bims-imicid 2021-10-24 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2021–10–24
fourteen papers selected by
Dylan Ryan, University of Cambridge

Dichotomous metabolic networks govern human ILC2 proliferation and function.
Mitochondrial complex II in intestinal epithelial cells regulates T cell-mediated immunopathology.
Itaconate as an inflammatory mediator and therapeutic target in cardiovascular medicine.
Metabolism-Associated Epigenetic and Immunoepigenetic Reprogramming in Liver Cancer.
AMP-activated protein kinase mediates lipopolysaccharide-induced proinflammatory responses and elevated bone resorption in differentiated osteoclasts.
Tumor-induced reshuffling of lipid composition on the endoplasmic reticulum membrane sustains macrophage survival and pro-tumorigenic activity.
ANT2 drives proinflammatory macrophage activation in obesity.
Immunomodulatory Effects of Tryptophan Metabolism in the Glioma Tumor Microenvironment.
MALT1 protease function in regulatory T cells induces MYC activity to promote mitochondrial function and cellular expansion.
Lactate in the tumour microenvironment: From immune modulation to therapy.
A Complex Metabolic Network Confers Immunosuppressive Functions to Myeloid-Derived Suppressor Cells (MDSCs) within the Tumour Microenvironment.
Irg1/itaconate metabolic pathway is a crucial determinant of dendritic cells immune-priming function and contributes to resolute allergen-induced airway inflammation.
Inhibition of mevalonate metabolism by statins augments the immunoregulatory phenotype of vascular endothelial cells and inhibits the costimulation of CD4+ T cells.
Phase separation drives RNA virus-induced activation of the NLRP6 inflammasome.

Nat Immunol. 2021 Oct 22.

Dichotomous metabolic networks govern human ILC2 proliferation and function.

Laura Surace, Jean-Marc Doisne, Carys A Croft, Anna Thaller, Pedro Escoll, Solenne Marie, Natalia Petrosemoli, Vincent Guillemot, Valerie Dardalhon, Davide Topazio, Antonia Cama, Carmen Buchrieser, Naomi Taylor, Ido Amit, Olimpia Musumeci, James P Di Santo.

Group 2 innate lymphoid cells (ILC2s) represent innate homologs of type 2 helper T cells (TH2) that participate in immune defense and tissue homeostasis through production of type 2 cytokines. While T lymphocytes metabolically adapt to microenvironmental changes, knowledge of human ILC2 metabolism is limited, and its key regulators are unknown. Here, we show that circulating 'naive' ILC2s have an unexpected metabolic profile with a higher level of oxidative phosphorylation (OXPHOS) than natural killer (NK) cells. Accordingly, ILC2s are severely reduced in individuals with mitochondrial disease (MD) and impaired OXPHOS. Metabolomic and nutrient receptor analysis revealed ILC2 uptake of amino acids to sustain OXPHOS at steady state. Following activation with interleukin-33 (IL-33), ILC2s became highly proliferative, relying on glycolysis and mammalian target of rapamycin (mTOR) to produce IL-13 while continuing to fuel OXPHOS with amino acids to maintain cellular fitness and proliferation. Our results suggest that proliferation and function are metabolically uncoupled in human ILC2s, offering new strategies to target ILC2s in disease settings.

DOI: https://doi.org/10.1038/s41590-021-01043-8
Nat Immunol. 2021 Oct 22.

Mitochondrial complex II in intestinal epithelial cells regulates T cell-mediated immunopathology.

Hideaki Fujiwara, Keisuke Seike, Michael D Brooks, Anna V Mathew, Ilya Kovalenko, Anupama Pal, Ho-Joon Lee, Daniel Peltier, Stephanie Kim, Chen Liu, Katherine Oravecz-Wilson, Lu Li, Yaping Sun, Jaeman Byun, Yoshinobu Maeda, Max S Wicha, Thomas L Saunders, Alnawaz Rehemtulla, Costas A Lyssiotis, Subramaniam Pennathur, Pavan Reddy.

