Immunometabolic Dysfunction Research Articles

Mesenchymal stem cell-derived small extracellular vesicles alleviate the immunometabolic dysfunction in murine septic encephalopathy

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection that results in high mortality and long-term sequela. The central nervous system (CNS) is susceptible to injury from infectious processes, which can lead to clinical symptoms of septic encephalopathy (SE). SE is linked to a profound energetic deficit associated with immune dysregulation. Here, we show that intravenous administration of adipose tissue mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) in septic mice improved disease outcomes by reducing SE clinical severity, restoring aerobic metabolism, and lowering pro-inflammatory cytokines in the cerebellum, a key region affected by SE. Our high throughput analysis showed that MSC-derived sEVs partially reversed sepsis-induced transcriptomic changes, highlighting the potential association of miRNA regulators in the cerebellum of MSC-derived sEV-treated mice with miRNAs identified in sEV cargo. MSC-derived sEVs could serve as a promising therapeutic agent in SE through their favorable immunometabolic properties.

Oxidative phosphorylation in HIV-1 infection: impacts on cellular metabolism and immune function.

Human Immunodeficiency Virus Type 1 (HIV-1) presents significant challenges to the immune system, predominantly characterized by CD4+ T cell depletion, leading to Acquired Immunodeficiency Syndrome (AIDS). Antiretroviral therapy (ART) effectively suppresses the viral load in people with HIV (PWH), leading to a state of chronic infection that is associated with inflammation. This review explores the complex relationship between oxidative phosphorylation, a crucial metabolic pathway for cellular energy production, and HIV-1, emphasizing the dual impact of HIV-1 infection and the metabolic and mitochondrial effects of ART. The review highlights how HIV-1 infection disrupts oxidative phosphorylation, promoting glycolysis and fatty acid synthesis to facilitate viral replication. ART can exacerbate metabolic dysregulation despite controlling viral replication, impacting mitochondrial DNA synthesis and enhancing reactive oxygen species production. These effects collectively contribute to significant changes in oxidative phosphorylation, influencing immune cell metabolism and function. Adenosine triphosphate (ATP) generated through oxidative phosphorylation can influence the metabolic landscape of infected cells through ATP-detected purinergic signaling and contributes to immunometabolic dysfunction. Future research should focus on identifying specific targets within this pathway and exploring the role of purinergic signaling in HIV-1 pathogenesis to enhance HIV-1 treatment modalities, addressing both viral infection and its metabolic consequences.

Obesity wars: hypothalamic sEVs a new hope.

There are currently several pharmacological therapies available for the treatment of obesity, targeting both the central nervous system (CNS) and peripheral tissues. In recent years, small extracellular vesicles (sEVs) have been shown to be involved in many pathophysiological conditions. Because of their special nanosized structure and contents, sEVs can activate receptors and trigger intracellular pathways in recipient cells. Notably, in addition to transferring molecules between cells, sEVs can also alter their phenotypic characteristics. The purpose of this review is to discuss how sEVs can be used as a CNS-targeted strategy for treating obesity. Furthermore, we will evaluate current findings, such as the sEV-mediated targeting of hypothalamic AMP-activated protein kinase (AMPK), and discuss how they can be translated into clinical application.

