Metabolic reprogramming of NK cells in chronic brucellar arthritis: role of the HIF-1α/mTOR axis
4 affiliations
- 1Department of Orthopedic Surgery, The First Affiliated Hospital of Shihezi University
- 2Department of Clinical Laboratory, The First Affiliated Hospital of Xinjiang Medical University.
- 3Center for Translational Medicine, The First Affiliated Hospital of Shihezi University
- 4Department of Pharmacy, The First Affiliated Hospital of Shihezi University
Abstract
Background: Brucellar arthritis is the most common complication of brucellosis, and its chronic progression is closely associated with immune cell dysfunction. Natural killer (NK) cells play a central role in anti-infective immunity; however, their functional status and regulatory mechanisms in brucellar arthritis remain poorly understood.
Methods: Peripheral blood and synovial tissue samples were collected from healthy controls, as well as from patients with acute-phase and chronic-phase brucellar arthritis. Single-cell RNA sequencing (scRNA-seq), flow cytometry, quantitative real-time PCR (qPCR), JC-1 mitochondrial membrane potential assay, Seahorse metabolic analysis, and Western blotting were employed to systematically evaluate NK cell phenotypes, functions, metabolic profiles, and HIF-1α/mTOR pathway activity. In vitro , heat-killed Brucella melitensis 16M (HKBA) was used to stimulate NK-92 cells and HIF-1α-knockout (KO) cell lines, with mTOR inhibitor intervention, to dissect the regulatory mechanism of the HIF-1α/mTOR axis in NK cell metabolic reprogramming.
Results: scRNA-seq revealed enrichment of NK cells in the synovium of brucellar arthritis patients, with aberrant expression of oxidative phosphorylation (OXPHOS)-related genes. Clinical sample analyses showed that, compared with healthy controls, the proportion of peripheral blood NK cells increased in both acute- and chronic-phase patients; however, NK cells from chronic-phase patients exhibited significantly reduced IFN-γ, Granzyme B, and CD107a degranulation levels. HIF-1α protein was consistently overexpressed in patient NK cells, whereas phosphorylated mTOR-pathway proteins (p-PI3K, p-AKT, p-mTOR) were markedly suppressed. In vitro , HKBA treatment inhibited mTOR pathway activity in NK-92 cells in a dose- and time-dependent manner and reduced mitochondrial membrane potential as shown by JC-1 staining. HIF-1α knockout significantly restored NK cell cytotoxic function, upregulated OXPHOS- and glycolysis-related gene expression, and improved mitochondrial membrane potential. Transcriptomic sequencing confirmed enrichment of mTOR signaling and energy metabolism gene sets after knockout. Importantly, mTOR pathway inhibition completely blocked the HIF-1α-knockout-mediated restoration of NK cell function and mitochondrial fitness, indicating that HIF-1α primarily drives NK cell metabolic and functional abnormalities through mTOR suppression.
Conclusions: Brucella infection induces HIF-1α overexpression, which suppresses mTOR signaling and drives metabolic reprogramming of NK cells characterized by impaired OXPHOS and functional exhaustion, thereby promoting chronicity of brucellar arthritis. Targeting the HIF-1α/mTOR axis may offer a novel therapeutic strategy for brucellar arthritis.
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BibTeX
@article{sheng2026metabolic,
title = {{Metabolic reprogramming of NK cells in chronic brucellar arthritis: role of the HIF-1α/mTOR axis}},
author = {Ganggang Sheng and Wenxuan Li and Da Liu and Xuanchen Ren and Mingyang Wei and Zijing Yang and Weiyu Tian and Fengbo Zhang and Yuejie Zhu and Fanxuan Zeng and Zhiqiang Zhao and Ping Xu and Hongyu Tian and Nannan Pang and Chaopeng Li and Zhendong Zhang},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1961240},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1961240/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Metabolic reprogramming of NK cells in chronic brucellar arthritis: role of the HIF-1α/mTOR axis
AU - Ganggang Sheng
AU - Wenxuan Li
AU - Da Liu
AU - Xuanchen Ren
AU - Mingyang Wei
AU - Zijing Yang
AU - Weiyu Tian
AU - Fengbo Zhang
AU - Yuejie Zhu
AU - Fanxuan Zeng
AU - Zhiqiang Zhao
AU - Ping Xu
AU - Hongyu Tian
AU - Nannan Pang
AU - Chaopeng Li
AU - Zhendong Zhang
PY - 2026
DA - 2026/10/06
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1961240
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1961240/full
AB - Background: Brucellar arthritis is the most common complication of brucellosis, and its chronic progression is closely associated with immune cell dysfunction. Natural killer (NK) cells play a central role in anti-infective immunity; however, their functional status and regulatory mechanisms in brucellar arthritis remain poorly understood. Methods: Peripheral blood and synovial tissue samples were collected from healthy controls, as well as from patients with acute-phase and chronic-phase brucellar arthritis. Single-cell RNA sequencing (scRNA-seq), flow cytometry, quantitative real-time PCR (qPCR), JC-1 mitochondrial membrane potential assay, Seahorse metabolic analysis, and Western blotting were employed to systematically evaluate NK cell phenotypes, functions, metabolic profiles, and HIF-1α/mTOR pathway activity. In vitro , heat-killed Brucella melitensis 16M (HKBA) was used to stimulate NK-92 cells and HIF-1α-knockout (KO) cell lines, with mTOR inhibitor intervention, to dissect the regulatory mechanism of the HIF-1α/mTOR axis in NK cell metabolic reprogramming. Results: scRNA-seq revealed enrichment of NK cells in the synovium of brucellar arthritis patients, with aberrant expression of oxidative phosphorylation (OXPHOS)-related genes. Clinical sample analyses showed that, compared with healthy controls, the proportion of peripheral blood NK cells increased in both acute- and chronic-phase patients; however, NK cells from chronic-phase patients exhibited significantly reduced IFN-γ, Granzyme B, and CD107a degranulation levels. HIF-1α protein was consistently overexpressed in patient NK cells, whereas phosphorylated mTOR-pathway proteins (p-PI3K, p-AKT, p-mTOR) were markedly suppressed. In vitro , HKBA treatment inhibited mTOR pathway activity in NK-92 cells in a dose- and time-dependent manner and reduced mitochondrial membrane potential as shown by JC-1 staining. HIF-1α knockout significantly restored NK cell cytotoxic function, upregulated OXPHOS- and glycolysis-related gene expression, and improved mitochondrial membrane potential. Transcriptomic sequencing confirmed enrichment of mTOR signaling and energy metabolism gene sets after knockout. Importantly, mTOR pathway inhibition completely blocked the HIF-1α-knockout-mediated restoration of NK cell function and mitochondrial fitness, indicating that HIF-1α primarily drives NK cell metabolic and functional abnormalities through mTOR suppression. Conclusions: Brucella infection induces HIF-1α overexpression, which suppresses mTOR signaling and drives metabolic reprogramming of NK cells characterized by impaired OXPHOS and functional exhaustion, thereby promoting chronicity of brucellar arthritis. Targeting the HIF-1α/mTOR axis may offer a novel therapeutic strategy for brucellar arthritis.
SN - 1664-3224
ER -