bims-imicid 2021-11-21 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2021–11–21
nineteen papers selected by
Dylan Ryan, University of Cambridge

The role of the electron transport chain in immunity.
Metabolic reprogramming of macrophages instigates CCL21-induced arthritis.
Accumulation of cholesterol suppresses oxidative phosphorylation and altered responses to inflammatory stimuli of macrophages.
Desmosterol suppresses macrophage inflammasome activation and protects against vascular inflammation and atherosclerosis.
Myeloid Cell-Specific IL-4 Receptor Knockout Partially Protects from Adipose Tissue Inflammation.
Dual NADPH oxidases DUOX1 and DUOX2 synthesize NAADP and are necessary for Ca2+ signaling during T cell activation.
CRISPR screens unveil signal hubs for nutrient licensing of T cell immunity.
Targeting T cell metabolism for immunotherapy.
Intercellular nanotubes mediate mitochondrial trafficking between cancer and immune cells.
Slit2-Mediated Metabolic Reprogramming in Bone Marrow-Derived Macrophages Enhances Antitumor Immunity.
Slit3 secreted from M2-like macrophages increases sympathetic activity and thermogenesis in adipose tissue.
Macrophage ROBOcalls rattle adipose nerves.
Metabolic imbalance of T cells in COVID-19 is hallmarked by basigin and mitigated by dexamethasone.
Efferocytosis induces macrophage proliferation to help resolve tissue injury.
The APPL1-Rab5 axis restricts NLRP3 inflammasome activation through early endosomal-dependent mitophagy in macrophages.
Indoleamine 2,3-dioxygenase 1 is essential for sustaining durable antibody responses.
Lipid droplet accumulation occurs early following Salmonella infection and contributes to intracellular bacterial survival and replication.
TM4SF5-dependent crosstalk between hepatocytes and macrophages to reprogram the inflammatory environment.
Multiple acyl-CoA dehydrogenase deficiency kills Mycobacterium tuberculosis in vitro and during infection.

FASEB J. 2021 Dec;35(12): e21974

The role of the electron transport chain in immunity.

Maureen Yin, Luke A J O'Neill.

  The electron transport chain (ETC) couples oxidative phosphorylation (OXPHOS) with ATP synthase to drive the generation of ATP. In immune cells, research surrounding the ETC has drifted away from bioenergetics since the discovery of cytochrome c (Cyt c) release as a signal for programmed cell death. Complex I has been shown to generate reactive oxygen species (ROS), with key roles identified in inflammatory macrophages and T helper 17 cells (TH 17) cells. Complex II is the site of reverse electron transport (RET) in inflammatory macrophages and is also responsible for regulating fumarate levels linking to epigenetic changes. Complex III also produces ROS which activate hypoxia-inducible factor 1-alpha (HIF-1α) and can participate in regulatory T cell (Treg ) function. Complex IV is required for T cell activation and differentiation and the proper development of Treg subsets. Complex V is required for TH 17 differentiation and can be expressed on the surface of tumor cells where it is recognized by anti-tumor T and NK cells. In this review, we summarize these findings and speculate on the therapeutic potential of targeting the ETC as an anti-inflammatory strategy.

Keywords:  T-lymphocytes; electron transport chain (ETC); immunometabolism; macrophage; mitochondria; oxidative phosphorylation

DOI:  https://doi.org/10.1096/fj.202101161R
Immunol Cell Biol. 2021 Nov 14.

Metabolic reprogramming of macrophages instigates CCL21-induced arthritis.

Katrien Van Raemdonck, Sadiq Umar, Karol Palasiewicz, Anja Meyer, Michael V Volin, Huan J Chang, Mina Al-Awqati, Ryan K Zomorrodi, Shiva Shahrara.

