Metabolic Reprogramming in Mitochondria of Myeloid Cells

Zuo, Hao; Wan, Yihong

doi:10.3390/cells9010005

Cited by 49 publications

(47 citation statements)

References 107 publications

(157 reference statements)

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“…Typically, catabolic metabolism in resting DCs is characterized by oxidative phosphorylation (OXPHOS) fueled by fatty acid oxidation (FAO) and limited glycolysis (Krawczyk et al, 2010, Gotoh et al, 2018, Zuo and Wan, 2019. During early DC activation by TLR agonists, DCs augment both aerobic glycolysis and OXPHOS to support the anabolic demands required for expansion of the ER and Golgi apparatus, de novo fatty acid (FA) synthesis, and production of inflammatory cytokines.…”

Section: Adj Enhances Cross-presentation Without Glycolytic Reprogrammentioning

confidence: 99%

Carbomer-based Nano-Emulsion Adjuvant Enhances Dendritic Cell Cross-presentation via Lipid Body Formation Independent of Glycolysis

Suresh

Lee

Kingstad-Bakke

et al. 2020

Preprint

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ADJ induces inflammasome activation in DCs, but deficiency for NLRP3, ASC or caspase 1 did not affect ADJ-mediated cross-presentationNext, we examined the effects of ADJ on the expression profiles of cytokines, chemokines and canonical cell surface markers of DC activation. Compared to untreated DCs, ADJ-treated DCs showed statistically significant, yet modest increases in expression of CD40, CD80, and CD86; no significant differences in expression were observed for MHC-I, MHC-II, or CCR7 (Fig. 1C).ADJ-treated DCs produced higher levels of IL-12 (p70), TNF-, IL-1, CCL3, CCL4, CXCL1, and RANTES, as compared to untreated DCs; no significant differences in expression were observed for IL-6, IL-10, and IFN- (Fig. 1D). Particularly, ADJ-stimulated DCs also produced significantly elevated levels of IL-1 and IL-18 (Fig. 1D), which is suggestive of inflammasome activation. Since inflammasome activation has been implicated in modulation of antigen presentation by DCs (Sokolovska et al., 2013, Li et al., 2019, we performed B3Z assays using DCs deficient in NLRP3, ASC, or caspase 1 to interrogate whether inflammasome activation is required for ADJ-induced cross-presentation in BMDCs. Surprisingly, loss of NLRP3, ASC or caspase 1 activity did not affect ADJ-induced cross-presentation by DCs, in vitro (Fig. 1E). To validate whether caspase 1 is required for cross-presentation in vivo, we immunized cohorts of wild type (WT) and caspase 1-deficient mice with ADJ+OVA, and quantified OVA SIINFEKLspecific CD8 T cells in spleens using MHC I tetramers at day 8 after immunization. Consistent with our results from B3Z assays, caspase 1 deficiency did not significantly affect the activation of SIINFEKL-specific CD8 T cells in spleens (Fig. 1F), suggesting that caspase 1 is not essential for ADJ-driven cross-presentation to CD8 T cells in vivo.

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Section: Adj Enhances Cross-presentation Without Glycolytic Reprogrammentioning

confidence: 99%

Carbomer-based Nano-Emulsion Adjuvant Enhances Dendritic Cell Cross-presentation via Lipid Body Formation Independent of Glycolysis

Suresh

Lee

Kingstad-Bakke

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Typically, catabolic metabolism in resting DCs is characterized by oxidative phosphorylation (OXPHOS) fueled by fatty acid oxidation (FAO) and limited glycolysis [ 46 – 48 ]. During early DC activation by TLR agonists, DCs augment both aerobic glycolysis and OXPHOS to support the anabolic demands required for expansion of the ER and Golgi apparatus, de novo fatty acid (FA) synthesis, and production of inflammatory cytokines.…”

