bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2023‒02‒26
33 papers selected by
Dylan Ryan
University of Cambridge

  1. Nat Immunol. 2023 Feb 23.
      Exposure of lipopolysaccharide triggers macrophage pro-inflammatory polarization accompanied by metabolic reprogramming, characterized by elevated aerobic glycolysis and a broken tricarboxylic acid cycle. However, in contrast to lipopolysaccharide, CD40 signal is able to drive pro-inflammatory and anti-tumorigenic polarization by some yet undefined metabolic programming. Here we show that CD40 activation triggers fatty acid oxidation (FAO) and glutamine metabolism to promote ATP citrate lyase-dependent epigenetic reprogramming of pro-inflammatory genes and anti-tumorigenic phenotypes in macrophages. Mechanistically, glutamine usage reinforces FAO-induced pro-inflammatory and anti-tumorigenic activation by fine-tuning the NAD+/NADH ratio via glutamine-to-lactate conversion. Genetic ablation of important metabolic enzymes involved in CD40-mediated metabolic reprogramming abolishes agonistic anti-CD40-induced antitumor responses and reeducation of tumor-associated macrophages. Together these data show that metabolic reprogramming, which includes FAO and glutamine metabolism, controls the activation of pro-inflammatory and anti-tumorigenic polarization, and highlight a therapeutic potential of metabolic preconditioning of tumor-associated macrophages before agonistic anti-CD40 treatments.
  2. Cell Rep Med. 2023 Feb 21. pii: S2666-3791(23)00033-2. [Epub ahead of print]4(2): 100941
      By restoring tryptophan, indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors aim to reactivate anti-tumor T cells. However, a phase III trial assessing their clinical benefit failed, prompting us to revisit the role of IDO1 in tumor cells under T cell attack. We show here that IDO1 inhibition leads to an adverse protection of melanoma cells to T cell-derived interferon-gamma (IFNγ). RNA sequencing and ribosome profiling shows that IFNγ shuts down general protein translation, which is reversed by IDO1 inhibition. Impaired translation is accompanied by an amino acid deprivation-dependent stress response driving activating transcription factor-4 (ATF4)high/microphtalmia-associated transcription factor (MITF)low transcriptomic signatures, also in patient melanomas. Single-cell sequencing analysis reveals that MITF downregulation upon immune checkpoint blockade treatment predicts improved patient outcome. Conversely, MITF restoration in cultured melanoma cells causes T cell resistance. These results highlight the critical role of tryptophan and MITF in the melanoma response to T cell-derived IFNγ and uncover an unexpected negative consequence of IDO1 inhibition.
    Keywords:  IDO1; IDO1 inhibition; IFNgamma; MITF; T cells; clinical trial; immunotherapy; melanoma; translation
  3. Sci Immunol. 2023 Feb 23. eadf0348
      The relationship between diabetes and COVID-19 is bi-directional: while individuals with diabetes and high blood glucose (hyperglycemia) are predisposed to severe COVID-19, SARS-CoV-2 infection can also cause hyperglycemia and exacerbate underlying metabolic syndrome. Therefore, interventions capable of breaking the network of SARS-CoV-2 infection, hyperglycemia, and hyper-inflammation, all factors that drive COVID-19 pathophysiology, are urgently needed. Here, we show that genetic ablation or pharmacological inhibition of mitochondrial pyruvate carrier (MPC) attenuates severe disease following influenza or SARS-CoV-2 pneumonia. MPC inhibition using a second-generation insulin sensitizer, MSDC-0602 K (MSDC), dampened pulmonary inflammation and promoted lung recovery, while concurrently reducing blood glucose levels and hyperlipidemia following viral pneumonia in obese mice. Mechanistically, MPC inhibition enhanced mitochondrial fitness and destabilized HIF-1α, leading to dampened virus-induced inflammatory responses in both murine and human lung macrophages. We further showed that MSDC enhanced responses to nirmatrelvir (the antiviral component of Paxlovid) to provide high levels of protection against severe host disease development following SARS-CoV-2 infection and suppressed cellular inflammation in human COVID-19 lung autopsies, demonstrating its translational potential for treating severe COVID-19. Collectively, we uncover a metabolic pathway that simultaneously modulates pulmonary inflammation, tissue recovery, and host metabolic health, presenting a synergistic therapeutic strategy to treat severe COVID-19, particularly in patients with underlying metabolic disease.
  4. J Leukoc Biol. 2023 Feb 01. 113(2): 164-190
      Several studies over the last decade have identified intimate links between cellular metabolism and macrophage function. Metabolism has been shown to both drive and regulate macrophage function by producing bioenergetic and biosynthetic precursors as well as metabolites (and other bioactive molecules) that regulate gene expression and signal transduction. Many studies have focused on lipopolysaccharide-induced reprogramming, assuming that it is representative of most inflammatory responses. However, emerging evidence suggests that diverse pathogen-associated molecular patterns (PAMPs) are associated with unique metabolic profiles, which may drive pathogen specific immune responses. Further, these metabolic pathways and processes may act as a rheostat to regulate the magnitude of an inflammatory response based on the biochemical features of the local microenvironment. In this review, we will discuss recent work examining the relationship between cellular metabolism and macrophage responses to viral PAMPs and describe how these processes differ from lipopolysaccharide-associated responses. We will also discuss how an improved understanding of the specificity of these processes may offer new insights to fine-tune macrophage function during viral infections or when using viral PAMPs as therapeutics.