  The current study was designed to delineate the functional significance of CCL21 on metabolic reprogramming in experimental arthritis and rheumatoid arthritis (RA) differentiated macrophages (MΦs). To characterize the influence of CCL21 on immunometabolism, its mechanism of action was elucidated by dysregulating glucose uptake in preclinical arthritis and RA MΦs. In CCL21 arthritic joints, the glycolytic intermediates, HIF1α, cMYC, and GLUT1 were overexpressed compared to oxidative regulators, ESSRγ and PGC1α. Interestingly, 2-DG therapy mitigated CCL21-induced arthritis by restraining the number of joint F480+ iNOS+ MΦs without impacting F480+ Arginase+ MΦs. Similar to the preclinical findings, blockade of glycolysis negated CCL21-polarized CD14+ CD86+ GLUT+ MΦ frequency; however, CD14+ CD206+ GLUT+ MΦs were not implicated in this process. In CCL21-induced arthritis and differentiated RA MΦs, the inflammatory imprint was uniquely intercepted by 2-DG via IL-6 downregulation. Despite, the more expansive inflammatory response of CCL21 in the arthritic joints relative to the differentiated RA MΦs, 2-DG was ineffective on joint TNFα, IL-1β, CCL2, and CCL5 enrichment. In contrast, disruption of glycolysis markedly impaired CCL21-induced HIF1α and cMYC signaling in arthritic mice. Notably, in RA MΦs, glycolysis interception was directed on dysregulating CCL21-enhanced HIF1α transcription. Nonetheless, in concurrence with the diminished IL-6 levels, CCL21-differentiation of CD14+ CD86+ GLUT1+ MΦs was reversed by glycolysis and HIIF1α inhibition. Moreover, in the CCL21 experimental arthritis or differentiated RA MΦs, the malfunctioning metabolic machinery was accompanied by impaired oxidative phosphorylation due to reduced PGC1α or PPARγ expression. CCL21 reconfigures naïve myeloid cells into glycolytic RA CD14+ CD86+ GLUT+ IL-6high HIF1αhigh MΦs, thus inhibiting the CCL21/CCR7 pathway may provide a promising therapeutic strategy.

Keywords:  CCL21-induced arthritis; CD14+CD86+GLUT+ macrophages; Glycolysis; Rheumatoid arthritis (RA)

DOI:  https://doi.org/10.1111/imcb.12512
Biochem Biophys Rep. 2021 Dec;28 101166

Accumulation of cholesterol suppresses oxidative phosphorylation and altered responses to inflammatory stimuli of macrophages.

Yi-Chou Chiu, Pei-Wen Chu, Hua-Ching Lin, Shau-Kwaun Chen.

  Hypercholesterolemia induces intracellular accumulation of cholesterol in macrophages and other immune cells, causing immunological dysfunctions. On cellular levels, cholesterol enrichment might lead to mitochondrial metabolic reprogramming and change macrophage functions. Additionally, as cholesterol is permeable to the plasma membrane and might integrate into the membranous organelles, such as endoplasmic reticulum or mitochondria, cholesterol enrichment might change the functions or properties of these organelles, and ultimately alters the cellular functions. In this study, we investigate the mitochondrial alterations and intracellular oxidative stress induced by accumulation of cholesterol in the macrophages, and the possible immunological impacts caused by these alterations. Macrophage cells RAW264.7 were treated with cholesterol to induce intracellular accumulation of cholesterol, which further triggered the reduced production of reactive oxygen/nitrogen species, as well as decrease of oxidative phosphorylation. Basal respiration rate, ATP production and non-mitochondrial oxygen consumption are all suppressed. In contrast, glycolysis remained unaltered in this cholesterol-enriched condition. Previous studies demonstrated that metabolic profiles are associated with macrophage polarization. We further verified whether this metabolic reprogramming influences the macrophage responses to pro-inflammatory or anti-inflammatory stimuli. Our results showed the changes of transcriptional regulations in both pro-inflammatory and anti-inflammatory genes, but not specific toward M1 or M2 polarization. Collectively, the accumulation of cholesterol induced mitochondrial metabolic reprogramming and suppressed the production of oxidative stress, and induced the alterations of macrophage functions.

Keywords:  Cholesterol; Inflammatory response; Macrophage; Oxidative phosphorylation; Oxidative stress

DOI:  https://doi.org/10.1016/j.bbrep.2021.101166
Proc Natl Acad Sci U S A. 2021 Nov 23. pii: e2107682118. [Epub ahead of print]118(47):

Desmosterol suppresses macrophage inflammasome activation and protects against vascular inflammation and atherosclerosis.

Xinbo Zhang, Jeffrey G McDonald, Binod Aryal, Alberto Canfrán-Duque, Emily L Goldberg, Elisa Araldi, Wen Ding, Yuhua Fan, Bonne M Thompson, Abhishek K Singh, Qian Li, George Tellides, Jose Ordovás-Montanes, Rolando García Milian, Vishwa Deep Dixit, Elina Ikonen, Yajaira Suárez, Carlos Fernández-Hernando.