Section: Resultsmentioning

confidence: 99%

Carbomer-based adjuvant elicits CD8 T-cell immunity by inducing a distinct metabolic state in cross-presenting dendritic cells

et al. 2021

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There is a critical need for adjuvants that can safely elicit potent and durable T cell-based immunity to intracellular pathogens. Here, we report that parenteral vaccination with a carbomer-based adjuvant, Adjuplex (ADJ), stimulated robust CD8 T-cell responses to subunit antigens and afforded effective immunity against respiratory challenge with a virus and a systemic intracellular bacterial infection. Studies to understand the metabolic and molecular basis for ADJ’s effect on antigen cross-presentation by dendritic cells (DCs) revealed several unique and distinctive mechanisms. ADJ-stimulated DCs produced IL-1β and IL-18, suggestive of inflammasome activation, but in vivo activation of CD8 T cells was unaffected in caspase 1-deficient mice. Cross-presentation induced by TLR agonists requires a critical switch to anabolic metabolism, but ADJ enhanced cross presentation without this metabolic switch in DCs. Instead, ADJ induced in DCs, an unique metabolic state, typified by dampened oxidative phosphorylation and basal levels of glycolysis. In the absence of increased glycolytic flux, ADJ modulated multiple steps in the cytosolic pathway of cross-presentation by enabling accumulation of degraded antigen, reducing endosomal acidity and promoting antigen localization to early endosomes. Further, by increasing ROS production and lipid peroxidation, ADJ promoted antigen escape from endosomes to the cytosol for degradation by proteasomes into peptides for MHC I loading by TAP-dependent pathways. Furthermore, we found that induction of lipid bodies (LBs) and alterations in LB composition mediated by ADJ were also critical for DC cross-presentation. Collectively, our model challenges the prevailing metabolic paradigm by suggesting that DCs can perform effective DC cross-presentation, independent of glycolysis to induce robust T cell-dependent protective immunity to intracellular pathogens. These findings have strong implications in the rational development of safe and effective immune adjuvants to potentiate robust T-cell based immunity.

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“…Inflammatory cytokines induce glycolytic programming accompanied by breaks in the TCA cycle and uncoupling of OXPHOS ( 43 , 45 , 46 ). OXPHOS uncoupling impairs ATP production from mitochondrial respiratory chain activity, causing an increase in ROS generation ( 72 ). To support glycolysis in response to pro-inflammatory cytokines, microglia upregulate expression of GLUTs to facilitate increased glucose ( 40 ).…”

Section: Microglial Metabolism In Admentioning

confidence: 99%

Mitochondrial Regulation of Microglial Immunometabolism in Alzheimer’s Disease

2021

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Alzheimer’s disease (AD) is an age-associated terminal neurodegenerative disease with no effective treatments. Dysfunction of innate immunity is implicated in the pathogenesis of AD, with genetic studies supporting a causative role in the disease. Microglia, the effector cells of innate immunity in the brain, are highly plastic and perform a diverse range of specialist functions in AD, including phagocytosing and removing toxic aggregates of beta amyloid and tau that drive neurodegeneration. These immune functions require high energy demand, which is regulated by mitochondria. Reflecting this, microglia have been shown to be highly metabolically flexible, reprogramming their mitochondrial function upon inflammatory activation to meet their energy demands. However, AD-associated genetic risk factors and pathology impair microglial metabolic programming, and metabolic derailment has been shown to cause innate immune dysfunction in AD. These findings suggest that immunity and metabolic function are intricately linked processes, and targeting microglial metabolism offers a window of opportunity for therapeutic treatment of AD. Here, we review evidence for the role of metabolic programming in inflammatory functions in AD, and discuss mitochondrial-targeted immunotherapeutics for treatment of the disease.

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Metabolic Reprogramming in Mitochondria of Myeloid Cells

Cited by 49 publications

References 107 publications

Carbomer-based Nano-Emulsion Adjuvant Enhances Dendritic Cell Cross-presentation via Lipid Body Formation Independent of Glycolysis

Carbomer-based Nano-Emulsion Adjuvant Enhances Dendritic Cell Cross-presentation via Lipid Body Formation Independent of Glycolysis

Carbomer-based adjuvant elicits CD8 T-cell immunity by inducing a distinct metabolic state in cross-presenting dendritic cells

Mitochondrial Regulation of Microglial Immunometabolism in Alzheimer’s Disease

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