Intestinal epithelial cell (IEC) damage by T cells contributes to graft-versus-host disease, inflammatory bowel disease and immune checkpoint blockade-mediated colitis. But little is known about the target cell-intrinsic features that affect disease severity. Here we identified disruption of oxidative phosphorylation and an increase in succinate levels in the IECs from several distinct in vivo models of T cell-mediated colitis. Metabolic flux studies, complemented by imaging and protein analyses, identified disruption of IEC-intrinsic succinate dehydrogenase A (SDHA), a component of mitochondrial complex II, in causing these metabolic alterations. The relevance of IEC-intrinsic SDHA in mediating disease severity was confirmed by complementary chemical and genetic experimental approaches and validated in human clinical samples. These data identify a critical role for the alteration of the IEC-specific mitochondrial complex II component SDHA in the regulation of the severity of T cell-mediated intestinal diseases.

DOI: https://doi.org/10.1038/s41590-021-01048-3
Biochem Soc Trans. 2021 Oct 19. pii: BST20210269. [Epub ahead of print]

Itaconate as an inflammatory mediator and therapeutic target in cardiovascular medicine.

Marina Diotallevi, Faseeha Ayaz, Thomas Nicol, Mark J Crabtree.

  Inflammation is a critical component of cardiovascular disease (CVD), encompassing coronary artery disease (CAD), cerebrovascular events and heart failure and is the leading cause of mortality worldwide. In recent years, metabolism has been placed centrally in the governance of the immune response. Termed immunometabolism, immune cells adapt cellular metabolic pathways to meet demands of activation and thus function. This rewiring influences not only the bioenergetics of the cell but altered metabolites act as signalling molecules to regulate cellular response. In this review, we focus on the TCA cycle derivative, itaconate, as one such metabolite with promising immunomodulatory and therapeutic potential in inflammatory cardiovascular disease.

Keywords:  cardiovascular disease; immunometabolism; inflammation; itaconate; metabolic reprogramming; oxidative stress

DOI:  https://doi.org/10.1042/BST20210269
Cancers (Basel). 2021 Oct 19. pii: 5250. [Epub ahead of print]13(20):

Metabolism-Associated Epigenetic and Immunoepigenetic Reprogramming in Liver Cancer.

Chaofan Fan, Shing Kam, Pierluigi Ramadori.

  Metabolic reprogramming and epigenetic changes have been characterized as hallmarks of liver cancer. Independently of etiology, oncogenic pathways as well as the availability of different energetic substrates critically influence cellular metabolism, and the resulting perturbations often cause aberrant epigenetic alterations, not only in cancer cells but also in the hepatic tumor microenvironment. Metabolic intermediates serve as crucial substrates for various epigenetic modulations, from post-translational modification of histones to DNA methylation. In turn, epigenetic changes can alter the expression of metabolic genes supporting on the one hand, the increased energetic demand of cancer cells and, on the other hand, influence the activity of tumor-associated immune cell populations. In this review, we will illustrate the most recent findings about metabolic reprogramming in liver cancer. We will focus on the metabolic changes characterizing the tumor microenvironment and on how these alterations impact on epigenetic mechanisms involved in the malignant progression. Furthermore, we will report our current knowledge about the influence of cancer-specific metabolites on epigenetic reprogramming of immune cells and we will highlight how this favors a tumor-permissive immune environment. Finally, we will review the current strategies to target metabolic and epigenetic pathways and their therapeutic potential in liver cancer, alone or in combinatorial approaches.

Keywords:  SAM; Warburg effect; acetyl-CoA; combinatorial therapy; guadecitabine; immunometabolism; liver cancer; metformin; resminostat

DOI:  https://doi.org/10.3390/cancers13205250
J Cell Biochem. 2021 Oct 19.

AMP-activated protein kinase mediates lipopolysaccharide-induced proinflammatory responses and elevated bone resorption in differentiated osteoclasts.

Yu-Hsu Chen, Kuang-Kai Hsueh, Pei-Wen Chu, Shau-Kwaun Chen.