  Cholesterol biosynthetic intermediates, such as lanosterol and desmosterol, are emergent immune regulators of macrophages in response to inflammatory stimuli or lipid overloading, respectively. However, the participation of these sterols in regulating macrophage functions in the physiological context of atherosclerosis, an inflammatory disease driven by the accumulation of cholesterol-laden macrophages in the artery wall, has remained elusive. Here, we report that desmosterol, the most abundant cholesterol biosynthetic intermediate in human coronary artery lesions, plays an essential role during atherogenesis, serving as a key molecule integrating cholesterol homeostasis and immune responses in macrophages. Depletion of desmosterol in myeloid cells by overexpression of 3β-hydroxysterol Δ24-reductase (DHCR24), the enzyme that catalyzes conversion of desmosterol to cholesterol, promotes the progression of atherosclerosis. Single-cell transcriptomics in isolated CD45+CD11b+ cells from atherosclerotic plaques demonstrate that depletion of desmosterol increases interferon responses and attenuates the expression of antiinflammatory macrophage markers. Lipidomic and transcriptomic analysis of in vivo macrophage foam cells demonstrate that desmosterol is a major endogenous liver X receptor (LXR) ligand involved in LXR/retinoid X receptor (RXR) activation and thus macrophage foam cell formation. Decreased desmosterol accumulation in mitochondria promotes macrophage mitochondrial reactive oxygen species production and NLR family pyrin domain containing 3 (NLRP3)-dependent inflammasome activation. Deficiency of NLRP3 or apoptosis-associated speck-like protein containing a CARD (ASC) rescues the increased inflammasome activity and atherogenesis observed in desmosterol-depleted macrophages. Altogether, these findings underscore the critical function of desmosterol in the atherosclerotic plaque to dampen inflammation by integrating with macrophage cholesterol metabolism and inflammatory activation and protecting from disease progression.

Keywords:  atherosclerosis; cholesterol; immunometabolism; macrophages

DOI:  https://doi.org/10.1073/pnas.2107682118
J Immunol. 2021 Nov 17. pii: ji2100699. [Epub ahead of print]

Myeloid Cell-Specific IL-4 Receptor Knockout Partially Protects from Adipose Tissue Inflammation.

Jan Ackermann, Lilli Arndt, Michaela Kirstein, Constance Hobusch, Georg Brinker, Nora Klöting, Julia Braune, Martin Gericke.

IL-4 receptor signaling is supposed to play a major role in anti-inflammatory polarization and proliferation of adipose tissue macrophages. In this study, we examined the metabolic and inflammatory phenotype of C57BL/6J mice (IIl4ra) with LysM-dependent knockout (IIl4ra Δmyel) of the IL-4 receptor α-chain (IL-4Rα), the mandatory signaling component of IL-4 and IL-13, on chow and high-fat diet. Lean IIl4ra Δmyel mice showed decreased insulin sensitivity, no divergent adipose tissue macrophage polarization, but an increased percentage of CD8+ T cells in visceral adipose tissue. After 20 wk of a high-fat diet, IIl4ra Δmyel mice exhibited higher glucose tolerance, no changes in the lymphocyte compartment and fewer M1 macrophages in visceral adipose tissue. In vivo adipose tissue macrophage proliferation measured by BrdU incorporation was unaffected by Il4ra knockout. Interestingly, we show that IL-4Rα signaling directly augmented Itgax (Cd11c) gene expression in bone marrow-derived macrophages and increased the amount of CD11c+ macrophages in adipose tissue explants. Myeloid cell-specific knockout of Il4ra deteriorated insulin sensitivity in lean mice but improved parameters of glucose homeostasis and partially protected from adipose tissue inflammation in obese mice. Hence, IL-4Rα signaling probably plays a minor role in maintaining the macrophage M2 population and proliferation rates in vivo. Moreover, our data indicate that IL-4 signaling plays a proinflammatory role in adipose tissue inflammation by directly upregulating CD11c on adipose tissue macrophages.

DOI: https://doi.org/10.4049/jimmunol.2100699
Sci Signal. 2021 Nov 16. 14(709): eabe3800

Dual NADPH oxidases DUOX1 and DUOX2 synthesize NAADP and are necessary for Ca2+ signaling during T cell activation.