    Keywords:  antiviral responses; immunometabolism; macrophage; mitochondria; pathogen-associated molecular patterns; pattern recognition receptors
  5. Front Immunol. 2022 ;13 1047661
      CD8 T cells play a central role in antiviral immunity. Type I interferons are among the earliest responders after virus exposure and can cause extensive reprogramming and antigen-independent bystander activation of CD8 T cells. Although bystander activation of pre-existing memory CD8 T cells is known to play an important role in host defense and immunopathology, its impact on naïve CD8 T cells remains underappreciated. Here we report that exposure to reovirus, both in vitro or in vivo, promotes bystander activation of naïve CD8 T cells within 24 hours and that this distinct subtype of CD8 T cell displays an innate, antiviral, type I interferon sensitized signature. The induction of bystander naïve CD8 T cells is STAT1 dependent and regulated through nicotinamide phosphoribosyl transferase (NAMPT)-mediated enzymatic actions within NAD+ salvage metabolic biosynthesis. These findings identify a novel aspect of CD8 T cell activation following virus infection with implications for human health and physiology.
    Keywords:  CD8 T cells; NAD+ salvage metabolism; antiviral immunity; bystander activation; immunometabolism; metabolic reprogramming; naïve CD8 T cells; type I interferons
  6. Biology (Basel). 2023 Feb 13. pii: 297. [Epub ahead of print]12(2):
      Transforming growth factor beta (TGFβ) receptor signalling regulates T cell development, differentiation and effector function. Expression of the immune-associated isoform of this cytokine, TGFβ1, is absolutely required for the maintenance of immunological tolerance in both mice and humans, whilst context-dependent TGFβ1 signalling regulates the differentiation of both anti- and pro-inflammatory T cell effector populations. Thus, distinct TGFβ-dependent T cell responses are implicated in the suppression or initiation of inflammatory and autoimmune diseases. In cancer settings, TGFβ signals contribute to the blockade of anti-tumour immune responses and disease progression. Given the key functions of TGFβ in the regulation of immune responses and the potential for therapeutic targeting of TGFβ-dependent pathways, the mechanisms underpinning these pleiotropic effects have been the subject of much investigation. This review focuses on accumulating evidence suggesting that modulation of T cell metabolism represents a major mechanism by which TGFβ influences T cell immunity.
    Keywords:  T cell activation; TGFβ; cytokines; immunometabolism; signaling
  7. Cancers (Basel). 2023 Feb 14. pii: 1211. [Epub ahead of print]15(4):
      The metabolic crosstalk between tumor cells and tumor-associated macrophages (TAMs) has emerged as a critical contributor to tumor development and progression. In breast cancer (BC), the abundance of immune-suppressive TAMs positively correlates with poor prognosis. However, little is known about how TAMs reprogram their metabolism in the BC microenvironment. In this work, we have assessed the metabolic and phenotypic impact of incubating THP-1-derived macrophages in conditioned media (CM) from two BC cell lines cultured in normoxia/hypoxia: MDA-MB-231 cells (highly metastatic, triple-negative BC), and MCF-7 cells (less aggressive, luminal BC). The resulting tumor-educated macrophages (TEM) displayed prominent differences in their metabolic activity and composition, compared to control cells (M0), as assessed by exo- and endometabolomics. In particular, TEM turned to the utilization of extracellular pyruvate, alanine, and branched chain keto acids (BCKA), while exhibiting alterations in metabolites associated with several intracellular pathways, including polyamines catabolism (MDA-TEM), collagen degradation (mainly MCF-TEM), adenosine accumulation (mainly MDA-TEM) and lipid metabolism. Interestingly, following a second-stage incubation in fresh RPMI medium, TEM still displayed several metabolic differences compared to M0, indicating persistent reprogramming. Overall, this work provided new insights into the metabolic plasticity of TEM, revealing potentially important nutritional exchanges and immunoregulatory metabolites in the BC TME.
    Keywords:  NMR metabolomics; breast cancer; cell metabolism; metabolic reprogramming; tumor microenvironment (TME); tumor-associated macrophages (TAM)
  8. Sci Rep. 2023 Feb 24. 13(1): 3257
      Lameness is a common condition in dairy cattle caused by infectious or noninfectious agents. Joint lesions are the second most common cause of lameness and can be diagnosed in association with the presentation of digit injuries. Fibroblast-like synoviocyte (FLS) are predominant cells of synovia and play a key role in the pathophysiology of joint diseases, thus increasing the expression of proinflammatory mediators. Tumor necrosis factor-alpha (TNF-α) is a potent proinflammatory cytokine involved in cyclooxygenase 2 (COX-2) and proinflammatory cytokine expression in FLS. Previously, TNF-α was demonstrated to increase hypoxia-inducible Factor 1 (HIF-1), a transcription factor that rewires cellular metabolism and increases the expression of interleukin (IL)-6 in bovine FLS (bFLS). Despite this, the proinflammatory effects of TNF-α in bFLS on metabolic reprogramming have been poorly studied. We hypothesized that TNF-α increases glycolysis and in this way controls the expression of IL-6, IL-8, and COX-2 in bFLS. Results first, gas chromatography/mass spectrometry (GC/MS)-based untargeted metabolomics revealed that bTNF-α altered the metabolism of bFLS, increasing glucose, isoleucine, leucine, methionine, valine, tyrosine, and lysine and decreasing malate, fumarate, α-ketoglutarate, stearate, palmitate, laurate, aspartate, and alanine. In addition, metabolic flux analysis using D-glucose-13C6 demonstrated an increase of pyruvate and a reduction in malate and citrate levels, suggesting a decreased flux toward the tricarboxylic acid cycle after bTNF-α stimulation. However, bTNF-α increased lactate dehydrogenase subunit A (LDHA), IL-6, IL-8, IL-1β and COX-2 expression, which was dependent on glycolysis and the PI3K/Akt pathway. The use of FX11 and dichloroacetate (DCA), an inhibitor of LDHA and pyruvate dehydrogenase kinase (PDK) respectively, partially reduced the expression of IL-6. Our results suggest that bTNF-α induces metabolic reprogramming that favors glycolysis in bFLS and increases IL-6, IL-8, IL-1β and COX-2/PGE2.
