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Dichotomous metabolic networks govern human ILC2 proliferation and function

ABSTRACT: 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. ILC2 metabolism has been largely unexplored. Di Santo and colleagues examine metabolic profiles from naive and cytokine-activated ILC2s and find that IL-33-triggered ILC2s rely on distinct metabolic pathways to sustain proliferation and function.

SUBMITTER: Surace L

PROVIDER: S-EPMC8553616 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Dichotomous metabolic networks govern human ILC2 proliferation and function

Project description:Group 2 innate lymphoid cells (ILC2) represent innate homologues of Th2 cells 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 “naïve” ILC2 have an unexpected metabolic profile with a higher level of oxidative phosphorylation (OXPHOS) than NK cells. Accordingly, ILC2 are severely reduced in patients with mitochondrial disease and impaired OXPHOS. Metabolomic and nutrient receptors analysis reveals ILC2 uptake amino acids to sustain OXPHOS at steady-state. Upon activation with interleukin 33 (IL-33), ILC2 become highly proliferative relying on glycolysis and 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 ILC2, offering new strategies to target ILC2 in disease settings.

2021-09-10 | GSE183669 | GEO

Dichotomous metabolic networks govern human ILC2 proliferation and function

Project description:Dichotomous metabolic networks govern human ILC2 proliferation and function

| PRJNA761663 | ENA

Reciprocal transcription factor networks govern tissue-resident ILC3 subset function and identity.

Project description:Innate lymphoid cells (ILCs) are guardians of mucosal immunity, yet the transcriptional networks that support their function remain poorly understood. We used inducible combinatorial deletion of key transcription factors (TFs) required for ILC development (RORγt, RORα and T-bet) to determine their necessity in maintaining ILC3 identity and function. Both RORγt and RORα were required to preserve optimum effector functions; however, RORα was sufficient to support robust interleukin-22 production among the lymphoid tissue inducer (LTi)-like ILC3 subset, but not natural cytotoxicity receptor (NCR)+ ILC3s. Lymphoid tissue inducer-like ILC3s persisted with only selective loss of phenotype and effector functions even after the loss of both TFs. In contrast, continued RORγt expression was essential to restrain transcriptional networks associated with type 1 immunity within NCR+ ILC3s, which coexpress T-bet. Full differentiation to an ILC1-like population required the additional loss of RORα. Together, these data demonstrate how TF networks integrate within mature ILCs after development to sustain effector functions, imprint phenotype and restrict alternative differentiation programs.

| S-EPMC7611981 | biostudies-literature

Insulin Directs Dichotomous Translational Regulation to Control Human Pluripotent Stem Cell Survival, Proliferation and Pluripotency.

Project description:Insulin is essential for diverse biological processes in human pluripotent stem cells (hPSCs). However, the underlying mechanism of insulin's multitasking ability remains largely unknown. Here, we show that insulin controls hPSC survival and proliferation by modulating RNA translation via distinct pathways. It activates AKT signaling to inhibit RNA translation of pro-apoptotic proteins such as NOXA/PMAIP1, thereby promoting hPSC survival. At the same time, insulin acts via the mTOR pathway to enhance another set of RNA translation for cell proliferation. Consistently, mTOR inhibition by rapamycin results in eIF4E phosphorylation and translational repression. It leads to a dormant state with sustained pluripotency but reduced cell growth. Together, our study uncovered multifaceted regulation by insulin in hPSC survival and proliferation, and highlighted RNA translation as a key step to mediate mitogenic regulation in hPSCs.

| S-EPMC9254461 | biostudies-literature

Reciprocal Transcription Factor Networks Govern Tissue-Resident ILC3 Subset Function and Identity

Project description:Innate lymphoid cells (ILCs) play important roles in health and tissue homeostasis. While the transcriptional networks that drive their development have been defined, the transcriptional requirements that support the phenotypes and functions of mature tissue-resident populations remain poorly understood. Here we employed combinatorial inducible deletion of core transcription factors (TFs) to test how co-operative and antagonistic networks operate to control function and identity. Utilizing single cell sequencing and epigenetic profiling we dissect the complex interplay between ROR family member TFs and T-bet in determining the function and phenotype of ILC3 and NCR-lineage ILCs, defining the ontogeny and surface phenotype across a continuum of ILC3s and mature ILC1s in the small intestine, alongside the differential requirements for ROR family TFs in the maintenance of effector functions and phenotype in mature ILCs. Combined, our data demonstrates how TF networks integrate in vivo to sustain effector functions and restrict alternative differentiation programmes.

2021-09-23 | GSE163149 | GEO

Dichotomous effects of aryl hydrocarbon receptor (AHR) activation on human fetoplacental endothelial cell function.