  Systemic and intracellular metabolic states are critical factors affecting immune cell functions. The metabolic regulator AMP-activated protein kinase (AMPK) senses AMP levels and mediates cellular responses to energy-restrained conditions. The ubiquitously expressed AMPK participates in various biological functions in numerous cell types, including innate immune cell macrophages and osteoclasts, which are their specialized derivatives in bone tissues. Previous studies have demonstrated that the activation of AMPK promotes macrophage polarization toward anti-inflammatory M2 status. Additionally, AMPK acts as a negative regulator of osteoclastogenesis, and upregulation of AMPK disrupts the differentiation of osteoclasts. However, the regulation and roles of AMPK in differentiated osteoclasts have not been characterized. Here, we report that inflammatory stimuli-regulated-AMPK activation of differentiated and undifferentiated osteoclasts in opposite ways. Lipopolysaccharide (LPS) inhibited the phosphorylation of AMPK in macrophages and undifferentiated osteoclasts, but it activated AMPK in differentiated osteoclasts. Inactivating AMPK decreased cellular responses against the activation of toll-like receptor signaling, including the transcriptional activation of proinflammatory cytokines and the bone resorption genes TRAP, and MMP9. The elevation of bone resorption by LPS stimulation was disrupted by AMPK inhibitor, indicating the pivotal roles of AMPK in inflammation-induced activities in differentiated osteoclasts. The AMPK activator metformin did not increase proinflammatory responses, possibly because other factors are also required for this regulation. Notably, changing the activation status of AMPK did not alter the expression levels of bone resorption genes in unstimulated osteoclasts, indicating the essential roles of AMPK in cellular responses to inflammatory stimuli but not in the maintenance of basal levels. Unlike its M2-polarizing roles in macrophages, AMPK was not responsive to the M2 stimulus of interleukin-4. Our observations revealed differences in the cellular properties of macrophages and osteoclasts as well as the complexity of regulatory mechanisms for osteoclast functions.

Keywords:  AMP-activated protein kinase (AMPK); inflammatory regulation; lipopolysaccharide (LPS); osteoclast

DOI:  https://doi.org/10.1002/jcb.30165
Nat Immunol. 2021 Oct 22.

Tumor-induced reshuffling of lipid composition on the endoplasmic reticulum membrane sustains macrophage survival and pro-tumorigenic activity.

Giusy Di Conza, Chin-Hsien Tsai, Hector Gallart-Ayala, Yi-Ru Yu, Fabien Franco, Lea Zaffalon, Xin Xie, Xiaoyun Li, Zhengtao Xiao, Lydia N Raines, Maryline Falquet, Antoine Jalil, Jason W Locasale, Piergiorgio Percipalle, David Masson, Stanley Ching-Cheng Huang, Fabio Martinon, Julijana Ivanisevic, Ping-Chih Ho.

Tumor-associated macrophages (TAMs) display pro-tumorigenic phenotypes for supporting tumor progression in response to microenvironmental cues imposed by tumor and stromal cells. However, the underlying mechanisms by which tumor cells instruct TAM behavior remain elusive. Here, we uncover that tumor-cell-derived glucosylceramide stimulated unconventional endoplasmic reticulum (ER) stress responses by inducing reshuffling of lipid composition and saturation on the ER membrane in macrophages, which induced IRE1-mediated spliced XBP1 production and STAT3 activation. The cooperation of spliced XBP1 and STAT3 reinforced the pro-tumorigenic phenotype and expression of immunosuppressive genes. Ablation of XBP1 expression with genetic manipulation or ameliorating ER stress responses by facilitating LPCAT3-mediated incorporation of unsaturated lipids to the phosphatidylcholine hampered pro-tumorigenic phenotype and survival in TAMs. Together, we uncover the unexpected roles of tumor-cell-produced lipids that simultaneously orchestrate macrophage polarization and survival in tumors via induction of ER stress responses and reveal therapeutic targets for sustaining host antitumor immunity.

DOI: https://doi.org/10.1038/s41590-021-01047-4
JCI Insight. 2021 Oct 22. pii: e147033. [Epub ahead of print]6(20):

ANT2 drives proinflammatory macrophage activation in obesity.