  9. bioRxiv. 2023 Feb 13. pii: 2023.02.13.528371. [Epub ahead of print]
      Lymphocyte activation gene 3 (Lag3) has emerged as the next-generation immune checkpoint molecule due to its ability to inhibit effector T cell activity. Foxp3 + regulatory T (Treg) cells, a master regulator of immunity and tolerance, also highly express Lag3. While Lag3 is thought to be necessary for Treg cell-mediated regulation of immunity, the precise roles and underlying mechanisms remain largely elusive. In this study, we report that Lag3 is indispensable for Treg cells to control autoimmune inflammation. Utilizing a newly generated Treg cell specific Lag3 mutant mouse model, we found that these animals are highly susceptible to autoimmune diseases, suggesting defective Treg cell function. Genome wide transcriptome analysis further uncovered that Lag3 mutant Treg cells upregulated genes involved in metabolic processes. Mechanistically, we found that Lag3 limits Treg cell expression of Myc, a key regulator of aerobic glycolysis. We further found that Lag3-dependent Myc expression determines Treg cells’ metabolic programming as well as the in vivo function to suppress autoimmune inflammation. Taken together, our results uncovered a novel function of Lag3 in supporting Treg cell suppressive function by regulating Myc-dependent metabolic programming.
  10. J Clin Invest. 2023 Feb 23. pii: e166031. [Epub ahead of print]
      Activation of STING signaling in dendritic cells (DCs) promotes antitumor immunity. Aerobic glycolysis is a metabolic hallmark of activated DCs, but how the glycolytic pathway intersects with STING signaling in tumor-infiltrating DCs remains elusive. Here, we show that glycolysis drives STING signaling to facilitate DC-mediated antitumor immune responses. Tumor-infiltrating DCs exhibited elevated glycolysis, and blockade of glycolysis by DC-specific Ldha/Ldhb double deletion resulted in defective antitumor immunity. Mechanistically, glycolysis augmented ATP production to boost STING activation and STING-dependent DC antitumor functions. Moreover, DC-intrinsic STING activation accelerated HIF-1a-mediated glycolysis and established a positive feedback loop. Importantly, glycolysis facilitated STING-dependent DC activity in tissue samples from non-small cell lung cancer patients. Our results provide mechanistic insight into how the crosstalk of glycolytic metabolism and STING signaling enhances DC antitumor activity and can be harnessed to improve cancer therapies.
    Keywords:  Cancer immunotherapy; Glucose metabolism; Immunology; Innate immunity; Metabolism
  11. Gut Microbes. 2023 Jan-Dec;15(1):15(1): 2181928
      Hypercaloric diets overactivate the intestinal immune system and disrupt the microbiome and epithelial cell functions, impairing glucose metabolism. The origins of this inflammatory cascade are poorly characterized. We investigated the involvement of intestinal proinflammatory group 1 innate lymphoid cells (ILC1s) in obesity progression and metabolic disruption. In obese mice, we studied longitudinally the ILC1s response to the diet and ILC1s depletion to address its role in obesity. ILC1s are required for the expansion of pro-inflammatory macrophages and ILC2s. ILC1s depletion induced the ILC3-IL-22 pathway, increasing mucin production, antimicrobial peptides, and neuroendocrine cells. These changes were translated into higher gut hormones and reduced insulinemia and adiposity. ILC1s depletion was also associated with a bloom in Akkermansia muciniphila and decreases in Bilophila spp. Intestinal-ILC1s are upstream activators of inflammatory signals, connecting immunity with the microbiome, the enteroendocrine system, and the intestinal barrier in the control of glucose metabolism and adiposity.
    Keywords:  Akkermansia muciniphila; ILC1s; Microbiota; high-sucrose high-fat diet; metabolism; obesity
  12. Biomedicine (Taipei). 2022 ;12(4): 9-19
      Over the last few decades, cancer has been regarded as an independent and self sustaining progression. The earliest hallmarks of cancer comprise of sustaining proliferative signalling, avoiding growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Nonetheless, two emerging hallmarks are being described: aberrant metabolic pathways and evasion of immune destruction. Changes in tumour cell metabolism are not restricted to tumour cells alone; the products of the altered metabolism have a direct impact on the activity of immune cells inside the tumour microenvironment, particularly tumour-associated macrophages (TAMs). The complicated process of cancer growth is orchestrated by metabolic changes dictating the tight mutual connection between these cells. Here, we discuss approaches to exploit the interaction of cancer cells' abnormal metabolic activity and TAMs. We also describe ways to exploit it by reprogramming fatty acid metabolism via TAMs.