Feng Gu, Aileen Krüger, Hannes G Roggenkamp, Rick Alpers, Dmitri Lodygin, Vincent Jaquet, Franziska Möckl, Lola C Hernandez C, Kai Winterberg, Andreas Bauche, Anette Rosche, Helmut Grasberger, John Y Kao, Daniel Schetelig, René Werner, Katrin Schröder, Michael Carty, Andrew G Bowie, Samuel Huber, Chris Meier, Hans-Willi Mittrücker, Joerg Heeren, Karl-Heinz Krause, Alexander Flügel, Björn-Philipp Diercks, Andreas H Guse.

[Figure: see text].

DOI: https://doi.org/10.1126/scisignal.abe3800
Nature. 2021 Nov 18.

CRISPR screens unveil signal hubs for nutrient licensing of T cell immunity.

Lingyun Long, Jun Wei, Seon Ah Lim, Jana L Raynor, Hao Shi, Jon P Connelly, Hong Wang, Cliff Guy, Boer Xie, Nicole M Chapman, Guotong Fu, Yanyan Wang, Hongling Huang, Wei Su, Jordy Saravia, Isabel Risch, Yong-Dong Wang, Yuxin Li, Mingming Niu, Yogesh Dhungana, Anil Kc, Peipei Zhou, Peter Vogel, Jiyang Yu, Shondra M Pruett-Miller, Junmin Peng, Hongbo Chi.

Nutrients are emerging regulators of adaptive immunity1. Selective nutrients interplay with immunological signals to activate mechanistic target of rapamycin complex 1 (mTORC1), a key driver of cell metabolism2-4, but how these environmental signals are integrated for immune regulation remains unclear. Here we use genome-wide CRISPR screening combined with protein-protein interaction networks to identify regulatory modules that mediate immune receptor- and nutrient-dependent signalling to mTORC1 in mouse regulatory T (Treg) cells. SEC31A is identified to promote mTORC1 activation by interacting with the GATOR2 component SEC13 to protect it from SKP1-dependent proteasomal degradation. Accordingly, loss of SEC31A impairs T cell priming and Treg suppressive function in mice. In addition, the SWI/SNF complex restricts expression of the amino acid sensor CASTOR1, thereby enhancing mTORC1 activation. Moreover, we reveal that the CCDC101-associated SAGA complex is a potent inhibitor of mTORC1, which limits the expression of glucose and amino acid transporters and maintains T cell quiescence in vivo. Specific deletion of Ccdc101 in mouse Treg cells results in uncontrolled inflammation but improved antitumour immunity. Collectively, our results establish epigenetic and post-translational mechanisms that underpin how nutrient transporters, sensors and transducers interplay with immune signals for three-tiered regulation of mTORC1 activity and identify their pivotal roles in licensing T cell immunity and immune tolerance.

DOI: https://doi.org/10.1038/s41586-021-04109-7
J Leukoc Biol. 2021 Nov 15.

Targeting T cell metabolism for immunotherapy.

Jie Gao, Yanbo Liu, Jian Wei, Linlan Jiang, Jianwen Mao, Chih-Hao Chang, Duojiao Wu.

  T cells play an important role in antitumor immunity. Numbers and function of T cells are controlled by regulating the uptake and utilization of nutrients, and their antitumor activity can be promoted by targeting metabolic pathways. In this review, we highlight the relationship between metabolism and cellular function of T cells. Specifically, we emphasize the metabolic state of tumor-infiltrating T cells and review key pathways that affect the antitumor function of T cells. In the field of tumor immunotherapy, targeting T cell metabolism to enhance the immune response is a new therapeutic strategy for enhancing immunotherapy combined with traditional treatments.

Keywords:  T cell; antitumor immunity; immunotherapy; metabolic reprogramming

DOI:  https://doi.org/10.1002/JLB.5MR0921-011R
Nat Nanotechnol. 2021 Nov 18.

Intercellular nanotubes mediate mitochondrial trafficking between cancer and immune cells.

Tanmoy Saha, Chinmayee Dash, Ruparoshni Jayabalan, Sachin Khiste, Arpita Kulkarni, Kiran Kurmi, Jayanta Mondal, Pradip K Majumder, Aditya Bardia, Hae Lin Jang, Shiladitya Sengupta.