Jae-Su Moon, Flavia Franco da Cunha, Jin Young Huh, Alexander Yu Andreyev, Jihyung Lee, Sushil K Mahata, Felipe Cg Reis, Chanond A Nasamran, Yun Sok Lee.

  Macrophage proinflammatory activation is an important etiologic component of the development of insulin resistance and metabolic dysfunction in obesity. However, the underlying mechanisms are not clearly understood. Here, we demonstrate that a mitochondrial inner membrane protein, adenine nucleotide translocase 2 (ANT2), mediates proinflammatory activation of adipose tissue macrophages (ATMs) in obesity. Ant2 expression was increased in ATMs of obese mice compared with lean mice. Myeloid-specific ANT2-knockout (ANT2-MKO) mice showed decreased adipose tissue inflammation and improved insulin sensitivity and glucose tolerance in HFD/obesity. At the molecular level, we found that ANT2 mediates free fatty acid-induced mitochondrial permeability transition, leading to increased mitochondrial reactive oxygen species production and damage. In turn, this increased HIF-1α expression and NF-κB activation, leading to proinflammatory macrophage activation. Our results provide a previously unknown mechanism for how obesity induces proinflammatory activation of macrophages with propagation of low-grade chronic inflammation (metaflammation).

Keywords:  Diabetes; Endocrinology; Innate immunity; Metabolism

DOI:  https://doi.org/10.1172/jci.insight.147033
Front Immunol. 2021 ;12 730289

Immunomodulatory Effects of Tryptophan Metabolism in the Glioma Tumor Microenvironment.

Yang Xu, Huikai Zhang, Qian Sun, Rongxin Geng, Fanen Yuan, Baohui Liu, Qianxue Chen.

  Gliomas are the most common primary malignant tumor in adults' central nervous system. While current research on glioma treatment is advancing rapidly, there is still no breakthrough in long-term treatment. Abnormalities in the immune regulatory mechanism in the tumor microenvironment are essential to tumor cell survival. The alteration of amino acid metabolism is considered a sign of tumor cells, significantly impacting tumor cells and immune regulation mechanisms in the tumor microenvironment. Despite the fact that the metabolism of tryptophan in tumors is currently discussed in the literature, we herein focused on reviewing the immune regulation of tryptophan metabolism in the tumor microenvironment of gliomas and analyzed possible immune targets. The objective is to identify potential targets for the treatment of glioma and improve the efficiency of immunotherapy.

Keywords:  glioma; immunomodulation; metabolism; tryptophan; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2021.730289
Eur J Immunol. 2021 Oct 20.

MALT1 protease function in regulatory T cells induces MYC activity to promote mitochondrial function and cellular expansion.

Marc Rosenbaum, Theresa Schnalzger, Thomas Engleitner, Christin Weiß, Ritu Mishra, Cora Mibus, Theresa Mitterer, Roland Rad, Jürgen Ruland.

  Regulatory T cells (Tregs) are essential for the inhibition of immunity and the maintenance of tissue homeostasis. Signals from the T cell antigen receptor (TCR) are critical for early Treg development, their expansion and inhibitory activity. Although TCR-engaged activation of the paracaspase MALT1 is important for these Treg activities, the MALT1 effector pathways in Tregs remain ill-defined. Here, we demonstrate that MALT1 protease activity controls the TCR-induced upregulation of the transcription factor MYC and the subsequent expression of MYC target genes in Tregs. These mechanisms are important for Treg-intrinsic mitochondrial function, optimal respiratory capacity and homeostatic Treg proliferation. Consistently, conditional deletion of Myc in Tregs results similar to MALT1 inactivation in a lethal autoimmune inflammatory syndrome. Together, these results identify a MALT1 protease-mediated link between TCR signaling in Tregs and MYC control that coordinates metabolism and Treg expansion for the maintenance of immune homeostasis. This article is protected by copyright. All rights reserved.

Keywords:  Immune regulation; Regulatory T cells; Signal transduction; TCR

DOI:  https://doi.org/10.1002/eji.202149355
EBioMedicine. 2021 Oct 13. pii: S2352-3964(21)00420-5. [Epub ahead of print]73 103627

Lactate in the tumour microenvironment: From immune modulation to therapy.

