Metabolic Enzyme Triosephosphate Isomerase 1 and Nicotinamide Phosphoribosyltransferase, Two Independent Inflammatory Indicators in Rheumatoid Arthritis: Evidences From Collagen-Induced Arthritis and Clinical Samples

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.

AMPK/SIRT1 Deficiency Drives Adjuvant-Induced Arthritis in Rats by Promoting Glycolysis-Mediated Monocytes Inflammatory Polarization

“…Previously, we reported that intensified inflammation in rheumatic subjects was accompanied by up-regulation of glycolytic enzymes, and triosephosphate isomerase 1 (TPI1) was identified as a new RA-related inflammatory indicator. 8 Meanwhile, it revealed that silent information regulator 1 (SIRT1) expression deficiency was another hallmark of RA-related inflammation based on data collected from collagen-induced arthritis (CIA), which conforms to the changes observed in RA patients. 8 Being an intersection of metabolism and immune regulatory signaling networks, SIRT1 promotes oxidative phosphorylation and M2 polarization of monocytes and macrophages.…”

“… 8 Meanwhile, it revealed that silent information regulator 1 (SIRT1) expression deficiency was another hallmark of RA-related inflammation based on data collected from collagen-induced arthritis (CIA), which conforms to the changes observed in RA patients. 8 Being an intersection of metabolism and immune regulatory signaling networks, SIRT1 promotes oxidative phosphorylation and M2 polarization of monocytes and macrophages. 9 , 10 These orchestrated functions endow SIRT1 with notable anti-inflammatory capacity.…”

“…In fact, similar fluctuation pattern in the expression of SIRT1 was observed in CIA rats. 8 Nonetheless, it can be concluded that SIRT1 expression is generally insufficient in rheumatic subjects. According to the current understanding about the role of SIRT1 in monocyte polarization, its overexpression at certain stages could be a self-protective reaction to hamper the rapid progression of inflammation.…”

“…Many studies have challenged the idea that SIRT1 expression is always insufficient under RA circumstances, and we also noticed that SIRT1 could be overexpressed in CIA rats at least at certain stages. 8 …”

Serum Metabolomics Analysis of the Anti-Inflammatory Effects of Gallic Acid on Rats With Acute Inflammation

“…Accumulating evidence indicates that metabolic disorders can trigger systemic inflammation, which in turn may play a role in pathophysiology or even aggravate the disease itself ( Wang et al, 2015 ; Wenzl et al, 2021 ). Furthermore, recent studies also inspired that therapies targeting to restore metabolic homeostasis have the potential to treat inflammation damage ( Zhuo et al, 2012 ; Lei et al, 2021 ). Therefore, studies focusing on the metabolic regulation of gallic acid may be valuable to explore the therapeutic effect and potential mechanisms of the candidate in the cure of inflammation disorder.…”