Surveying the Metabolic and Dysfunctional Profiles of T Cells and NK Cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Millions globally suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The inflammatory symptoms, illness onset, recorded outbreak events, and physiological variations provide strong indications that ME/CFS, at least sometimes, has an infectious origin, possibly resulting in a chronic unidentified viral infection. Meanwhile, studies exposing generalized metabolic disruptions in ME/CFS have stimulated interest in isolated immune cells with an altered metabolic state. As the metabolism dictates the cellular function, dissecting the biomechanics of dysfunctional immune cells in ME/CFS can uncover states such as exhaustion, senescence, or anergy, providing insights into the consequences of these phenotypes in this disease. Despite the similarities that are seen metabolically between ME/CFS and other chronic viral infections that result in an exhausted immune cell state, immune cell exhaustion has not yet been verified in ME/CFS. This review explores the evidence for immunometabolic dysfunction in ME/CFS T cell and natural killer (NK) cell populations, comparing ME/CFS metabolic and functional features to dysfunctional immune cell states, and positing whether anergy, exhaustion, or senescence could be occurring in distinct immune cell populations in ME/CFS, which is consistent with the hypothesis that ME/CFS is a chronic viral disease. This comprehensive review of the ME/CFS immunometabolic literature identifies CD8+ T cell exhaustion as a probable contender, underscores the need for further investigation into the dysfunctional state of CD4+ T cells and NK cells, and explores the functional implications of molecular findings in these immune-cell types. Comprehending the cause and impact of ME/CFS immune cell dysfunction is critical to understanding the physiological mechanisms of ME/CFS, and developing effective treatments to alleviate the burden of this disabling condition.

B cell contribution to immunometabolic dysfunction and impaired immune responses in obesity.

Obesity increases the risk of type 2 diabetes mellitus, cardiovascular disease, fatty liver disease, and cancer. It is also linked with more severe complications from infections, including COVID-19, and poor vaccine responses. Chronic, low-grade inflammation and associated immune perturbations play an important role in determining morbidity in people living with obesity. The contribution of B cells to immune dysregulation and meta-inflammation associated with obesity has been documented by studies over the past decade. With a focus on human studies, here we consolidate the observations demonstrating that there is altered B cell subset composition, differentiation, and function both systemically and in the adipose tissue of individuals living with obesity. Finally, we discuss the potential factors that drive B cell dysfunction in obesity and propose a model by which altered B cell subset composition in obesity underlies dysfunctional B cell responses to novel pathogens.

Immune senescence in multiple myeloma-a role for mitochondrial dysfunction?

Age-related immune dysfunction is primarily mediated by immunosenescence which results in ineffective clearance of infective pathogens, poor vaccine responses and increased susceptibility to multi-morbidities. Immunosenescence-related immunometabolic abnormalities are associated with accelerated aging, an inflammatory immune response (inflammaging) and ultimately frailty syndromes. In addition, several conditions can accelerate the development of immunosenescence, including cancer. This is a bi-directional interaction since inflammaging may create a permissive environment for tumour development. Multiple myeloma (MM) is a mature B-cell malignancy that presents in the older population. MM exemplifies the interaction of age- (Host Response Biology; HRB) and disease-related immunological dysfunction, contributing to the development of a frailty syndrome which impairs the therapeutic impact of recent advances in treatment strategies. Understanding the mechanisms by which accelerated immunological aging is induced and the ways in which a tumour such as MM influences this process is key to overcoming therapeutic barriers. A link between cellular mitochondrial dysfunction and the acquisition of an abnormal immune phenotype has recently been described and has widespread physiological consequence beyond the impact on the immune system. Here we outline our current understanding of normal immune aging, describe the mechanism of immunometabolic dysfunction in accelerating this process, and propose the role these processes are playing in the pathogenesis of MM.

Physiological Systems in Promoting Frailty.

Frailty is a complex syndrome affecting a growing sector of the global population as medical developments have advanced human mortality rates across the world. Our current understanding of frailty is derived from studies conducted in the laboratory as well as the clinic, which have generated largely phenotypic information. Far fewer studies have uncovered biological underpinnings driving the onset and progression of frailty, but the stage is set to advance the field with preclinical and clinical assessment tools, multiomics approaches together with physiological and biochemical methodologies. In this article, we provide comprehensive coverage of topics regarding frailty assessment, preclinical models, interventions, and challenges as well as clinical frameworks and prevalence. We also identify central biological mechanisms that may be at play including mitochondrial dysfunction, epigenetic alterations, and oxidative stress that in turn, affect metabolism, stress responses, and endocrine and neuromuscular systems. We review the role of metabolic syndrome, insulin resistance and visceral obesity, focusing on glucose homeostasis, adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and nicotinamide adenine dinucleotide (NAD+ ) as critical players influencing the age-related loss of health. We further focus on how immunometabolic dysfunction associates with oxidative stress in promoting sarcopenia, a key contributor to slowness, weakness, and fatigue. We explore the biological mechanisms involved in stem cell exhaustion that affect regeneration and may contribute to the frailty-associated decline in resilience and adaptation to stress. Together, an overview of the interplay of aging biology with genetic, lifestyle, and environmental factors that contribute to frailty, as well as potential therapeutic targets to lower risk and slow the progression of ongoing disease is covered. © 2022 American Physiological Society. Compr Physiol 12:1-46, 2022.