Zi-Hao Wang, Wen-Bei Peng, Pei Zhang, Xiang-Ping Yang, Qiong Zhou.

  Disordered metabolic states, which are characterised by hypoxia and elevated levels of metabolites, particularly lactate, contribute to the immunosuppression in the tumour microenvironment (TME). Excessive lactate secreted by metabolism-reprogrammed cancer cells regulates immune responses via causing extracellular acidification, acting as an energy source by shuttling between different cell populations, and inhibiting the mechanistic (previously 'mammalian') target of rapamycin (mTOR) pathway in immune cells. This review focuses on recent advances in the regulation of immune responses by lactate, as well as therapeutic strategies targeting lactate anabolism and transport in the TME, such as those involving glycolytic enzymes and monocarboxylate transporter inhibitors. Considering the multifaceted roles of lactate in cancer metabolism, a comprehensive understanding of how lactate and lactate-targeting therapies regulate immune responses in the TME will provide insights into the complex relationships between metabolism and antitumour immunity.

Keywords:  Cancer immunity; Cancer metabolism; Glycolytic enzymes; Lactate; Monocarboxylate transporters; Tumour microenvironment

DOI:  https://doi.org/10.1016/j.ebiom.2021.103627
Cells. 2021 Oct 09. pii: 2700. [Epub ahead of print]10(10):

A Complex Metabolic Network Confers Immunosuppressive Functions to Myeloid-Derived Suppressor Cells (MDSCs) within the Tumour Microenvironment.

Francesca Hofer, Gianna Di Sario, Chiara Musiu, Silvia Sartoris, Francesco De Sanctis, Stefano Ugel.

  Myeloid-derived suppressor cells (MDSCs) constitute a plastic and heterogeneous cell population among immune cells within the tumour microenvironment (TME) that support cancer progression and resistance to therapy. During tumour progression, cancer cells modify their metabolism to sustain an increased energy demand to cope with uncontrolled cell proliferation and differentiation. This metabolic reprogramming of cancer establishes competition for nutrients between tumour cells and leukocytes and most importantly, among tumour-infiltrating immune cells. Thus, MDSCs that have emerged as one of the most decisive immune regulators of TME exhibit an increase in glycolysis and fatty acid metabolism and also an upregulation of enzymes that catabolise essential metabolites. This complex metabolic network is not only crucial for MDSC survival and accumulation in the TME but also for enhancing immunosuppressive functions toward immune effectors. In this review, we discuss recent progress in the field of MDSC-associated metabolic pathways that could facilitate therapeutic targeting of these cells during cancer progression.

Keywords:  cancer; immunometabolism; inflammation; myeloid-derived suppressor cells (MDSC); tumour-microenvironment (TME)

DOI:  https://doi.org/10.3390/cells10102700
Mucosal Immunol. 2021 Oct 20.

Irg1/itaconate metabolic pathway is a crucial determinant of dendritic cells immune-priming function and contributes to resolute allergen-induced airway inflammation.

Anil Kumar Jaiswal, Jyoti Yadav, Sangeet Makhija, Suman Mazumder, Amit Kumar Mitra, Amol Suryawanshi, Maninder Sandey, Amarjit Mishra.

Itaconate is produced from the mitochondrial TCA cycle enzyme aconitase decarboxylase (encoded by immune responsive gene1; Irg1) that exerts immunomodulatory function in myeloid cells. However, the role of the Irg1/itaconate pathway in dendritic cells (DC)-mediated airway inflammation and adaptive immunity to inhaled allergens, which are the primary antigen-presenting cells in allergic asthma, remains largely unknown. House dust mite (HDM)-challenged Irg1-/- mice displayed increases in eosinophilic airway inflammation, mucous cell metaplasia, and Th2 cytokine production with a mechanism involving impaired mite antigen presentations by DC. Adoptive transfer of HDM-pulsed DC from Irg1-deficient mice into naïve WT mice induced a similar phenotype of elevated type 2 airway inflammation and allergic sensitization. Untargeted metabolite analysis of HDM-pulsed DC revealed itaconate as one of the most abundant polar metabolites that potentially suppress mitochondrial oxidative damage. Furthermore, the immunomodulatory effect of itaconate was translated in vivo, where intranasal administration of 4-octyl itaconate 4-OI following antigen priming attenuated the manifestations of HDM-induced airway disease and Th2 immune response. Taken together, these data demonstrated for the first time a direct regulatory role of the Irg1/itaconate pathway in DC for the development of type 2 airway inflammation and suggest a possible therapeutic target in modulating allergic asthma.