Project description:IntroductionMaternal cigarette smoking is associated with elevated fetoplacental vascular resistance and fetal growth restriction (FGR). While studies have demonstrated varying effects of nicotine on blood flow, the role of polycyclic aromatic hydrocarbons (PAHs), abundant toxins in cigarette smoke that cross the placenta, has not been elucidated. We hypothesized that exposure of human fetoplacental endothelial cells (ECs) to the PAH benzo[a]yrene (BaP) would result in up-regulation of cyclooxygenase-2 (PTGS2) and preferential production of vasoconstrictive prostanoids via activation of the aryl hydrocarbon receptor (AHR) pathway.MethodsECs were isolated, cultured, and treated with vehicle or BaP. ECs were subjected to real-time PCR, western blotting, enzyme immunoassays, wound scratch assays, tube formation assays, and RNA interference against AHR. Statistical analyses were performed with Student's t-test, one-way ANOVA followed by multiple comparisons testing when appropriate, or the Kruskal-Wallis H test.ResultsBaP induced PTGS2 expression (p < 0.05) and production of the stable metabolite of prostacyclin (p = 0.001) in fetoplacental ECs without affecting thromboxane. These effects were ablated by PTGS2 inhibition (p < 0.01) and RNA interference of AHR (p < 0.001). Surprisingly, despite the induction of prostacyclin, EC migration (p = 0.007) and tube formation (p = 0.003) were inhibited by BaP. AHR inhibition, however, rescued tube formation (p = 0.008).DiscussionBaP-mediated AHR activation results in induction of PTGS2 expression and enhanced production of prostacyclin metabolite. Despite an increase in this vasodilatory and pro-angiogenic prostanoid, BaP exposure also impairs EC migration and angiogenesis through AHR. This suggests that PAH may adversely affect the fetoplacental vasculature through its regulation of angiogenesis.

| S-EPMC4964606 | biostudies-literature

Tissue signals imprint ILC2 identity with anticipatory function.

Project description:Group 2 innate lymphoid cells (ILC2s) are distributed systemically and produce type 2 cytokines in response to a variety of stimuli, including the epithelial cytokines interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP). Transcriptional profiling of ILC2s from different tissues, however, grouped ILC2s according to their tissue of origin, even in the setting of combined IL-25-, IL-33-receptor-, and TSLP-receptor-deficiency. Single-cell profiling confirmed a tissue-organizing transcriptome and identified ILC2 subsets expressing distinct activating receptors, including the major subset of skin ILC2s, which were activated preferentially by IL-18. Tissue ILC2 subsets were unaltered in number and expression in germ-free mice, suggesting that endogenous, tissue-derived signals drive the maturation of ILC2 subsets by controlling expression of distinct patterns of activating receptors, thus anticipating tissue-specific perturbations occurring later in life.

| S-EPMC6202223 | biostudies-literature

ICAM-1 controls development and function of ILC2.

Project description:Group 2 innate lymphoid cells (ILC2s) are emerging as key players in the pathogenesis of allergic airway inflammation. The mechanisms regulating ILC2, however, are not fully understood. Here, we found that ICAM-1 is required for the development and function of ILC2. ICAM-1-deficient (ICAM-1-/- ) mice displayed significantly lower levels of ILC2s in the bone marrow and peripheral tissues than wild-type controls. CLP transfer and in vitro culture assays revealed that the regulation of ILC2 by ICAM-1 is cell intrinsic. Furthermore, ILC2s from ICAM-1-/- mice were functionally impaired, as indicated by the diminished production of type-2 cytokines in response to IL-33 challenge. The reduction in lung ILC2s caused a clear remission of airway inflammation in ICAM-1-/- mice after administration of papain or Alternaria alternata. We further demonstrate that ILC2 defects caused by ICAM-1 deficiency are due to ERK signaling-dependent down-regulation of GATA3 protein. Collectively, these observations identify ICAM-1 as a novel regulator of ILC2.

| S-EPMC6080904 | biostudies-literature

Cathepsin L Regulates Metabolic Networks Controlling Rapid Cell Growth and Proliferation.

Project description:Rapidly proliferating cells reshape their metabolism to satisfy their ever-lasting need for cellular building blocks. This phenomenon is exemplified in certain malignant conditions such as cancer but also during embryonic development when cells rely heavily on glycolytic metabolism to exploit its metabolic intermediates for biosynthetic processes. How cells reshape their metabolism is not fully understood. Here we report that loss of cathepsin L (Cts L) is associated with a fast proliferation rate and enhanced glycolytic metabolism that depend on lactate dehydrogenase A (LDHA) activity. Using mass spectrometry analysis of cells treated with a pan cathepsin inhibitor, we observed an increased abundance of proteins involved in central carbon metabolism. Further inspection of putative Cts L targets revealed an enrichment for glycolytic metabolism that was independently confirmed by metabolomic and biochemical analyses. Moreover, proteomic analysis of Cts L-knockout cells identified LDHA overexpression that was demonstrated to be a key metabolic junction in these cells. Lastly, we show that Cts L inhibition led to increased LDHA protein expression, suggesting a causal relationship between LDHA expression and function. In conclusion, we propose that Cts L regulates this metabolic circuit to keep cell division under control, suggesting the therapeutic potential of targeting this protein and its networks in cancer.

| S-EPMC6601214 | biostudies-literature

An objective function exploiting suboptimal solutions in metabolic networks.

Project description:BackgroundFlux Balance Analysis is a theoretically elegant, computationally efficient, genome-scale approach to predicting biochemical reaction fluxes. Yet FBA models exhibit persistent mathematical degeneracy that generally limits their predictive power.ResultsWe propose a novel objective function for cellular metabolism that accounts for and exploits degeneracy in the metabolic network to improve flux predictions. In our model, regulation drives metabolism toward a region of flux space that allows nearly optimal growth. Metabolic mutants deviate minimally from this region, a function represented mathematically as a convex cone. Near-optimal flux configurations within this region are considered equally plausible and not subject to further optimizing regulation. Consistent with relaxed regulation near optimality, we find that the size of the near-optimal region predicts flux variability under experimental perturbation.ConclusionAccounting for suboptimal solutions can improve the predictive power of metabolic FBA models. Because fluctuations of enzyme and metabolite levels are inevitable, tolerance for suboptimality may support a functionally robust metabolic network.

| S-EPMC4016239 | biostudies-literature

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