    Keywords:  Fatty acid metabolism; Invasion; Metastasis; Oleic acid; Palmitic acid; Tumour-associated macrophages
  13. Antioxidants (Basel). 2023 Feb 15. pii: 489. [Epub ahead of print]12(2):
      Itaconate has emerged as a novel anti-inflammatory and antioxidative endogenous metabolite, yet its role in allergic airway inflammation (AAI) and the underlying mechanism remains elusive. Here, the itaconate level in the lung was assessed by High Performance Liquid Chromatography (HPLC), and the effects of the Irg1/itaconate pathway on AAI and alveolar macrophage (AM) immune responses were evaluated using an ovalbumin (OVA)-induced AAI model established by wild type (WT) and Irg1-/- mice, while the mechanism of this process was investigated by metabolomics analysis, mitochondrial/cytosolic protein fractionation and transmission electron microscopy in the lung tissues. The results demonstrated that the Irg1 mRNA/protein expression and itaconate production in the lung were significantly induced by OVA. Itaconate ameliorated while Irg1 deficiency augmented AAI, and this may be attributed to the fact that itaconate suppressed mitochondrial events such as NLRP3 inflammasome activation, oxidative stress and metabolic dysfunction. Furthermore, we identified that the Irg1/itaconate pathway impacted the NLRP3 inflammasome activation and oxidative stress in AMs. Collectively, our findings provide evidence for the first time, supporting the conclusion that in the allergic lung, the itaconate level is markedly increased, which directly regulates AMs' immune responses. We therefore propose that the Irg1/itaconate pathway in AMs is a potential anti-inflammatory and anti-oxidative therapeutic target for AAI.
    Keywords:  Irg1; NLRP3 inflammasome; allergic airway inflammation; alveolar macrophage; itaconate; mitochondrial; oxidative stress
  14. Elife. 2023 Feb 21. pii: e84708. [Epub ahead of print]12
      The essential role of store-operated Ca2+ entry (SOCE) through Ca2+ release-activated Ca2+ (CRAC) channels in T cells is well established. In contrast, the contribution of individual Orai isoforms to SOCE and their downstream signaling functions in B cells are poorly understood. Here, we demonstrate changes in expression of Orai isoforms in response to B cell activation. We show that both Orai3 and Orai1 mediate native CRAC channels in B cells. The combined loss of Orai1 and Orai3, but not Orai3 alone, impairs SOCE, proliferation and survival, nuclear factor of activated T cells (NFAT) activation, mitochondrial respiration, glycolysis, and the metabolic reprogramming of primary B cells in response to antigenic stimulation. Nevertheless, combined deletion of Orai1 and Orai3 in B cells did not compromise humoral immunity to influenza A virus infection in mice, suggesting that other in vivo co-stimulatory signals can overcome the requirement of BCR-mediated CRAC channel function in B cells. Our results shed important new light on the physiological roles of Orai1 and Orai3 proteins in SOCE and effector functions of B lymphocytes.
    Keywords:  biochemistry; cell biology; chemical biology; mouse
  15. Biomolecules. 2023 Jan 30. pii: 258. [Epub ahead of print]13(2):
      Butyrate, a short-chain fatty acid, is utilized by the gut epithelium as energy and it improves the gut epithelial barrier. More recently, it has been associated with beneficial effects on immune and cardiovascular homeostasis. Conversely, tumor necrosis factor alpha (TNFα) is a pro-inflammatory and pro-hypertensive cytokine. While butyrate and TNFα are both linked with hypertension, studies have not yet addressed their interaction in the colon. Here, we investigated the capacity of butyrate to modulate a host of effects of TNFα in primary rodent colonic cells in vitro. We measured ATP levels, cell viability, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), mitochondrial oxidative phosphorylation, and glycolytic activity in colonocytes following exposure to either butyrate or TNFα, or both. To address the potential mechanisms, transcripts related to oxidative stress, cell fate, and cell metabolism (Pdk1, Pdk2, Pdk4, Spr, Slc16a1, Slc16a3, Ppargc1a, Cs, Lgr5, Casp3, Tnfr2, Bax, Bcl2, Sod1, Sod2, and Cat) were measured, and untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) was employed to profile the metabolic responses of colonocytes following exposure to butyrate and TNFα. We found that both butyrate and TNFα lowered cellular ATP levels towards a quiescent cell energy phenotype, characterized by decreased oxygen consumption and extracellular acidification. Co-treatment with butyrate ameliorated TNFα-induced cytotoxicity and the reduction in cell viability. Butyrate also opposed the TNFα-mediated decrease in MMP and mitochondrial-to-intracellular calcium ratios, suggesting that butyrate may protect colonocytes against TNFα-induced cytotoxicity by decreasing mitochondrial calcium flux. The relative expression levels of pyruvate dehydrogenase kinase 4 (Pdk4) were increased via co-treatment of butyrate and TNFα, suggesting the synergistic inhibition of glycolysis. TNFα alone reduced the expression of monocarboxylate transporters slc16a1 and slc16a3, suggesting effects of TNFα on butyrate uptake into colonocytes. Of the 185 metabolites that were detected with LC-MS, the TNFα-induced increase in biopterin produced the only significant change, suggesting an alteration in mitochondrial biogenesis in colonocytes. Considering the reports of elevated colonic TNFα and reduced butyrate metabolism in many conditions, including in hypertension, the present work sheds light on cellular interactions between TNFα and butyrate in colonocytes that may be important in understanding conditions of the colon.
    Keywords:  ROS1; TNFα; biopterin; butyrate; colonic epithelium; hypertension; metabolism; metabolomics; mitochondria
  16. Front Oncol. 2023 ;13 1124715
      Immune cells play a key role in host defence against infection and cancer. Unlike infection, cancer is a multidimensional disease where cancer cells require continuous activation of certain pathways to sustain their growth and survival. The tumour milieu plays an important role in defining the metabolic reprogramming to support this growth and evasion from the immune system. Cancer and stromal cells modulate each other's metabolism during cancer progression or regression. The mechanism related to change in the metabolism and its role in the crosstalk between tumour and immune cells is still an area of immense importance. Current treatment modalities can be immensely complemented and benefited by targeting the immuno-oncology metabolism, that can improve patient prognosis. This emerging aspect of immune-oncology metabolism is reviewed here, discussing therapeutic possibilities within various metabolic pathways and their effect on immune and cancer cell metabolism.
