2. Academic Validation
  3. The Glycolysis-HIF-1α axis induces IL-1β of macrophages in rheumatoid arthritis

The Glycolysis-HIF-1α axis induces IL-1β of macrophages in rheumatoid arthritis

  • Arthritis Res Ther. 2025 Sep 26;27(1):180. doi: 10.1186/s13075-025-03647-z.
Yimeng Jia # 1 2,  Rongli Li # 1 3,  Linfang Huang 4,  Xunyao Wu 5,  Lidan Zhao 1 2,  Huaxia Yang 1 2,  Xin You 1 2,  Yunyun Fei 6 7 8
Affiliations

Affiliations

  • 1 Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, #1 Shuai-Fu-Yuan, Dongcheng District, Beijing, China.
  • 2 National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), The Ministry of Education Key Laboratory, Beijing, China.
  • 3 Department of Rheumatology and Immunology, the First People's Hospital of Yunnan Province, the affiliated hospital of Kunming University of Science and Technology, Kunming, Yunnan, China.
  • 4 Department of Rheumatology and Immunology, Yueyang Central Hospital, Yueyang, 414000, Hunan, China.
  • 5 Department of Medical Research Center, Peking Union Medical College Hospital, Beijing, China.
  • 6 Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, #1 Shuai-Fu-Yuan, Dongcheng District, Beijing, China. feiyunyun@pumch.cn.
  • 7 National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), The Ministry of Education Key Laboratory, Beijing, China. feiyunyun@pumch.cn.
  • 8 Department of Heath Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China. feiyunyun@pumch.cn.
  • # Contributed equally.
PMID: 41013704 DOI: 10.1186/s13075-025-03647-z
Abstract

Background: Rheumatoid arthritis (RA) is an aggressive, systemic autoimmune disease in which overactivated macrophages play a critical role in its pathogenesis. This study aimed to explore the potential role of glycolytic reprogramming in the production of proinflammatory cytokines by macrophages in RA.

Methods: The Seahorse assay was conducted on RA or healthy control (HC) serum-treated human monocyte-derived macrophages (HMDMs) to evaluate glycolysis levels. RNA Sequencing was performed to identify activated signaling pathways and key molecules in HMDMs stimulated by RA serum. The proinflammatory cytokines and hypoxia-inducible factor 1α (HIF-1α) were verified by Western blotting and quantitative polymerase chain reaction (qPCR).

Results: We found that HMDMs stimulated with RA serum showed higher aerobic glycolysis levels than those treated with HC serum, along with higher expression of glycolysis-related genes, including hexokinase2 (HK2), Pyruvate Kinase L/R (PKLR), and phosphoglycerate kinase 1 (PGK1). Furthermore, RA serum-treated macrophages exhibited a higher level of interleukin-1 beta (IL-1β), and the expression of IL-1β positively correlated with HK2. Inhibition of glycolysis by 3-bromopyruvate (3BrPA) or HK2 knockdown significantly suppressed IL-1β production in macrophages. The HIF-1α-associated signaling pathways and HIF-1α protein levels were also elevated in RA serum-treated macrophages. Inhibition of glycolysis by 3BrPA or knockdown of HK2 reduced HIF-1α. Inhibiting HIF-1α can suppress IL-1β production of RA serum-treated macrophages, and vice versa. TNF-α and IL-1β enhanced HIF-1α and IL-1β expression in macrophages, an effect attenuated by glycolysis inhibition. Blocking TNF-α and IL-1β in RA serum diminished both glycolysis and IL-1β production.

Conclusion: Our findings demonstrate that RA serum triggers aerobic glycolysis in macrophages, which promotes HIF-1α to drive IL-1β production. Notably, IL-1β within RA serum amplifies its own expression via this glycolysis-HIF-1α axis, establishing a pathogenic positive feedback loop in RA.

Keywords

Glycolysis; HIF-1α; IL-1β; Macrophage; Rheumatoid arthritis.

Figures
Products
Inhibitors & Agonists
Other Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z