function and allergic airway inflammation. Our findings reveal evolutionarily conserved but distinct functions of JAK1 in sensory neurons across tissues. This biology raises the possibility that therapeutic JAK inhibitors may be further optimized for tissue-specific efficacy to enhance precision medicine in the future.

Keywords:  AAV; CGRP; ILC2; JAK1; afferent nerves; allergic lung inflammation; atopic disorders; neuropeptide; sensory neurons; vagus nerve

DOI:  https://doi.org/10.1016/j.cell.2023.11.027
Nat Commun. 2023 Dec 16. 14(1): 8381

Chemical modulation of cytosolic BAX homodimer potentiates BAX activation and apoptosis.

Nadege Gitego, Bogos Agianian, Oi Wei Mak, Vasantha Kumar Mv, Emily H Cheng, Evripidis Gavathiotis.

The BCL-2 family protein BAX is a major regulator of physiological and pathological cell death. BAX predominantly resides in the cytosol in a quiescent state and upon stress, it undergoes conformational activation and mitochondrial translocation leading to mitochondrial outer membrane permeabilization, a critical event in apoptosis execution. Previous studies reported two inactive conformations of cytosolic BAX, a monomer and a dimer, however, it remains unclear how they regulate BAX. Here we show that, surprisingly, cancer cell lines express cytosolic inactive BAX dimers and/or monomers. Expression of inactive dimers, results in reduced BAX activation, translocation and apoptosis upon pro-apoptotic drug treatments. Using the inactive BAX dimer structure and a pharmacophore-based drug screen, we identify a small-molecule modulator, BDM19 that binds and activates cytosolic BAX dimers and prompts cells to apoptosis either alone or in combination with BCL-2/BCL-XL inhibitor Navitoclax. Our findings underscore the role of the cytosolic inactive BAX dimer in resistance to apoptosis and demonstrate a strategy to potentiate BAX-mediated apoptosis.

DOI: https://doi.org/10.1038/s41467-023-44084-3
JCI Insight. 2023 Dec 22. pii: e165324. [Epub ahead of print]8(24):

PPARγ agonist treatment reduces fibroadipose tissue in secondary lymphedema by exhausting fibroadipogenic PDGFRα+ mesenchymal cells.

Ziyu Chen, Soheila Ali Akbari Ghavimi, Mengfan Wu, John McNamara, Olga Barreiro, David Maridas, Radomir Kratchmarov, Ashley Siegel, Sarah Djeddi, Maria Gutierrez-Arcelus, Patrick J Brennan, Timothy P Padera, Ulrich von Andrian, Babak Mehrara, Arin K Greene, C Ronald Kahn, Dennis P Orgill, Indranil Sinha, Vicki Rosen, Shailesh Agarwal.

  Secondary lymphedema occurs in up to 20% of patients after lymphadenectomy performed for the surgical management of tumors involving the breast, prostate, uterus, and skin. Patients develop progressive edema of the affected extremity due to retention of protein-rich lymphatic fluid. Despite compression therapy, patients progress to chronic lymphedema in which noncompressible fibrosis and adipose tissue are deposited within the extremity. The presence of fibrosis led to our hypothesis that rosiglitazone, a PPARγ agonist that inhibits fibrosis, would reduce fibrosis in a mouse model of secondary lymphedema after hind limb lymphadenectomy. In vivo, rosiglitazone reduced fibrosis in the hind limb after lymphadenectomy. Our findings verified that rosiglitazone reestablished the adipogenic features of TGF-β1-treated mesenchymal cells in vitro. Despite this, rosiglitazone led to a reduction in adipose tissue deposition. Single-cell RNA-Seq data obtained from human tissues and flow cytometric and histological evaluation of mouse tissues demonstrated increased presence of PDGFRα+ cells in lymphedema; human tissue analysis verified these cells have the capacity for adipogenic and fibrogenic differentiation. Upon treatment with rosiglitazone, we noted a reduction in the overall quantity of PDGFRα+ cells and LipidTOX+ cells. Our findings provide a framework for treating secondary lymphedema as a condition of fibrosis and adipose tissue deposition, both of which, paradoxically, can be prevented with a pro-adipogenic agent.