    Keywords:  cancer; immune cells; immuno-oncology; metabolic reprogramming; metabolism; therapeutics; tumour immunology
  17. Int Immunopharmacol. 2023 Feb 22. pii: S1567-5769(23)00163-7. [Epub ahead of print]117 109840
      Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is defined as chronic inflammation in the gastrointestinal tract. Notably, more than 20% of people with IBD experience depressive symptoms. Understanding the immunological mechanism of chronic intestinal inflammation on cognitive behavior has become a key research focus. Previous studies have shown that a dysregulated immune response contributes to chronic inflammation and depressive symptoms. The tolerant phenotype exhibited by immune cells regulates the course of chronic inflammation in distinct ways. In addition, neuroglia, such as microglia and astrocytes specific to the brain, are also influenced by deregulated inflammation to mediate the development of depressive symptoms. The kynurenine pathway (KP), a significant tryptophan metabolic pathway, transforms tryptophan into a series of KP metabolites that modulate chronic inflammation and depressive symptoms. In particular, indoleamine 2,3-dioxygenase 1 (IDO1), a rate-limiting enzyme in the KP, is activated by chronic inflammation and leads to the production of kynurenine. In addition, disruption of the brain-gut axis induced by IBD allows kynurenine to cross the blood-brain barrier (BBB) and form a series of neuroactive kynurenine metabolites in glial cells. Among them, quinolinic acid continuously accumulates in the brain, indicating depression. Thus, KP metabolites are critical for driving the comorbidity of IBD and depressive symptoms. In this review, the pathological mechanism of KP metabolite-mediated chronic intestinal inflammation and depressive symptoms by regulating the immune response is summarized according to the latest reports.
    Keywords:  Depressive symptom; Immune response; Inflammatory bowel disease; Kynurenine pathway
  18. Antibiotics (Basel). 2023 Feb 08. pii: 357. [Epub ahead of print]12(2):
      Immunometabolic modulation of macrophages can play an important role in the innate immune response of chickens triggered with a multiplicity of insults. In this study, the immunometabolic role of two antibiotics (oxytetracycline and gentamicin) and four plant extracts (thyme essential oil, grape seed extract, garlic oil, and capsicum oleoresin) were investigated on a chicken macrophage-like cell line (HD11) during a Salmonella Enteritidis infection. To study the effect of these substances, kinome peptide array analysis, Seahorse metabolic assay, and gene expression techniques were employed. Oxytetracycline, to which the bacterial strain was resistant, thyme essential oil, and capsicum oleoresin did not show any noteworthy immunometabolic effect. Garlic oil affected glycolysis, but this change was not detected by the kinome analysis. Gentamicin and grape seed extract showed the best immunometabolic profile among treatments, being able to both help the host with the activation of immune response pathways and with maintaining a less inflammatory status from a metabolic point of view.
    Keywords:  HD11; Salmonella Enteritidis; antibiotic alternatives; cellular metabolism; foodborne diseases; innate immunity; plant extracts
  19. Cancer Immunol Immunother. 2023 Feb 25.
      The metabolic stress present in the tumor microenvironment of many cancers can attenuate T cell antitumor activity, which is intrinsically controlled by the mitochondrial plasticity, dynamics, metabolism, and biogenesis within these T cells. Previous studies have reported that the complement C1q binding protein (C1QBP), a mitochondrial protein, is responsible for maintenance of mitochondrial fitness in tumor cells; however, its role in T cell mitochondrial function, particularly in the context of an antitumor response, remains unclear. Here, we show that C1QBP is indispensable for T cell antitumor immunity by maintaining mitochondrial integrity and homeostasis. This effect holds even when only one allele of C1qbp is functional. Further analysis of C1QBP in the context of chimeric antigen receptor (CAR) T cell therapy against the murine B16 melanoma model confirmed the cell-intrinsic role of C1QBP in regulating the antitumor functions of CAR T cells. Mechanistically, we found that C1qbp knocking down impacted mitochondrial biogenesis via the AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha signaling pathway, as well as mitochondrial morphology via the phosphorylation of mitochondrial dynamics protein dynamin-related protein 1. In summary, our study provides a novel mitochondrial target to potentiate the plasticity and metabolic fitness of mitochondria within T cells, thus improving the immunotherapeutic potential of these T cells against tumors.
    Keywords:  Antitumor immunity; C1QBP; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial metabolism; Mitochondrial plasticity
  20. Cells. 2023 Feb 10. pii: 570. [Epub ahead of print]12(4):
      Alveolar macrophages (AM) are long-lived tissue-resident innate immune cells of the airways. AM are key effectors of recognition, initiation, and resolution of the host defense against microbes and play an essential role in mediating host responses to Streptococcus pneumoniae infection. Lipid metabolism in AM can significantly impact cellular function and biology. Dysregulated metabolism contributes to an accumulation of lipids, unfolded protein response induction, and inflammatory cytokine production. Our study was designed to investigate the impact of Ch25h on mediating innate immune responses by macrophages during S. pneumoniae infection. Using wild-type and Ch25-/- mice, we examined the role of cholesterol metabolism on inflammatory cytokine production and bacterial clearance. Our results demonstrate that Ch25h plays an important role in the initiation and intensity of cytokine and chemokine production in the lung during S. pneumoniae infection. In the absence of Ch25h, there was enhanced phagocytosis and bacterial clearance. Taken together, our findings demonstrate the important role of Ch25h in modulating host responsiveness to S. pneumoniae infection.
