Metabolic Enzyme Triosephosphate Isomerase 1 and Nicotinamide Phosphoribosyltransferase, Two Independent Inflammatory
Ming Lei1, Meng-Qing Tao1,2, Yi-Jin Wu1,2
1Xin'an Medicine Research Center, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, China.
Abstract:
Metabolic intervention is a novel anti-rheumatic approach. The glycolytic regulator NAMPT has been identified as a therapeutic target of rheumatoid arthritis (RA), while other metabolic regulators coordinating NAMPT to perpetuate inflammation are yet to be investigated. We continuously monitored and validated expression changes of Nampt and inflammatory indicators in peripheral while blood cells from rats with collagen-induced arthritis (CIA). Gene transcriptional profiles of Nampt+ and Nampt++ samples from identical CIA rats were compared by RNA-sequencing. Observed gene expression changes were validated in another batch of CIA rats, and typical metabolic regulators with persistent changes during inflammatory courses were further investigated in human subjects. According to expression differences of identified genes, RA patients were assigned into different subsets. Clinical manifestation and cytokine profiles among them were compared afterwards. Nampt overexpression typically occurred in CIA rats during early stages, when iNos and Il-1β started to be up-regulated. Among differentially expressed genes between Nampt+ and Nampt++ CIA rat samples, changes of Tpi1, the only glycolytic enzyme identified were sustained in the aftermath of acute inflammation. Similar to NAMPT, TPI1 expression in RA patients was higher than general population, which was synchronized with increase in RFn as well as inflammatory monocytes-related cytokines like Eotaxin. Meanwhile, RANTES levels were relatively low when NAMPT and TPI1 were overexpressed. Reciprocal interactions between TPI1 and HIF-1α were observed. HIF-1α promoted TPI1 expression, while TPI1 co-localized with HIF-1α in nucleus of inflammatory monocytes. In short, although NAMPT and TPI1 dominate different stages of CIA, they similarly provoke monocyte-mediated inflammation.
Insights
Metabolic regulators NAMPT and TPI1 drive inflammation in rheumatoid arthritis (RA). Targeting these pathways, particularly TPI1 and its interaction with HIF-1α, offers novel anti-rheumatic strategies.
Area of Science:
- Immunometabolism
- Rheumatoid Arthritis Pathogenesis
- Molecular Biology
Background:
- Metabolic intervention is a promising anti-rheumatic approach.
- NAMPT is a known therapeutic target in rheumatoid arthritis (RA).
- Other metabolic regulators involved in RA inflammation remain under investigation.
Purpose of the Study:
- To investigate metabolic regulators coordinating with NAMPT in rheumatoid arthritis (RA).
- To explore the role of TPI1 and its interaction with HIF-1α in RA.
- To stratify RA patients based on gene expression and compare clinical manifestations.
Main Methods:
- Monitoring of Nampt and inflammatory indicators in collagen-induced arthritis (CIA) rat models.
- RNA-sequencing to compare gene expression in Nampt-expressing CIA rat samples.
- Validation in human subjects and patient stratification based on gene expression differences.
Main Results:
- Nampt overexpression correlated with early-stage CIA and upregulation of iNos and Il-1β.
- TPI1, a glycolytic enzyme, showed sustained expression changes in CIA rats and elevated levels in RA patients.
- TPI1 expression correlated with inflammatory monocyte markers and reciprocal interaction with HIF-1α was observed.
Conclusions:
- Both NAMPT and TPI1 contribute to monocyte-mediated inflammation in RA, despite dominating different disease stages.
- TPI1, regulated by HIF-1α, plays a significant role in RA pathogenesis.
- Understanding these metabolic pathways offers potential for novel anti-rheumatic therapies.
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