Cancer progresses by evading the immune system. Elucidating diverse immune evasion strategies is a critical step in the search for next-generation immunotherapies for cancer. Here we report that cancer cells can hijack the mitochondria from immune cells via physical nanotubes. Mitochondria are essential for metabolism and activation of immune cells. By using field-emission scanning electron microscopy, fluorophore-tagged mitochondrial transfer tracing and metabolic quantification, we demonstrate that the nanotube-mediated transfer of mitochondria from immune cells to cancer cells metabolically empowers the cancer cells and depletes the immune cells. Inhibiting the nanotube assembly machinery significantly reduced mitochondrial transfer and prevented the depletion of immune cells. Combining a farnesyltransferase and geranylgeranyltransferase 1 inhibitor, namely, L-778123, which partially inhibited nanotube formation and mitochondrial transfer, with a programmed cell death protein 1 immune checkpoint inhibitor improved the antitumour outcomes in an aggressive immunocompetent breast cancer model. Nanotube-mediated mitochondrial hijacking can emerge as a novel target for developing next-generation immunotherapy agents for cancer.

DOI: https://doi.org/10.1038/s41565-021-01000-4
Front Immunol. 2021 ;12 753477

Slit2-Mediated Metabolic Reprogramming in Bone Marrow-Derived Macrophages Enhances Antitumor Immunity.

Kirti Kaul, Martin Benej, Sanjay Mishra, Dinesh K Ahirwar, Marshleen Yadav, Kristin I Stanford, Naduparambil K Jacob, Nicholas C Denko, Ramesh K Ganju.

  Slit2 exerts antitumor effects in various cancers; however, the underlying mechanism, especially its role in regulating the immune, especially in the bone marrow niche, system is still unknown. Elucidating the behavior of macrophages in tumor progression can potentially improve immunotherapy. Using a spontaneous mammary tumor virus promoter-polyoma middle T antigen (PyMT) breast cancer mouse model, we observed that Slit2 increased the abundance of antitumor M1 macrophage in the bone marrow upon differentiation in vitro. Moreover, myeloablated PyMT mice injected with Slit2-treated bone marrow allografts showed a marked reduction in tumor growth, with enhanced recruitment of M1 macrophage in their tumor stroma. Mechanistic studies revealed that Slit2 significantly enhanced glycolysis and reduced fatty acid oxidation in bone marrow-derived macrophages (BMDMs). Slit2 treatment also altered mitochondrial respiration metabolites in macrophages isolated from healthy human blood that were treated with plasma from breast cancer patients. Overall, this study, for the first time, shows that Slit2 increases BMDM polarization toward antitumor phenotype by modulating immune-metabolism. Furthermore, this study provides evidence that soluble Slit2 could be developed as novel therapeutic strategy to enhance antitumor immune response.

Keywords:  PyMT; Slit2; breast cancer; immunometabolism; macrophage polarization

DOI:  https://doi.org/10.3389/fimmu.2021.753477
Nat Metab. 2021 Nov;3(11): 1536-1551

Slit3 secreted from M2-like macrophages increases sympathetic activity and thermogenesis in adipose tissue.

Yi-Na Wang, Yan Tang, Zhihui He, Hong Ma, Linyuan Wang, Yang Liu, Qiqi Yang, Dongning Pan, Cuiqing Zhu, Shuwen Qian, Qi-Qun Tang.

Beiging of white adipose tissue (WAT) is associated with an increase of anti-inflammatory M2-like macrophages in WAT. However, mechanisms through which M2-like macrophages affect beiging are incompletely understood. Here, we show that the macrophage cytokine Slit3 is secreted by adipose tissue macrophages and promotes cold adaptation by stimulating sympathetic innervation and thermogenesis in mice. Analysing the transcriptome of M2-like macrophages in murine inguinal WAT (iWAT) after cold exposure, we identify Slit3 as a secreted cytokine. Slit3 binds to the ROBO1 receptor on sympathetic neurons to stimulate Ca2+/calmodulin-dependent protein kinase II signalling and norepinephrine release, which enhances adipocyte thermogenesis. Adoptive transfer of Slit3-overexpressing M2 macrophages to iWAT promotes beiging and thermogenesis, whereas mice that lack Slit3 in myeloid cells are cold-intolerant and gain more weight. Our findings shed new light on the integral role of M2-like macrophages for adipose tissue homeostasis and uncover the macrophage-Slit3-sympathetic neuron-adipocyte signalling axis as a regulator of long-term cold adaptation.

DOI: https://doi.org/10.1038/s42255-021-00482-9
Nat Metab. 2021 Nov;3(11): 1441-1442

Macrophage ROBOcalls rattle adipose nerves.

Michael P Czech.

DOI: https://doi.org/10.1038/s42255-021-00484-7
J Clin Invest. 2021 11 15. pii: e148225. [Epub ahead of print]131(22):

Metabolic imbalance of T cells in COVID-19 is hallmarked by basigin and mitigated by dexamethasone.