    Keywords:  Ch25h; Streptococcus pneumoniae; alveolar macrophage
  21. Biochem Soc Trans. 2023 Feb 23. pii: BST20220014. [Epub ahead of print]
      Mitochondria have long been appreciated as the metabolic hub of cells. Emerging evidence also posits these organelles as hubs for innate immune signalling and activation, particularly in macrophages. Macrophages are front-line cellular defenders against endogenous and exogenous threats in mammals. These cells use an array of receptors and downstream signalling molecules to respond to a diverse range of stimuli, with mitochondrial biology implicated in many of these responses. Mitochondria have the capacity to both divide through mitochondrial fission and coalesce through mitochondrial fusion. Mitochondrial dynamics, the balance between fission and fusion, regulate many cellular functions, including innate immune pathways in macrophages. In these cells, mitochondrial fission has primarily been associated with pro-inflammatory responses and metabolic adaptation, so can be considered as a combative strategy utilised by immune cells. In contrast, mitochondrial fusion has a more protective role in limiting cell death under conditions of nutrient starvation. Hence, fusion can be viewed as a cellular survival strategy. Here we broadly review the role of mitochondria in macrophage functions, with a focus on how regulated mitochondrial dynamics control different functional responses in these cells.
    Keywords:  inflammation; macrophages; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; neuroinflammation
  22. Nat Commun. 2023 Feb 18. 14(1): 929
      Pyroptosis, a type of Gasdermin-mediated cell death, contributes to an exacerbation of inflammation. To test the hypothesis that GSDME-mediated pyroptosis aggravates the progression of atherosclerosis, we generate ApoE and GSDME dual deficiency mice. As compared with the control mice, GSDME-/-/ApoE-/- mice show a reduction of atherosclerotic lesion area and inflammatory response when induced with a high-fat diet. Human atherosclerosis single-cell transcriptome analysis demonstrates that GSDME is mainly expressed in macrophages. In vitro, oxidized low-density lipoprotein (ox-LDL) induces GSDME expression and pyroptosis in macrophages. Mechanistically, ablation of GSDME in macrophages represses ox-LDL-induced inflammation and macrophage pyroptosis. Moreover, the signal transducer and activator of transcription 3 (STAT3) directly correlates with and positively regulates GSDME expression. This study explores the transcriptional mechanisms of GSDME during atherosclerosis development and indicates that GSDME-mediated pyroptosis in the progression of atherosclerosis could be a potential therapeutic approach for atherosclerosis.
  23. Biomolecules. 2023 Jan 24. pii: 223. [Epub ahead of print]13(2):
      Sepsis is a dysregulated host response to infection that causes potentially life-threatening organ dysfunction. We investigated the serum metabolomic profile at hospital admission for patients with bacterial sepsis. The study included 60 patients; 35 patients fulfilled the most recent 2016 Sepsis-3 criteria whereas the remaining 25 patients only fulfilled the previous Sepsis-2 criteria and could therefore be classified as having systemic inflammatory response syndrome (SIRS). A total of 1011 identified metabolites were detected in our serum samples. Ninety-seven metabolites differed significantly when comparing Sepsis-3 and Sepsis-2/SIRS patients; 40 of these metabolites constituted a heterogeneous group of amino acid metabolites/peptides. When comparing patients with and without bacteremia, we identified 51 metabolites that differed significantly, including 16 lipid metabolites and 11 amino acid metabolites. Furthermore, 42 metabolites showed a highly significant association with the maximal total Sequential Organ Failure Assessment (SOFA )score during the course of the disease (i.e., Pearson's correlation test, p-value < 0.005, and correlation factor > 0.6); these top-ranked metabolites included 23 amino acid metabolites and a subset of pregnenolone/progestin metabolites. Unsupervised hierarchical clustering analyses based on all 42 top-ranked SOFA correlated metabolites or the subset of 23 top-ranked amino acid metabolites showed that most Sepsis-3 patients differed from Sepsis-2/SIRS patients in their systemic metabolic profile at the time of hospital admission. However, a minority of Sepsis-3 patients showed similarities with the Sepsis-2/SIRS metabolic profile even though several of them showed a high total SOFA score. To conclude, Sepsis-3 patients are heterogeneous with regard to their metabolic profile at the time of hospitalization.
    Keywords:  SOFA score; bacteremia; metabolism; metabolomics; organ failure; sepsis
  24. Cancer Cell. 2023 Feb 09. pii: S1535-6108(23)00009-0. [Epub ahead of print]
      Increased glucose metabolism and uptake are characteristic of many tumors and used clinically to diagnose and monitor cancer progression. In addition to cancer cells, the tumor microenvironment (TME) encompasses a wide range of stromal, innate, and adaptive immune cells. Cooperation and competition between these cell populations supports tumor proliferation, progression, metastasis, and immune evasion. Cellular heterogeneity leads to metabolic heterogeneity because metabolic programs within the tumor are dependent not only on the TME cellular composition but also on cell states, location, and nutrient availability. In addition to driving metabolic plasticity of cancer cells, altered nutrients and signals in the TME can lead to metabolic immune suppression of effector cells and promote regulatory immune cells. Here we discuss how metabolic programming of cells within the TME promotes tumor proliferation, progression, and metastasis. We also discuss how targeting metabolic heterogeneity may offer therapeutic opportunities to overcome immune suppression and augment immunotherapies.
