PGC-1<i>α</i>-Dependent Mitochondrial Adaptation Is Necessary to Sustain IL-2-Induced Activities in Human NK Cells

Miranda, Dante; Jara, Claudia; Ibáñez, Jorge; Ahumada, Viviana; Acuña-Castillo, Claudio; Martín, Ana Jiménez; Córdova, A. Fernández de; Montoya, Margarita

doi:10.1155/2016/9605253

Cited by 17 publications

(21 citation statements)

References 47 publications

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“…The metabolism of NK cell is highly dependent on mTORC1, a complex functioning as a nutrient and metabolic sensor and coordinating protein synthesis [39]. The mTORC1 activity of NK cells were shown to elevate upon cytokine stimulation, promoting glycolytic flux enhancement [26,27,59]. Our data demonstrated that NK cells from HSP patients possessed a lower mTORC1 activity than that from healthy children upon cytokine stimulation, in line with the decreased NK cell glycolysis rate in HSP patients based on our study.…”

Section: Discussionsupporting

confidence: 83%

Decreased glycolysis induced dysfunction of NK cells in Henoch-Schonlein purpura patients

Chai

Wang

et al. 2020

BMC Immunol

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Background Henoch-Schonlein purpura (HSP) is the most common systemic vasculitis of the childhood. However, its mechanisms and pathogenesis still need more exploration. Natural killer (NK) cells are innate lymphocytes, and there is a growing appreciation that cellular metabolism is important in determining the immune responsiveness of lymphocytes. Thus, we aimed to analyze the NK cells phenotype and explore the association between glucose metabolism and NK cells function in HSP patients. Results A total number of 64 HSP patients and 34 healthy children were included. The HSP patients were divided into two groups according to whether accompanied with nephritis or not. NK cells in HSP patients without nephritis showed a reduced frequency in peripheral blood, a down-regulated expression of activating receptors both NKp30 and NKp46, and an attenuated cytotoxic function against tumor cells. In addition, the function impairment of NK cells was shown to exacerbate in HSPN. Our data further revealed an aberrant metabolic reprogramming of NK cells in HSP patients. Upon stimulation with cytokines (IL-15, IL-12 and IL-2), NK cells from healthy controls switched to an elevated glycolysis rate to support their effector function. By contrast, the glycolysis rate of activated NK cells in HSP group was not significantly up-regulated from the resting level possibly owing to the inhibition of mTORC1. Conclusions Our study found that HSP patients were accompanied with dysfunction of NK cells. We concluded that the dysfunction of NK cells in HSP patients was induced with a decreased glycolysis rate and suggested that metabolic reprogramming of NK cells might be a player in the pathogenesis of HSP.

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Section: Discussionsupporting

confidence: 83%

Decreased glycolysis induced dysfunction of NK cells in Henoch-Schonlein purpura patients

Chai

Wang

et al. 2020

BMC Immunol

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“…However, there is evidence for roles in tumor-immune cell interactions; for example, PGC-1β has an important function in M2 macrophages, the macrophage population that promotes tumor escape and progression [60]. Furthermore, activation of cytolytic immune cells, such as natural killer (NK) cells or CD8+ T-cell subsets seems to rely on glycolysis [61, 62]; however, recent studies indicate a pivotal role for PGC-1α and oxidative metabolism in proper functions of NK cells and tumor-infiltrating T cells [63, 64], suggesting the multiple facets of PGC-1 functions within tumor niches. Understanding the involvement of PGC-1 coactivators between tumor and immune cells will be instrumental to help improve cancer immunotherapies.…”

Section: Discussionmentioning

confidence: 99%

PGC-1 Coactivators: Shepherding the Mitochondrial Biogenesis of Tumors

2016

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As coordinators of energy demands and nutritional supplies, the PGC-1 family of transcriptional coactivators regulates mitochondrial biogenesis to control the cellular bioenergetic state. Aside from maintaining normal and adapted cell physiology, recent studies indicate that PGC-1 coactivators also serve important functions in cancer cells. In fact, by balancing mitochondrial energy production with demands for cell proliferation, these factors are involved in almost every step of tumorigenesis. In this review, we discuss the interplay between PGC-1 coactivators and cancer pathogenesis, including tumor initiation, metastatic spread, and response to treatment. Given their involvement in the functional biology of cancers, identification of regulatory targets that influence PGC-1 expression and activity may reveal novel strategies suitable for mono- or combinatorial cancer therapies.

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“…At the mitochondrial level, cytokine stimulation can also induce significant changes. Miranda et al looked at IL2 induced mitochondrial changes in human NK cells (21). They showed that IL2 stimulation increased both the mitochondrial mass and the mitochondrial membrane potential.…”

Section: Nk Cell Metabolismmentioning

confidence: 99%

“…In this study, TGFβ signaling via the canonical pathway culminated in the upregulation of PGC-1α expression. Interestingly, PGC-1α mediated increases in mitochondrial mass and polarization has been shown to be essential for NK cell IFNγ production (21).…”

Section: Tgfβ and Mitochondrial Structure And Functionmentioning

confidence: 99%

NK Cell Metabolism and TGFβ – Implications for Immunotherapy

Slattery

Gardiner

2019

Front. Immunol.

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NK cells are innate lymphocytes which play an essential role in protection against cancer and viral infection. Their functions are dictated by many factors including the receptors they express, cytokines they respond to and changes in the external environment. These cell processes are regulated within NK cells at many levels including genetic, epigenetic and expression (RNA and protein) levels. The last decade has revealed cellular metabolism as another level of immune regulation. Specific immune cells adopt metabolic configurations that support their functions, and this is a dynamic process with cells undergoing metabolic reprogramming during the course of an immune response. Upon activation with pro-inflammatory cytokines, NK cells upregulate both glycolysis and oxphos metabolic pathways and this supports their anti-cancer functions. Perturbation of these pathways inhibits NK cell effector functions. Anti-inflammatory cytokines such as TGFβ can inhibit metabolic changes and reduce functional outputs. Although a lot remains to be learned, our knowledge of potential molecular mechanisms involved is growing quickly. This review will discuss our current knowledge on the role of TGFβ in regulating NK cell metabolism and will draw on a wider knowledge base regarding TGFβ regulation of cellular metabolic pathways, in order to highlight potential ways in which TGFβ might be targeted to contribute to the exciting progress that is being made in terms of adoptive NK cell therapies for cancer.

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PGC-1α-Dependent Mitochondrial Adaptation Is Necessary to Sustain IL-2-Induced Activities in Human NK Cells

Cited by 17 publications

References 47 publications

Decreased glycolysis induced dysfunction of NK cells in Henoch-Schonlein purpura patients

Decreased glycolysis induced dysfunction of NK cells in Henoch-Schonlein purpura patients

PGC-1 Coactivators: Shepherding the Mitochondrial Biogenesis of Tumors

NK Cell Metabolism and TGFβ – Implications for Immunotherapy

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