Peter J Siska, Sonja-Maria Decking, Nathalie Babl, Carina Matos, Christina Bruss, Katrin Singer, Jana Klitzke, Marian Schön, Jakob Simeth, Josef Köstler, Heiko Siegmund, Ines Ugele, Michael Paulus, Alexander Dietl, Kristina Kolodova, Louisa Steines, Katharina Freitag, Alice Peuker, Gabriele Schönhammer, Johanna Raithel, Bernhard Graf, Florian Geismann, Matthias Lubnow, Matthias Mack, Peter Hau, Christopher Bohr, Ralph Burkhardt, Andre Gessner, Bernd Salzberger, Ralf Wagner, Frank Hanses, Florian Hitzenbichler, Daniel Heudobler, Florian Lüke, Tobias Pukrop, Wolfgang Herr, Daniel Wolff, Rainer Spang, Hendrik Poeck, Petra Hoffmann, Jonathan Jantsch, Christoph Brochhausen, Dirk Lunz, Michael Rehli, Marina Kreutz, Kathrin Renner.

  Metabolic pathways regulate immune responses and disrupted metabolism leads to immune dysfunction and disease. Coronavirus disease 2019 (COVID-19) is driven by imbalanced immune responses, yet the role of immunometabolism in COVID-19 pathogenesis remains unclear. By investigating 87 patients with confirmed SARS-CoV-2 infection, 6 critically ill non-COVID-19 patients, and 47 uninfected controls, we found an immunometabolic dysregulation in patients with progressed COVID-19. Specifically, T cells, monocytes, and granulocytes exhibited increased mitochondrial mass, yet only T cells accumulated intracellular reactive oxygen species (ROS), were metabolically quiescent, and showed a disrupted mitochondrial architecture. During recovery, T cell ROS decreased to match the uninfected controls. Transcriptionally, T cells from severe/critical COVID-19 patients showed an induction of ROS-responsive genes as well as genes related to mitochondrial function and the basigin network. Basigin (CD147) ligands cyclophilin A and the SARS-CoV-2 spike protein triggered ROS production in T cells in vitro. In line with this, only PCR-positive patients showed increased ROS levels. Dexamethasone treatment resulted in a downregulation of ROS in vitro and T cells from dexamethasone-treated patients exhibited low ROS and basigin levels. This was reflected by changes in the transcriptional landscape. Our findings provide evidence of an immunometabolic dysregulation in COVID-19 that can be mitigated by dexamethasone treatment.

Keywords:  Inflammation; Metabolism; Mitochondria; Monocytes; T cells

DOI:  https://doi.org/10.1172/JCI148225
Cell Metab. 2021 Nov 10. pii: S1550-4131(21)00527-1. [Epub ahead of print]

Efferocytosis induces macrophage proliferation to help resolve tissue injury.

Brennan D Gerlach, Patrick B Ampomah, Arif Yurdagul, Chuang Liu, Max C Lauring, Xiaobo Wang, Canan Kasikara, Na Kong, Jinjun Shi, Wei Tao, Ira Tabas.

  Apoptotic cell clearance by macrophages (efferocytosis) promotes resolution signaling pathways, which can be triggered by molecules derived from the phagolysosomal degradation of apoptotic cells. We show here that nucleotides derived from the hydrolysis of apoptotic cell DNA by phagolysosomal DNase2a activate a DNA-PKcs-mTORC2/Rictor pathway that increases Myc to promote non-inflammatory macrophage proliferation. Efferocytosis-induced proliferation expands the pool of resolving macrophages in vitro and in mice, including zymosan-induced peritonitis, dexamethasone-induced thymocyte apoptosis, and atherosclerosis regression. In the dexamethasone-thymus model, hematopoietic Rictor deletion blocked efferocytosing macrophage proliferation, apoptotic cell clearance, and tissue resolution. In atherosclerosis regression, silencing macrophage Rictor or DNase2a blocked efferocyte proliferation, apoptotic cell clearance, and plaque stabilization. In view of previous work showing that other types of apoptotic cell cargo can promote resolution in individual efferocytosing macrophages, the findings here suggest that signaling-triggered apoptotic cell-derived nucleotides can amplify this benefit by increasing the number of these macrophages.