    Keywords:  immune; metabolism; metastasis; plasticity; tumor microenvironment
  25. J Periodontal Res. 2023 Feb 17.
      BACKGROUND AND OBJECTIVE: G protein-coupled receptor 40 (GPR40) is a receptor for medium- and long-chain free fatty acids (FFAs). GPR40 activation improves type 2 diabetes mellitus (T2DM), metabolic syndrome (MetS), and the complications of T2DM and MetS. Periodontitis, a common oral inflammatory disease initiated by periodontal pathogens, is another complication of T2DM and MetS. Since FFAs play a key role in the pathogenesis of MetS which exacerbates periodontal inflammation and GPR40 is a FFA receptor with anti-inflammatory properties, it is important to define the role of GPR40 in MetS-associated periodontitis.MATERIALS AND METHODS: We induced MetS and periodontitis by high-fat diet and periodontal injection of lipopolysaccharide (LPS), respectively, in wild-type and GPR40-deficient mice and determined alveolar bone loss and periodontal inflammation using micro-computed tomography, histology, and osteoclast staining. We also performed in vitro study to determine the role of GPR40 in the expression of proinflammatory genes.
    RESULTS: The primary outcome of the study is that GPR40 deficiency increased alveolar bone loss and enhanced osteoclastogenesis in control mice and the mice with both MetS and periodontitis. GPR40 deficiency also augmented periodontal inflammation in control mice and the mice with both MetS and periodontitis. Furthermore, GPR40 deficiency led to increased plasma lipids and insulin resistance in control mice but had no effect on the metabolic parameters in mice with MetS alone. For mice with both MetS and periodontitis, GPR40 deficiency increased insulin resistance. Finally, in vitro studies with macrophages showed that deficiency or inhibition of GPR40 upregulated proinflammatory genes while activation of GPR40 downregulated proinflammatory gene expression stimulated synergistically by LPS and palmitic acid.
    CONCLUSION: GPR40 deficiency worsens alveolar bone loss and periodontal inflammation in mice with both periodontitis and MetS, suggesting that GPR40 plays a favorable role in MetS-associated periodontitis. Furthermore, GPR40 deficiency or inhibition in macrophages further upregulated proinflammatory and pro-osteoclastogenic genes induced by LPS and palmitic acid, suggesting that GPR40 has anti-inflammatory and anti-osteoclastogenic properties.
    Keywords:  fatty acid receptor; inflammation; metabolic syndrome; periodontitis
  26. Front Cell Infect Microbiol. 2023 ;13 1098457
      Introduction: Chagas cardiomyopathy, a disease caused by Trypanosoma cruzi (T. cruzi) infection, is a major contributor to heart failure in Latin America. There are significant gaps in our understanding of the mechanism for infection of human cardiomyocytes, the pathways activated during the acute phase of the disease, and the molecular changes that lead to the progression of cardiomyopathy.Methods: To investigate the effects of T. cruzi on human cardiomyocytes during infection, we infected induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) with the parasite and analyzed cellular, molecular, and metabolic responses at 3 hours, 24 hours, and 48 hours post infection (hpi) using transcriptomics (RNAseq), proteomics (LC-MS), and metabolomics (GC-MS and Seahorse) analyses.
    Results: Analyses of multiomic data revealed that cardiomyocyte infection caused a rapid increase in genes and proteins related to activation innate and adaptive immune systems and pathways, including alpha and gamma interferons, HIF-1α signaling, and glycolysis. These responses resemble prototypic responses observed in pathogen-activated immune cells. Infection also caused an activation of glycolysis that was dependent on HIF-1α signaling. Using gene editing and pharmacological inhibitors, we found that T. cruzi uptake was mediated in part by the glucose-facilitated transporter GLUT4 and that the attenuation of glycolysis, HIF-1α activation, or GLUT4 expression decreased T. cruzi infection. In contrast, pre-activation of pro-inflammatory immune responses with LPS resulted in increased infection rates.
    Conclusion: These findings suggest that T. cruzi exploits a HIF-1α-dependent, cardiomyocyte-intrinsic stress-response activation of glycolysis to promote intracellular infection and replication. These chronic immuno-metabolic responses by cardiomyocytes promote dysfunction, cell death, and the emergence of cardiomyopathy.
    Keywords:  Chagas cardiomyopathy; Trypanosoma cruzi; glycolysis; inflammation; metabolism
  27. Trends Plant Sci. 2023 Feb 18. pii: S1360-1385(23)00049-3. [Epub ahead of print]
      The regulatory mechanisms of apoplastic reactive oxygen species (ROS) production during pattern-triggered immunity (PTI) are well known. However, how ROS levels are regulated during effector-triggered immunity (ETI) remains largely unknown. Recently, Zhang et al. discovered that MAPK-Alfin-like 7 module enhances nucleotide-binding, leucine-rich repeat receptor (NLR)-mediated immunity by negatively regulating genes encoding ROS scavenging enzymes, deepening our understanding of ROS control during ETI in plants.
    Keywords:  Alfin; MAPK; NLR-mediated immunity; ROS; phosphorylation
  28. Mol Med. 2023 Feb 21. 29(1): 25
      BACKGROUND: Dendritic cell (DC) dysfunction plays a central role in sepsis-induced immunosuppression. Recent research has indicated that collective mitochondrial fragmentation contributes to the dysfunction of immune cells observed during sepsis. PTEN-induced putative kinase 1 (PINK1) has been characterized as a guide for impaired mitochondria that can keep mitochondrial homeostasis. However, its role in the function of DCs during sepsis and the related mechanisms remain obscure. In our study, we elucidated the effect of PINK1 on DC function during sepsis and its underlying mechanism of action.METHODS: Cecal ligation and puncture (CLP) surgery and lipopolysaccharide (LPS) treatment were used as in vivo and in vitro sepsis models, respectively.