Keywords:  Adipose tissue; Cell Biology; Fibrosis

DOI:  https://doi.org/10.1172/jci.insight.165324
Nat Immunol. 2023 Dec 15.

Human serous cavity macrophages and dendritic cells possess counterparts in the mouse with a distinct distribution between species.

Jichang Han, Alexandre Gallerand, Emma C Erlich, Beth A Helmink, Iris Mair, Xin Li, Shaina R Eckhouse, Francesca M Dimou, Baddr A Shakhsheer, Hannah M Phelps, Mandy M Chan, Rachel L Mintz, Daniel D Lee, Joel D Schilling, Conor M Finlay, Judith E Allen, Claudia V Jakubzick, Kathryn J Else, Emily J Onufer, Nan Zhang, Gwendalyn J Randolph.

In mouse peritoneal and other serous cavities, the transcription factor GATA6 drives the identity of the major cavity resident population of macrophages, with a smaller subset of cavity-resident macrophages dependent on the transcription factor IRF4. Here we showed that GATA6+ macrophages in the human peritoneum were rare, regardless of age. Instead, more human peritoneal macrophages aligned with mouse CD206+ LYVE1+ cavity macrophages that represent a differentiation stage just preceding expression of GATA6. A low abundance of CD206+ macrophages was retained in C57BL/6J mice fed a high-fat diet and in wild-captured mice, suggesting that differences between serous cavity-resident macrophages in humans and mice were not environmental. IRF4-dependent mouse serous cavity macrophages aligned closely with human CD1c+CD14+CD64+ peritoneal cells, which, in turn, resembled human peritoneal CD1c+CD14-CD64- cDC2. Thus, major populations of serous cavity-resident mononuclear phagocytes in humans and mice shared common features, but the proportions of different macrophage differentiation stages greatly differ between the two species, and dendritic cell (DC2)-like cells were especially prominent in humans.

DOI: https://doi.org/10.1038/s41590-023-01688-7
Redox Biol. 2023 Dec 09. pii: S2213-2317(23)00390-7. [Epub ahead of print]69 102989

LncRNA H19 inhibition impairs endoplasmic reticulum-mitochondria contact in hepatic cells and augments gluconeogenesis by increasing VDAC1 levels.

Arun Nandwani, Shalu Rathore, Malabika Datta.

  Inspite of exerting independent cellular functions, the endoplasmic-reticulum (ER) and the mitochondria also physically connect at specific sites termed mitochondria-associated ER membranes (MAMs) and these sites consist of several tethering proteins that play varied roles in diverse cellular processes. However, the regulation of these tethering proteins within the cell is relatively less studied. Here, we show that several MAM proteins are significantly altered in the liver during diabetes and among these, the lncRNA, H19 regulates the levels of VDAC1. Inhibition of H19 expression using H19 specific siRNA altered VDAC1, mitochondrial Ca2+ and oxygen consumption rate, ATP and ROS levels and enhanced ER and mitochondria coupling in Hepa 1-6 cells. While H19 inhibition did not impact lipid accumulation, levels of gluconeogenic genes were significantly increased. JNK-phosphorylation and IRS1-Ser307-phosphorylation were increased by H19 inhibition and this was associated with abrogation of insulin-stimulated AKT (Ser-473) phosphorylation and glucose uptake in Hepa 1-6 cells. While inhibition of VDAC1 expression using siRNAs and with metformin significantly rescued the effects of H19 inhibition, VDAC1 overexpression alone exerted effects similar to H19 inhibition, suggesting that VDAC1 increase mediates the adverse effects of H19. In-vivo H19 inhibition using specific siRNAs increased hepatic VDAC1, pJNK and pIRS1 (Ser307) levels and decreased AKT (Ser-473) phosphorylation in mice. These suggest an important role of the H19-VDAC1 axis in ER-mitochondria coupling and regulation of gluconeogenesis in the liver during diabetes.