Childhood immuno-metabolic markers and risk of depression and psychosis in adulthood: A prospective birth cohort study

BackgroundMetabolic and inflammatory disorders commonly co-occur with depression and psychosis, with emerging evidence implicating immuno-metabolic dysfunction in their aetiology. Previous studies have reported metabolic dysfunction and inflammation in adults with depression and psychosis. However, longitudinal studies testing the direction of association, and the effects of different dimensions of early-life immuno-metabolic dysfunction on adult psychopathology are limited. MethodsUsing data from 3258 birth cohort participants we examined longitudinal associations of three metabolic hormones (leptin, adiponectin, insulin) at age 9 with risks for depression- and psychosis-spectrum outcomes at age 24. In addition, using nine immuno-metabolic biomarkers (leptin, adiponectin, insulin, interleukin-6, C-Reactive protein, low density lipoprotein, high density lipoprotein, triglycerides, and BMI), we constructed an exploratory bifactor model showing a general immuno-metabolic factor and three specific factors (adiposity, inflammation, and insulin resistance), which were also used as exposures. ResultsChildhood leptin was associated with adult depressive episode (adjusted odds ratio (aOR)= 1.31; 95% CI, 1.02–1.71) and negative symptoms (aOR=1.15; 95% CI, 1.07–1.24), but not positive psychotic symptoms. The general immuno-metabolic factor was associated with atypical depressive symptoms (aOR=1.07; 95% CI, 1.01–1.14) and psychotic experiences (aOR=1.21; 95% CI, 1.02–1.44). The adiposity factor was associated with negative symptoms (aOR=1.07; 95% CI 1.02–1.12). Point estimates tended to be larger in women, though 95% credible intervals overlapped with those for men. In women, the inflammatory factor was associated with depressive episodes (aOR=1.27; 95% CI, 1.03–1.57). ConclusionsWhile general immuno-metabolic dysfunction in childhood may contribute to risks for both psychotic and depressive symptoms in adulthood, childhood adiposity and inflammation appear to be particularly linked to affective (depressive and negative), but not positive psychotic symptoms.

Bacteroides uniformis CECT 7771 alleviates inflammation within the gut-adipose tissue axis involving TLR5 signaling in obese mice

This study investigated the immune mechanisms whereby administration of Bacteroides uniformis CECT 7771 reduces metabolic dysfunction in obesity. C57BL/6 adult male mice were fed a standard diet or a Western diet high in fat and fructose, supplemented or not with B. uniformis CECT 7771 for 14 weeks. B. uniformis CECT 7771 reduced body weight gain, plasma cholesterol, triglyceride, glucose, and leptin levels; and improved oral glucose tolerance in obese mice. Moreover, B. uniformis CECT 7771 modulated the gut microbiota and immune alterations associated with obesity, increasing Tregs and reducing B cells, total macrophages and the M1/M2 ratio in both the gut and epididymal adipose tissue (EAT) of obese mice. B. uniformis CECT 7771 also increased the concentration of the anti-inflammatory cytokine IL-10 in the gut, EAT and peripheral blood, and protective cytokines TSLP and IL-33, involved in Treg induction and type 2 innate lymphoid cells activation, in the EAT. It also restored the obesity–reduced TLR5 expression in the ileum and EAT. The findings indicate that the administration of a human intestinal bacterium with immunoregulatory properties on the intestinal mucosa helps reverse the immuno-metabolic dysfunction caused by a Western diet acting over the gut-adipose tissue axis.