Keywords:  DNase2a; Erk1/2 signaling; MerTK; Myc; atherosclerosis; efferocytosis; inflammation resolution; mTORC2/Rictor; macrophage; macrophage proliferation

DOI:  https://doi.org/10.1016/j.cmet.2021.10.015
Nat Commun. 2021 Nov 17. 12(1): 6637

The APPL1-Rab5 axis restricts NLRP3 inflammasome activation through early endosomal-dependent mitophagy in macrophages.

Kelvin Ka Lok Wu, KeKao Long, Huige Lin, Parco Ming Fai Siu, Ruby Lai Chong Hoo, Dewei Ye, Aimin Xu, Kenneth King Yip Cheng.

Although mitophagy is known to restrict NLRP3 inflammasome activation, the underlying regulatory mechanism remains poorly characterized. Here we describe a type of early endosome-dependent mitophagy that limits NLRP3 inflammasome activation. Deletion of the endosomal adaptor protein APPL1 impairs mitophagy, leading to accumulation of damaged mitochondria producing reactive oxygen species (ROS) and oxidized cytosolic mitochondrial DNA, which in turn trigger NLRP3 inflammasome overactivation in macrophages. NLRP3 agonist causes APPL1 to translocate from early endosomes to mitochondria, where it interacts with Rab5 to facilitate endosomal-mediated mitophagy. Mice deficient for APPL1 specifically in hematopoietic cell are more sensitive to endotoxin-induced sepsis, obesity-induced inflammation and glucose dysregulation. These are associated with increased expression of systemic interleukin-1β, a major product of NLRP3 inflammasome activation. Our findings indicate that the early endosomal machinery is essential to repress NLRP3 inflammasome hyperactivation by promoting mitophagy in macrophages.

DOI: https://doi.org/10.1038/s41467-021-26987-1
Immunity. 2021 Nov 15. pii: S1074-7613(21)00411-8. [Epub ahead of print]

Indoleamine 2,3-dioxygenase 1 is essential for sustaining durable antibody responses.

Shivana M Lightman, Jennifer L Peresie, Louise M Carlson, G Aaron Holling, Mackenzie M Honikel, Colin A Chavel, Michael J Nemeth, Scott H Olejniczak, Kelvin P Lee.

  Humoral immunity is essential for protection against pathogens, emphasized by the prevention of 2-3 million deaths worldwide annually by childhood immunizations. Long-term protective immunity is dependent on the continual production of neutralizing antibodies by the subset of long-lived plasma cells (LLPCs). LLPCs are not intrinsically long-lived, but require interaction with LLPC niche stromal cells for survival. However, it remains unclear which and how these interactions sustain LLPC survival and long-term humoral immunity. We now have found that the immunosuppressive enzyme indoleamine 2,3- dioxygenase 1 (IDO1) is required to sustain antibody responses and LLPC survival. Activation of IDO1 occurs upon the engagement of CD80/CD86 on the niche dendritic cells by CD28 on LLPC. Kynurenine, the product of IDO1 catabolism, activates the aryl hydrocarbon receptor in LLPC, reinforcing CD28 expression and survival signaling. These findings expand the immune function of IDO1 and uncover a novel pathway for sustaining LLPC survival and humoral immunity.

Keywords:  IDO1; PC niche; durable humoral immunity; long lived plasma cells; plasma cell survival

DOI:  https://doi.org/10.1016/j.immuni.2021.10.005
Mol Microbiol. 2021 Nov 16.

Lipid droplet accumulation occurs early following Salmonella infection and contributes to intracellular bacterial survival and replication.

Ellen Kiarely Souza, Filipe S Pereira-Dutra, Matheus A Rajão, Felipe Ferraro-Moreira, Taynná C Goltara-Gomes, Tamires Cunha-Fernandes, Julia da Cunha Santos, Elisa B Prestes, Warrison A Andrade, Dario S Zamboni, Marcelo T Bozza, Patrícia T Bozza.