Keywords:  Ca(2+); Diabetes; ER-Mitochondria communication; Gluconeogenesis; JNK; Liver; ROS; lncRNA

DOI:  https://doi.org/10.1016/j.redox.2023.102989
Nat Commun. 2023 Dec 20. 14(1): 8469

Amino acid catabolite markers for early prognostication of pneumonia in patients with COVID-19.

Rae Maeda, Natsumi Seki, Yoshifumi Uwamino, Masatoshi Wakui, Yu Nakagama, Yasutoshi Kido, Miwa Sasai, Shu Taira, Naoya Toriu, Masahiro Yamamoto, Yoshiharu Matsuura, Jun Uchiyama, Genki Yamaguchi, Makoto Hirakawa, Yun-Gi Kim, Masayo Mishima, Motoko Yanagita, Makoto Suematsu, Yuki Sugiura.

Effective early-stage markers for predicting which patients are at risk of developing SARS-CoV-2 infection have not been fully investigated. Here, we performed comprehensive serum metabolome analysis of a total of 83 patients from two cohorts to determine that the acceleration of amino acid catabolism within 5 days from disease onset correlated with future disease severity. Increased levels of de-aminated amino acid catabolites involved in the de novo nucleotide synthesis pathway were identified as early prognostic markers that correlated with the initial viral load. We further employed mice models of SARS-CoV2-MA10 and influenza infection to demonstrate that such de-amination of amino acids and de novo synthesis of nucleotides were associated with the abnormal proliferation of airway and vascular tissue cells in the lungs during the early stages of infection. Consequently, it can be concluded that lung parenchymal tissue remodeling in the early stages of respiratory viral infections induces systemic metabolic remodeling and that the associated key amino acid catabolites are valid predictors for excessive inflammatory response in later disease stages.

DOI: https://doi.org/10.1038/s41467-023-44266-z
Cell Death Discov. 2023 Dec 15. 9(1): 457

Targeting AKT induced Ferroptosis through FTO/YTHDF2-dependent GPX4 m6A methylation up-regulating and degradating in colorectal cancer.

Ge Zhang, Wunan Mi, Chuyue Wang, Jiehan Li, Yizheng Zhang, Nannan Liu, Meimei Jiang, Guiyun Jia, Feng Wang, Ge Yang, Lingling Zhang, Jiangang Wang, Yang Fu, Yingjie Zhang.

Ferroptosis is a new type of iron-dependent programmed cell death induced by lipid peroxidation. However, the underlying mechanisms and function in tumor therapy still remain undisclosed especially in post-transcription regulation. Here, we found that targeting AKT significantly induced GPX4 dependent ferroptosis and suppressed colorectal cancer growth both in vitro and in vivo. During this process, demethylase FTO was downregulated, which increased the m6A methylation level of GPX4, subsequently recognized by YTHDF2 and degraded. Prediction results showed that there are three potential methylated sites (193/647/766), and 193 site was identified as the right one, which was demethylated by FTO and read by YTHDF2. In parallel, AKT inhibition caused the accumulation of ROS which had a negative feedback on GPX4 expression. In addition, protective autophagy was initiated by MK2206 stimulation, while blocking autophagy further increased ferroptosis and markedly enhanced the anti-tumor activity of MK2206. In a word, inhibiting AKT activated ferroptosis through FTO/YTHDF2/GPX4 axis to suppress colon cancer progression, which raised FTO/GPX4 as potential biomarkers and targets in colorectal cancer therapy.

DOI: https://doi.org/10.1038/s41420-023-01746-x
J Biochem. 2023 Dec 15. pii: mvad105. [Epub ahead of print]

Merlin/NF2 regulates SLC7A11/xCT expression and cell viability under glucose deprivation at high cell density in glioblastoma cells.

Itsuki Yamaguchi, Hironori Katoh.