    RESULTS: We found that changes in mitochondrial PINK1 expression of DCs paralleled changes in DC function during sepsis. The ratio of DCs expressing MHC-II, CD86, and CD80, the mRNAs level of dendritic cells expressing TNF-α and IL-12, and the level of DC-mediated T-cell proliferation were all decreased, both in vivo and in vitro during sepsis, when PINK1 was knocked out. This suggested that PINK1 knockout prevented the function of DCs during sepsis. Furthermore, PINK1 knockout inhibited Parkin RBR E3 ubiquitin protein (Parkin)-dependent mitophagy and enhanced dynamin-related protein 1 (Drp1)-related mitochondrial fission, and the negative effects of PINK1 knockout on DC function following LPS treatment were reversed by Parkin activation and Drp1 inhibitor. Knockout of PINK1 also increased apoptosis of DCs and the mortality of CLP mice.
    CONCLUSION: Our results indicated that PINK1 protected against DC dysfunction during sepsis through the regulation of mitochondrial quality control.
    Keywords:  Dendritic cells; Mitochondrial fission; Mitochondrial quality control; Mitophagy; PINK1; Sepsis
  29. JCI Insight. 2023 Feb 22. pii: e166655. [Epub ahead of print]8(4):
      Short-chain fatty acids, including butyrate, have multiple metabolic benefits in individuals who are lean but not in individuals with metabolic syndrome, with the underlying mechanisms still being unclear. We aimed to investigate the role of gut microbiota in the induction of metabolic benefits of dietary butyrate. We performed antibiotic-induced microbiota depletion of the gut and fecal microbiota transplantation (FMT) in APOE*3-Leiden.CETP mice, a well-established translational model for developing human-like metabolic syndrome, and revealed that dietary butyrate reduced appetite and ameliorated high-fat diet-induced (HFD-induced) weight gain dependent on the presence of gut microbiota. FMT from butyrate-treated lean donor mice, but not butyrate-treated obese donor mice, into gut microbiota-depleted recipient mice reduced food intake, attenuated HFD-induced weight gain, and improved insulin resistance. 16S rRNA and metagenomic sequencing on cecal bacterial DNA of recipient mice implied that these effects were accompanied by the selective proliferation of Lachnospiraceae bacterium 28-4 in the gut as induced by butyrate. Collectively, our findings reveal a crucial role of gut microbiota in the beneficial metabolic effects of dietary butyrate as strongly associated with the abundance of Lachnospiraceae bacterium 28-4.
    Keywords:  Endocrinology; Microbiology; Obesity
  30. Nat Chem Biol. 2023 Feb 23.
      Creatine kinases (CKs) provide local ATP production in periods of elevated energetic demand, such as during rapid anabolism and growth. Thus, creatine energetics has emerged as a major metabolic liability in many rapidly proliferating cancers. Whether CKs can be targeted therapeutically is unknown because no potent or selective CK inhibitors have been developed. Here we leverage an active site cysteine present in all CK isoforms to develop a selective covalent inhibitor of creatine phosphagen energetics, CKi. Using deep chemoproteomics, we discover that CKi selectively engages the active site cysteine of CKs in cells. A co-crystal structure of CKi with creatine kinase B indicates active site inhibition that prevents bidirectional phosphotransfer. In cells, CKi and its analogs rapidly and selectively deplete creatine phosphate, and drive toxicity selectively in CK-dependent acute myeloid leukemia. Finally, we use CKi to uncover an essential role for CKs in the regulation of proinflammatory cytokine production in macrophages.
  31. J Biol Chem. 2023 Feb 17. pii: S0021-9258(23)00175-8. [Epub ahead of print] 103043
      Hyperlactatemia often occurs in critically ill patients during severe sepsis/septic shock and is a powerful predictor of mortality. Lactate is the end product of glycolysis. While hypoxia due to inadequate oxygen delivery may result in anaerobic glycolysis, sepsis also enhances glycolysis under hyperdynamic circulation with adequate oxygen delivery. However, the molecular mechanisms involved are not fully understood. Mitogen-activated protein kinase (MAPK)a families regulate many aspects of the immune response during microbial infections. MAPK phosphatase (MKP)-1 serves as a feedback control mechanism for p38 and JNK MAPK activities via dephosphorylation. Here, we found that mice deficient in Mkp-1 exhibited substantially enhanced expression and phosphorylation of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB) 3, a key enzyme that regulates glycolysis following systemic E. coli infection. Enhanced PFKFB3 expression was observed in a variety of tissues and cell types, including hepatocytes, macrophages, and epithelial cells. In bone marrow-derived macrophages (BMDM), Pfkfb3 was robustly induced by both E. coli and lipopolysaccharide (LPS), and Mkp-1 deficiency enhanced PFKFB3 expression with no effect on Pfkfb3 mRNA stability. PFKFB3 induction was correlated with lactate production in both WT and Mkp-1-/- BMDM following LPS stimulation. Furthermore, we determined that a PFKFB3 inhibitor markedly attenuated lactate production, highlighting the critical role of PFKFB3 in the glycolysis program. Finally, pharmacological inhibition of p38 MAPK, but not JNK, substantially attenuated PFKFB3 expression and lactate production. Taken together, our studies suggest a critical role of p38 MAPK and MKP-1 in the regulation of glycolysis during sepsis.
    Keywords:  Infection; c-Jun N-terminal kinase (JNK); dual-specificity phosphoprotein phosphatase; glycolysis; p38 MAPK; sepsis