DOI: https://doi.org/10.1038/s41385-021-00462-y
Am J Transplant. 2021 Oct 22.

Inhibition of mevalonate metabolism by statins augments the immunoregulatory phenotype of vascular endothelial cells and inhibits the costimulation of CD4+ T cells.

Timna Agur, Johannes Wedel, Sayantan Bose, A G Pramoda Sahankumari, Daniel Goodman, Sek Wong Kong, Chandra C Ghosh, David M Briscoe.

The statin family of therapeutics are widely used clinically as cholesterol lowering agents, and their effects to target intracellular mevalonate production is a key mechanism of action. In this study, we performed full transcriptomic RNA sequencing and qPCR to evaluate the effects of mevalonate on the immunoregulatory phenotype of endothelial cells (EC). We find that mevalonate-dependent gene regulation includes a reduction in the expression of multiple pro-inflammatory genes including TNFSF4 (OX40-L) and TNFSF18 (GITR-L) and a co-incident induction of immunoregulatory genes including LGALS3 (Galectin-3) and LGALS9 (Galectin-9). In functional assays, pretreatment of EC with simvastatin to inhibit mevalonate metabolism resulted in a dose-dependent reduction in the costimulation of CD45RO+ CD4+ T cell proliferation as well as IL-2, IFNγ and IL-6 production vs. vehicle-treated EC. In contrast, pre-treatment of EC with L-mevalonate in combination with simvastatin reversed phenotypic and functional responses. Collectively, these results indicate that relative mevalonate metabolism by EC is critical to sustain EC-dependent mechanisms of immunity. Our findings have broad relevance for the repurposing of statins as therapeutics to augment immunoregulation and/or to inhibit local tissue pro-inflammatory cytokine production following transplantation.

DOI: https://doi.org/10.1111/ajt.16872
Cell. 2021 Oct 14. pii: S0092-8674(21)01115-6. [Epub ahead of print]

Phase separation drives RNA virus-induced activation of the NLRP6 inflammasome.

Chen Shen, Runzhi Li, Roberto Negro, Jiewei Cheng, Setu M Vora, Tian-Min Fu, Anmin Wang, Kaixin He, Liudmila Andreeva, Pu Gao, Zhigang Tian, Richard A Flavell, Shu Zhu, Hao Wu.

  NLRP6 is important in host defense by inducing functional outcomes including inflammasome activation and interferon production. Here, we show that NLRP6 undergoes liquid-liquid phase separation (LLPS) upon interaction with double-stranded RNA (dsRNA) in vitro and in cells, and an intrinsically disordered poly-lysine sequence (K350-354) of NLRP6 is important for multivalent interactions, phase separation, and inflammasome activation. Nlrp6-deficient or Nlrp6K350-354A mutant mice show reduced inflammasome activation upon mouse hepatitis virus or rotavirus infection, and in steady state stimulated by intestinal microbiota, implicating NLRP6 LLPS in anti-microbial immunity. Recruitment of ASC via helical assembly solidifies NLRP6 condensates, and ASC further recruits and activates caspase-1. Lipoteichoic acid, a known NLRP6 ligand, also promotes NLRP6 LLPS, and DHX15, a helicase in NLRP6-induced interferon signaling, co-forms condensates with NLRP6 and dsRNA. Thus, LLPS of NLRP6 is a common response to ligand stimulation, which serves to direct NLRP6 to distinct functional outcomes depending on the cellular context.

Keywords:  IDRs; LLPS; MHV; NLRP6; RV; dsRNA; inflammasome; liquid-liquid phase separation

DOI:  https://doi.org/10.1016/j.cell.2021.09.032