  The cystine/glutamate transporter SLC7A11/xCT is highly expressed in many cancer cells and plays an important role in antioxidant activity by supplying cysteine for glutathione synthesis. Under glucose-depleted conditions, however, SLC7A11-mediated cystine uptake causes oxidative stress and cell death called disulfidptosis, a new form of cell death. We previously reported that high cell density (HD) promotes lysosomal degradation of SLC7A11 in glioblastoma cells, allowing them to survive under glucose-depleted conditions. In this study, we found that the neurofibromatosis type 2 gene, Merlin/NF2 is a key regulator of SLC7A11 in glioblastoma cells at HD. Deletion of Merlin increased SLC7A11 protein level and cystine uptake at HD, leading to promotion of cell death under glucose deprivation. Furthermore, HD significantly decreased SLC7A11 mRNA level, which was restored by Merlin deletion. This study suggests that Merlin suppresses glucose deprivation-induced cell death by downregulating SLC7A11 expression in glioblastoma cells at HD.

Keywords:  amino acid transport; cell death; cell density; glioblastoma; transcriptional regulation

DOI:  https://doi.org/10.1093/jb/mvad105
Cell Death Dis. 2023 Dec 20. 14(12): 850

TRIM21-mediated Sohlh2 ubiquitination suppresses M2 macrophage polarization and progression of triple-negative breast cancer.

Ruihong Zhang, Ying Shen, Qi Zhang, Xiaoning Feng, Xuyue Liu, Xiaoning Huo, Jinhao Sun, Jing Hao.

Lung metastasis is the major cause of death in patients with triple-negative breast cancer (TNBC). Tumor-associated macrophages (TAMs) represent the M2-like phenotype with potent immunosuppressive activity, and play a pro-tumor role in TNBC lung metastasis. Sohlh2 belongs to the basic helix-loop-helix transcription factor family. However, its role in macrophages polarization remains unknown, especially in TNBC progression. Here we demonstrated that Sohlh2 overexpression promoted M2 macrophage polarization. Moreover, high expression of Sohlh2 in M2-like macrophage enhanced TNBC cell growth, migration and lung metastasis in vivo and in vitro. Mechanistically, we revealed that Sohlh2 functioned through up-regulating LXRα, ABCA1, ABCG1 expression and disturbing the lipid homeostasis on the membrane of macrophages. Sohlh2 could directly bind to the promoter of LXRα and promote its transcription activity. E3 ubiquitin ligase TRIM21 promoted Sohlh2 ubiquitination and degradation, and suppressed M2 macrophage polarization and TNBC progression. Collectively, our findings suggested that Sohlh2 in macrophage could be a novel therapeutic target for TNBC metastatic treatment.

DOI: https://doi.org/10.1038/s41419-023-06383-x
Blood Adv. 2023 Dec 19. pii: bloodadvances.2022009557. [Epub ahead of print]

ZAP-70 augments tonic B-cell receptor and CCR7 signaling in IGHV unmutated chronic lymphocytic leukemia.

Ingo Ringshausen, Jingyu Chen, Vijitha Sathiaseelan, Chandra Sr Chilamakuri, Constanze A Jakwerth, Clive S D'Santos, Valar Nila Roamio Franklin.

Expression of ZAP-70 in a subset of CLL patients positively correlates with the absence of IGHV mutations and is indicative of a more active disease and shorter treatment free survival. We recently demonstrated that ZAP-70 regulates the constitutive expression of CCL3 and CCL4, activation of AKT and expression of MYC in the absence of an overt BCR signal, bona fide functions of BCR activation. We here provide evidence that these features relate to the presence of a constitutive tonic BCR signal, exclusively found in IGHV unmutated CLL and dependent on the ZAP-70 mediated activation of AKT and its downstream target GSK3b. These findings are associated with increased steady state activation of CD19 and SRC. Notably this tonic BCR signal is not present in IGHV mutated CLL cells, discordantly expressing ZAP-70. Quantitative mass spectrometry and phosphoprotein-analyses indicate that this ZAP-70-dependent, tonic BCR-signal regulates CLL cell migration through phosphorylation of LCP1 on serine-5. Indeed, we show that CCL19- and CCL21-induced chemotaxis is regulated by and dependent on the expression of ZAP-70 through its function to enhance CCR7 signaling to LCP1. Thus, our data demonstrate that ZAP-70 converges a tonic BCR signal, exclusively present in IGHV unmutated CLL, and CCR7-mediated chemotaxis.