Divergent immunometabolic changes in adipose tissue and skeletal muscle with ageing in healthy humans.

Ageing is associated with increased systemic inflammation and metabolic dysfunction that contributes to the development of age-associated diseases. The role of adipose tissue in immunometabolic alterations that take place with ageing is unknown in humans. We show, in healthy, active and lean older adults, that adipose tissue, but not skeletal muscle, displays considerable pro-inflammatory transcriptomic, cellular and secretory changes, as well as a reduction in insulin signalling proteins compared to younger adults. These findings indicate that adipose tissue undergoes substantial immunometabolic alterations with ageing, and that these changes are tissue-specific and more profound than those observed in skeletal muscle or in the circulation. These results identify adipose tissue as an important tissue in the biological ageing process in humans, which may exhibit signs of immunometabolic dysfunction prior to systemic manifestation. Ageing and obesity are both characterized by inflammation and a deterioration in metabolic health. It is now clear that adipose tissue plays a major role in inflammation and metabolic control in obesity, although little is known about the role of adipose tissue in human ageing. To understand how ageing impacts adipose tissue, we characterized subcutaneous adipose tissue and skeletal muscle samples from twelve younger (27±4years [Young]) and twelve older (66±5years [Old]) active/non-obese males. We performed a wide-range of whole-body and tissue measures, including RNA-sequencing and multicolour flow cytometry. We also measured a range of inflammatory and metabolic proteins in the circulation and their release by adipose tissue, exvivo. Both adipose tissue and muscle had ∼2-fold more immune cells per gram of tissue with ageing. In adipose tissue, this immune cell infiltration was driven by increased memory/effector T-cells, whereas, in muscle, the accumulation was driven by memory/effector T-cells and macrophages. Transcriptomic analysis revealed that, with ageing, adipose tissue, but not muscle, was enriched for inflammatory transcripts/pathways related to acquired and innate immunity. Ageing also increased the adipose tissue pro-inflammatory secretory profile. Insulin signalling protein content was reduced in adipose tissue, but not muscle. Our findings indicate that adipose tissue undergoes substantial immunometabolic changes with ageing in humans, and that these changes are tissue-specific and more profound than those observed in the circulation and skeletal muscle.

Elevated type I interferon responses potentiate metabolic dysfunction, inflammation, and accelerated aging in mtDNA mutator mice.

Mitochondrial dysfunction is a key driver of inflammatory responses in human disease. However, it remains unclear whether alterations in mitochondria-innate immune cross-talk contribute to the pathobiology of mitochondrial disorders and aging. Using the polymerase gamma (POLG) mutator model of mitochondrial DNA instability, we report that aberrant activation of the type I interferon (IFN-I) innate immune axis potentiates immunometabolic dysfunction, reduces health span, and accelerates aging in mutator mice. Mechanistically, elevated IFN-I signaling suppresses activation of nuclear factor erythroid 2-related factor 2 (NRF2), which increases oxidative stress, enhances proinflammatory cytokine responses, and accelerates metabolic dysfunction. Ablation of IFN-I signaling attenuates hyperinflammatory phenotypes by restoring NRF2 activity and reducing aerobic glycolysis, which combine to lessen cardiovascular and myeloid dysfunction in aged mutator mice. These findings further advance our knowledge of how mitochondrial dysfunction shapes innate immune responses and provide a framework for understanding mitochondria-driven immunopathology in POLG-related disorders and aging.

Decreased Intestinal Microbiome Diversity in Pediatric Sepsis: A Conceptual Framework for Intestinal Dysbiosis to Influence Immunometabolic Function.