  Salmonellosis is a public health problem caused by Salmonella sp., a highly adapted facultative intracellular pathogen. After internalization, Salmonella sp. manipulates several host processes, mainly through the activation of the type III secretion system (T3SS), including modification of host lipid metabolism and lipid droplet (LD) accumulation. LDs are dynamic and complex lipid-rich organelles involved in several cellular processes. The present study investigated the mechanism involved in LD biogenesis in Salmonella-infected macrophages and its role in bacterial pathogenicity. Here, we reported that S. Typhimurium induced a rapid time-dependent increase of LD formation in macrophages. The LD biogenesis was demonstrated to depend on Salmonella's viability and SPI1-related T3SS activity, with the participation of Toll-Like Receptor (TLR) signaling. We also observed that LD accumulation occurs through TLR2 dependent signaling and is counter-regulated by TLR4. Lastly, the pharmacological modulation of LD formation by inhibiting diacylglycerol O-acyltransferase 1 (DGAT1) and cytosolic phospholipase A2 (cPLA2) significantly reduced the intracellular bacterial proliferation and impaired the prostaglandin E2 (PGE2 ) synthesis. Collectively, our data suggest the role of LDs on S. Typhimurium intracellular survival and replication in macrophages. This data set provides new perspectives for future investigations about LDs in host-pathogen interaction.

Keywords:  Lipid droplets; Lipid metabolism; PGE2; Salmonella Typhimurium; TLRs

DOI:  https://doi.org/10.1111/mmi.14844
Cell Rep. 2021 Nov 16. pii: S2211-1247(21)01500-X. [Epub ahead of print]37(7): 110018

TM4SF5-dependent crosstalk between hepatocytes and macrophages to reprogram the inflammatory environment.

Eunmi Kim, Hyejin Um, Jinsoo Park, Jae Woo Jung, Ji Eon Kim, Haesong Lee, Eun-Ae Shin, Yangie Pinanga, Hyejin Lee, Seo Hee Nam, Jung Weon Lee.

  Chronic injury to hepatocytes results in inflammation, steatohepatitis, fibrosis, and nonalcoholic fatty liver disease (NAFLD). The tetraspanin TM4SF5 is implicated in fibrosis and cancer. We investigate the role of TM4SF5 in communication between hepatocytes and macrophages (MΦs) and its possible influence on the inflammatory microenvironment that may lead to NAFLD. TM4SF5 induction in differentiated MΦs promotes glucose uptake, glycolysis, and glucose sensitivity, leading to M1-type MΦ activation. Activated M1-type MΦs secrete pro-inflammatory interleukin-6 (IL-6), which induces the secretion of CCL20 and CXCL10 from TM4SF5-positive hepatocytes. Although TM4SF5-dependent secretion of these chemokines enhances glycolysis in M0 MΦs, further chronic exposure reprograms MΦs for an increase in the proportion of M2-type MΦs in the population, which may support diet- and chemical-induced NAFLD progression. We suggest that TM4SF5 expression in MΦs and hepatocytes is critically involved in modulating the inflammatory environment during NAFLD progression.

Keywords:  TM4SF5; cytokines/chemokines; diet animal model; fibrosis; glycolysis; hepatocytes; inflammation; macrophages; metabolism; nonalcoholic fatty liver disease

DOI:  https://doi.org/10.1016/j.celrep.2021.110018
Nat Commun. 2021 Nov 15. 12(1): 6593

Multiple acyl-CoA dehydrogenase deficiency kills Mycobacterium tuberculosis in vitro and during infection.

Tiago Beites, Robert S Jansen, Ruojun Wang, Adrian Jinich, Kyu Y Rhee, Dirk Schnappinger, Sabine Ehrt.

The human pathogen Mycobacterium tuberculosis depends on host fatty acids as a carbon source. However, fatty acid β-oxidation is mediated by redundant enzymes, which hampers the development of antitubercular drugs targeting this pathway. Here, we show that rv0338c, which we refer to as etfD, encodes a membrane oxidoreductase essential for β-oxidation in M. tuberculosis. An etfD deletion mutant is incapable of growing on fatty acids or cholesterol, with long-chain fatty acids being bactericidal, and fails to grow and survive in mice. Analysis of the mutant's metabolome reveals a block in β-oxidation at the step catalyzed by acyl-CoA dehydrogenases (ACADs), which in other organisms are functionally dependent on an electron transfer flavoprotein (ETF) and its cognate oxidoreductase. We use immunoprecipitation to show that M. tuberculosis EtfD interacts with FixA (EtfB), a protein that is homologous to the human ETF subunit β and is encoded in an operon with fixB, encoding a homologue of human ETF subunit α. We thus refer to FixA and FixB as EtfB and EtfA, respectively. Our results indicate that EtfBA and EtfD (which is not homologous to human EtfD) function as the ETF and oxidoreductase for β-oxidation in M. tuberculosis and support this pathway as a potential target for tuberculosis drug development.

DOI: https://doi.org/10.1038/s41467-021-26941-1