DOI: https://doi.org/10.1182/bloodadvances.2022009557
Cell Rep. 2023 Dec 19. pii: S2211-1247(23)01596-6. [Epub ahead of print]43(1): 113584

Subcutaneous white adipose tissue independently regulates burn-induced hypermetabolism via immune-adipose crosstalk.

Carly M Knuth, Dalia Barayan, Ju Hee Lee, Christopher Auger, Lauar de Brito Monteiro, Zachary Ricciuti, Dea Metko, Lisa Wells, Hoon-Ki Sung, Robert A Screaton, Marc G Jeschke.

  Severe burns induce a chronic hypermetabolic state that persists well past wound closure, indicating that additional internal mechanisms must be involved. Adipose tissue is suggested to be a central regulator in perpetuating hypermetabolism, although this has not been directly tested. Here, we show that thermogenic adipose tissues are activated in parallel to increases in hypermetabolism independent of cold stress. Using an adipose tissue transplantation model, we discover that burn-derived subcutaneous white adipose tissue alone is sufficient to invoke a hypermetabolic response in a healthy recipient mouse. Concomitantly, transplantation of healthy adipose tissue alleviates metabolic dysfunction in a burn recipient. We further show that the nicotinic acetylcholine receptor signaling pathway may mediate an immune-adipose crosstalk to regulate adipose tissue remodeling post-injury. Targeting this pathway could lead to innovative therapeutic interventions to counteract hypermetabolic pathologies.

Keywords:  CP: Metabolism; adipose tissue; browning; burn injury; hypermetabolism; inflammation

DOI:  https://doi.org/10.1016/j.celrep.2023.113584
Nat Commun. 2023 Dec 15. 14(1): 8356

Rho GTPase activity crosstalk mediated by Arhgef11 and Arhgef12 coordinates cell protrusion-retraction cycles.

Suchet Nanda, Abram Calderon, Arya Sachan, Thanh-Thuy Duong, Johannes Koch, Xiaoyi Xin, Djamschid Solouk-Stahlberg, Yao-Wen Wu, Perihan Nalbant, Leif Dehmelt.

Rho GTPases play a key role in the spatio-temporal coordination of cytoskeletal dynamics during cell migration. Here, we directly investigate crosstalk between the major Rho GTPases Rho, Rac and Cdc42 by combining rapid activity perturbation with activity measurements in mammalian cells. These studies reveal that Rac stimulates Rho activity. Direct measurement of spatio-temporal activity patterns show that Rac activity is tightly and precisely coupled to local cell protrusions, followed by Rho activation during retraction. Furthermore, we find that the Rho-activating Lbc-type GEFs Arhgef11 and Arhgef12 are enriched at transient cell protrusions and retractions and recruited to the plasma membrane by active Rac. In addition, their depletion reduces activity crosstalk, cell protrusion-retraction dynamics and migration distance and increases migration directionality. Thus, our study shows that Arhgef11 and Arhgef12 facilitate exploratory cell migration by coordinating cell protrusion and retraction by coupling the activity of the associated regulators Rac and Rho.

DOI: https://doi.org/10.1038/s41467-023-43875-y
Proc Natl Acad Sci U S A. 2023 Dec 19. 120(51): e2300474120

Pleural macrophages translocate to the lung during infection to promote improved influenza outcomes.

James P Stumpff, Sang Yong Kim, Matthew I McFadden, Andrew Nishida, Roksana Shirazi, Yael Steuerman, Irit Gat-Viks, Adriana Forero, Meera G Nair, Juliet Morrison.