The intestinal microbiome can modulate immune function through production of microbial-derived short-chain fatty acids. We explored whether intestinal dysbiosis in children with sepsis leads to changes in microbial-derived short-chain fatty acids in plasma and stool that are associated with immunometabolic dysfunction in peripheral blood mononuclear cells. Prospective observational pilot study. Single academic PICU. Forty-three children with sepsis/septic shock and 44 healthy controls. Stool and plasma samples were serially collected for sepsis patients; stool was collected once for controls. The intestinal microbiome was assessed using 16S ribosomal RNA sequencing and alpha- and beta-diversity were determined. We measured short-chain fatty acids using liquid chromatography, peripheral blood mononuclear cell mitochondrial respiration using high-resolution respirometry, and immune function using ex vivo lipopolysaccharide-stimulated whole blood tumor necrosis factor-α. Sepsis patients exhibited reduced microbial diversity compared with healthy controls, with lower alpha- and beta-diversity. Reduced microbial diversity among sepsis patients (mainly from lower abundance of commensal obligate anaerobes) was associated with increased acetic and propionic acid and decreased butyric, isobutyric, and caproic acid. Decreased levels of plasma butyric acid were further associated with lower peripheral blood mononuclear cell mitochondrial respiration, which in turn, was associated with lower lipopolysaccharide-stimulated tumor necrosis factor-α. However, neither intestinal dysbiosis nor specific patterns of short-chain fatty acids were associated with lipopolysaccharide-stimulated tumor necrosis factor-α. Intestinal dysbiosis was associated with altered short-chain fatty acid metabolites in children with sepsis, but these findings were not linked directly to mitochondrial or immunologic changes. More detailed mechanistic studies are needed to test the role of microbial-derived short-chain fatty acids in the progression of sepsis.

Neuroinflammation and Precision Medicine in Pediatric Neurocritical Care: Multi-Modal Monitoring of Immunometabolic Dysfunction.

The understanding of molecular biology in neurocritical care (NCC) is expanding rapidly and recognizing the important contribution of neuroinflammation, specifically changes in immunometabolism, towards pathological disease processes encountered across all illnesses in the NCC. Additionally, the importance of individualized inflammatory responses has been emphasized, acknowledging that not all individuals have the same mechanisms contributing towards their presentation. By understanding cellular processes that drive disease, we can make better personalized therapy decisions to improve patient outcomes. While the understanding of these cellular processes is evolving, the ability to measure such cellular responses at bedside to make acute care decisions is lacking. In this overview, we review cellular mechanisms involved in pathological neuroinflammation with a focus on immunometabolic dysfunction and review non-invasive bedside tools that have the potential to measure indirect and direct markers of shifts in cellular metabolism related to neuroinflammation. These tools include near-infrared spectroscopy, transcranial doppler, elastography, electroencephalography, magnetic resonance imaging and spectroscopy, and cytokine analysis. Additionally, we review the importance of genetic testing in providing information about unique metabolic profiles to guide individualized interpretation of bedside data. Together in tandem, these modalities have the potential to provide real time information and guide more informed treatment decisions.

Circulating Exosomes Control CD4+ T Cell Immunometabolic Functions via the Transfer of miR-142 as a Novel Mediator in Myocarditis

CD4+ Tcells undergo immunometabolic activation to mount an immunogenic response during experimental autoimmune myocarditis (EAM). Exosomes are considered key messengers mediating multiple Tcell functions in autoimmune responses. However, the role of circulating exosomes in EAM immunopathogenesis and CD4+ Tcell dysfunction remains elusive. Our objective was to elucidate the mechanism of action for circulating exosomes in EAM pathogenesis. We found that serum exosomes harvested from EAM mice induced CD4+ Tcell immunometabolic dysfunction. Treatment with the exosome inhibitor GW4869 protected mice from developing EAM, underlying that exosomes are indispensable for the pathogenesis of EAM. Furthermore, by transfer of EAM exosomes, we confirmed that circulating exosomes initiate the Tcell pathological immune response, driving the EAM pathological process. Mechanistically, EAM-circulating exosomes selectively loaded abundant microRNA (miR)-142. We confirmed methyl-CpG binding domain protein 2 (MBD2) and suppressor of cytokine signaling 1 (SOCS1) as functional target genes of miR-142. The miR-142/MBD2/MYC and miR-142/SOCS1 communication axes are critical to exosome-mediated immunometabolic turbulence. Moreover, the invivo injection of the miR-142 inhibitor alleviated cardiac injury in EAM mice. This effect was abrogated by pretreatment with EAM exosomes. Collectively, our results indicate a newly endogenous mechanism whereby circulating exosomes regulate CD4+ Tcell immunometabolic dysfunction and EAM pathogenesis via cargo miR-142.