  Seasonal influenza results in 3 to 5 million cases of severe disease and 250,000 to 500,000 deaths annually. Macrophages have been implicated in both the resolution and progression of the disease, but the drivers of these outcomes are poorly understood. We probed mouse lung transcriptomic datasets using the Digital Cell Quantifier algorithm to predict immune cell subsets that correlated with mild or severe influenza A virus (IAV) infection outcomes. We identified a unique lung macrophage population that transcriptionally resembled small serosal cavity macrophages and whose presence correlated with mild disease. Until now, the study of serosal macrophage translocation in the context of viral infections has been neglected. Here, we show that pleural macrophages (PMs) migrate from the pleural cavity to the lung after infection with IAV. We found that the depletion of PMs increased morbidity and pulmonary inflammation. There were increased proinflammatory cytokines in the pleural cavity and an influx of neutrophils within the lung. Our results show that PMs are recruited to the lung during IAV infection and contribute to recovery from influenza. This study expands our knowledge of PM plasticity and identifies a source of lung macrophages independent of monocyte recruitment and local proliferation.

Keywords:  influenza; macrophages; pleural cavity; tissue deconvolution; transcriptomics

DOI:  https://doi.org/10.1073/pnas.2300474120
Cell Metab. 2023 Dec 14. pii: S1550-4131(23)00449-7. [Epub ahead of print]

Mitochondrial fatty acid synthesis is an emergent central regulator of mammalian oxidative metabolism.

Riley J Wedan, Jacob Z Longenecker, Sara M Nowinski.

  Contrary to their well-known functions in nutrient breakdown, mitochondria are also important biosynthetic hubs and express an evolutionarily conserved mitochondrial fatty acid synthesis (mtFAS) pathway. mtFAS builds lipoic acid and longer saturated fatty acids, but its exact products, their ultimate destination in cells, and the cellular significance of the pathway are all active research questions. Moreover, why mitochondria need mtFAS despite their well-defined ability to import fatty acids is still unclear. The identification of patients with inborn errors of metabolism in mtFAS genes has sparked fresh research interest in the pathway. New mammalian models have provided insights into how mtFAS coordinates many aspects of oxidative mitochondrial metabolism and raise questions about its role in diseases such as obesity, diabetes, and heart failure. In this review, we discuss the products of mtFAS, their function, and the consequences of mtFAS impairment across models and in metabolic disease.

Keywords:  fatty acids; inborn errors of metabolism; lipid metabolism; lipids; mitochondria; mitochondrial fatty acid synthesis; mouse models; mtFAS

DOI:  https://doi.org/10.1016/j.cmet.2023.11.017
Cell Rep. 2023 Dec 19. pii: S2211-1247(23)01607-8. [Epub ahead of print]43(1): 113595

Synaptic plasticity via receptor tyrosine kinase/G-protein-coupled receptor crosstalk.

Cristina Lao-Peregrin, Guoqing Xiang, Jihye Kim, Ipsit Srivastava, Alexandra B Fall, Danielle M Gerhard, Piia Kohtala, Daegeon Kim, Minseok Song, Mikel Garcia-Marcos, Joshua Levitz, Francis S Lee.

  Cellular signaling involves a large repertoire of membrane receptors operating in overlapping spatiotemporal regimes and targeting many common intracellular effectors. However, both the molecular mechanisms and the physiological roles of crosstalk between receptors, especially those from different superfamilies, are poorly understood. We find that the receptor tyrosine kinase (RTK) TrkB and the G-protein-coupled receptor (GPCR) metabotropic glutamate receptor 5 (mGluR5) together mediate hippocampal synaptic plasticity in response to brain-derived neurotrophic factor (BDNF). Activated TrkB enhances constitutive mGluR5 activity to initiate a mode switch that drives BDNF-dependent sustained, oscillatory Ca2+ signaling and enhanced MAP kinase activation. This crosstalk is mediated, in part, by synergy between Gβγ, released by TrkB, and Gαq-GTP, released by mGluR5, to enable physiologically relevant RTK/GPCR crosstalk.

Keywords:  BDNF; CP: Cell biology; CP: Neuroscience; G-protein-coupled receptor; GBA motif; TrkB; calcium signaling; metabotropic glutamate receptor; neuromodulation; neurotrophin; receptor tyrosine kinase; synaptic plasticity

DOI:  https://doi.org/10.1016/j.celrep.2023.113595