Dysfunctional Immunometabolism in HIV Infection: Contributing Factors and Implications for Age-Related Comorbid Diseases.

An increasing body of evidence indicates that persons living with HIV (PLWH) display dysfunctional immunometabolism. Here, we provide an updated review of this topic and its relationship to HIV-associated immune stimuli and age-related disease. HIV infection alters immunometabolism by increasing reliance on aerobic glycolysis for energy and productive infection and repurposing oxidative phosphorylation machinery for immune cell proliferation and survival. Recent studies in PLWH with diabetes mellitus or cardiovascular disease have identified an association with elevated T cell and monocyte glucose metabolism, respectively. Immunometabolic dysfunction has also been observed in PLWH in frailty and additional studies suggest a role for immunometabolism in non-AIDS defining cancers and neurocognitive disease. There is a plethora of HIV-associated immune stimuli that could drive immunometabolic dysfunction and age-related disease in PLWH, but studies directly examining their relationship are lacking. Immunometabolic dysfunction is characteristic of HIV infection and is a potential link between HIV-associated stimuli and age-related comorbidities.

Mechanisms by which Obesity Dysregulates Immunometabolic State in Asthma

Childhood asthma and obesity are two of the most common chronic diseases worldwide. As body mass increases, there is an increase in asthma prevalence, supporting a possible pathophysiological link. While the mechanism of that link remains unclear, immunometabolic dysfunction is increasingly appreciated as a key mechanism in immunological disease and hereperwe tested that hypothesis. Prospective immunometabolic study of pediatric asthma and obesity with recruitment of obese asthmatics (OA), non-obese asthmatics (A), obese non-asthmatics (O) and healthy controls (HC). Asthmatics were recruited from our Allergy clinic with deep clinical metadata. To assess the underlying mechanisms of immune dysfunction, we used peripheral blood mass cytometry (CyTOF), flow cytometry, serum metabolomics and cytokine analysis and high dimensional systems immunology analytics. A second cohort of asthmatics (OA and A) was assessed as well. Human in vitro culture of PBMCs and a mouse model of obese asthma were then used to test hypothesized mechanisms of T cell dysfunction from these studies. Pediatric atopic OA demonstrated alterations in T cell differentiation including increased type 2 immunity and T cell exhaustion. OA also demonstrated altered serum metabolites including glutamate and acetate, which were shown to underlie some of the immune dysfunction using in vitro and in vivo studies. We have identified novel insights into the mechanistic links between metabolic disturbances and immune dysfunction in obesity and asthma. We are further extending mechanistic testing in mouse models of obese asthma and in vitro in human studies to move towards identification of novel therapeutic strategies targeting these mechanisms.

Relationship between Health Costs and Inflammatory Profile in Public Health.

The association between obesity and physical activity level is well established in the literature, as well as its consequences that lead to chronic noncommunicable diseases. In addition, it is also possible to obtain the immunometabolic mechanism that explains the pathway of associations between obesity, chronic noncommunicable diseases and the level of physical activity. It also seems clear that treating illnesses has a financial impact on healthcare systems around the world, so it seems important to assess the financial impact on the healthcare system of individuals with immunometabolic dysfunction. This study aimed to assess whether there is a correlation between metabolic and inflammatory markers and healthcare costs according to body adiposity and habitual physical activity (HPA). This is a cross-sectional study, where the sample includes men and women aged over 50. Participants underwent evaluations that included the following variables: i) immunometabolic markers, ii) healthcare costs, iii) obesity, iv) habitual physical activity, and v) history of personal illness. Statistical significance was set at values lower than 5% and the software used was BioEstat. The correlation between metabolic and inflammatory markers and healthcare costs demonstrated a positive and significant relationship, adjusted for obesity and HPA, between glucose concentrations and exam costs (r = 0.343, p-value = 0.007) and total cost (r = 261; p-value = 0.043); HOMA index and cost of exams (r = 0.267; pvalue = 0.038); and IL-10 and cost of medical consultation (r = 0.297; p-value = 0.020). Metabolic and inflammatory markers may be related to the costs of consultations and examinations, independent of obesity and HPA.

1685: IMMUNOMETABOLIC DYSFUNCTION IN OBESITY WITH SEPSIS

1685: IMMUNOMETABOLIC DYSFUNCTION IN OBESITY WITH SEPSIS

Immunometabolic Dysfunction of Natural Killer Cells Mediated by the Hypoxia-CD73 Axis in Solid Tumors.

NK cell infiltration into solid tumors is often low and is largely represented by the poorly-cytotoxic CD56bright subset. Numerous studies have demonstrated that CD73, overexpressed under conditions of hypoxia, is involved in a variety of physiological processes, while its overexpression has been correlated with tumor invasiveness, metastasis and poorer patient survival in many cancers. Hypoxia itself favors aggressive glycolytic fueling of cancer cells, in turn driving reprogramming of NK cell metabolism. In addition, the hypoxia-driven activity of CD73 immunometabolically impairs NK cells in tumors, due to its catalytic role in the generation of the highly immunosuppressive metabolite adenosine. Adenosinergic signaling was shown to alter NK cell metabolic programs, leading to tumor-promoting environments characterized by NK cell dysfunction. Despite the demonstrated role of NK cell responses in the context of CD73 targeting, the engagement of NK cells in the setting of hypoxia/CD73 signaling has not been extensively studied or exploited. Here, we discuss available evidence on the role of hypoxic signaling on CD73-mediated activity, and how this relates to the immunometabolic responses of NK cells, with a particular focus on the therapeutic targeting of these pathways.

NLRP1 inflammasome mediates immuno-metabolic dysfunction in follicular niche of PCOS

Investigating mechanism of chronic inflammation in PCOS ovary regulated by NLRP inflammasome To determine whether NLRP expression is associated with inflammatory status in follicular niche of PCOS patients, we analyzed expression level of NLRP genes in ovarian granulosa cells isolated from 35 women with PCOS and 32 healthy adult female controls undergoing in vitro fertilization and embryo treatment (IVF-ET)at the Reproductive Center of Peking University Third Hospital. PCOS patients were diagnosed by Rotterdam-PCOS criteria. Ovarian Granulosa cells was isolated by Ficoll density gradient centrifugation and gene expression was detected by Real-time RT-PCR analysis. Furthermore, we tested IL18 and IL 1B protein level in follicular fluids from these patients by ELSA.LCMS/MS was applied to quantify long-chain fatty acids in in follicular fluid. Human ovarian granulosa cell line KGN was used for in vitro cell tests. Activation of NLRP inflammasome and MMP-9 production was detected by western blotting. Our results showed that IL18 level in follicular fluid of PCOS patients is significantly higher than female controls, besides, IL18 protein level is positively correlated with BMI, which indicated potential link between inflammation and lipid metabolic aberration in follicular microenvironment of PCOS. We also found that NLRP1 transcription level is higher in PCOS women than healthy women. Inflammasome-activating stimuli induced phosphorylation of caspase-1 in granulosa cell line KGN. Long-chain fatty acids from abnormal lipid metabolism is significantly elevated in follicular fluids from PCOS patients. Based on existing results, we infer that up-regulation of NLRP1 in ovarian granulosa cells may be related to lipid metabolic dysfunction in PCOS and result in elevated IL18 secretion in follicular fluid of PCOS women, possibly through NLRP1 inflammasome assembly and activation.