Norisoboldine induces the development of Treg cells by promoting fatty acid oxidation‐mediated H3K27 acetylation of Foxp3

Abstract

Norisoboldine (NOR), an alkaloid isolated from Radix Lindera, was previously reported to promote the differentiation of regulatory T cells (Treg cells), an important subtype of lymphocytes capable of controlling autoimmune diseases. The present study was performed to explore the mechanism of NOR in the view of cellular metabolism. A global metabolomic analysis indicated that NOR preferentially altered the fatty acid oxidation (FAO) pathway and elevated the content of related metabolites during Treg cell differentiation. The detection of oxygen consumption rate (OCR) and mRNA expression of FAO‐related enzymes demonstrated that NOR promoted FAO in the early stage of Treg cell differentiation. Consistently, pharmacological or genetic inhibition of FAO markedly diminished the induction of NOR on Treg cell differentiation. Furthermore, NOR was shown to elevate the level of acetyl‐CoA derived from FAO and acetylation of lysine 27 on histone 3 (H3K27) at the Foxp3 promoter and CNS2 regions. A knockdown of CPT1, the rate‐limiting enzyme of FAO, weakened the promotion of NOR on the development, acetyl‐CoA level, and acetylation of H3K27 of Treg cells in vitro and in the mice with collagen‐induced arthritis, and attenuated the anti‐arthritic effect of NOR. These findings demonstrate that NOR induces the development of Treg cells through promoting FAO, therefore, facilitating gene transcription of Foxp3 via acetyl‐CoA‐mediated H3K27 acetylation modification, and FAO might serve as a novel target to induce Treg cell development.

Sphingosine 1‐phosphate combining with S1PR4 promotes regulatory T cell differentiation related to FAO through Nrf2/PPARα

“…Further mechanistic studies revealed that enhances the acetylation of H3K27 in the promoter and CNS1 regions of Foxp3 through the acetyl-CoA derived from FAO. 9,46 AMPK activators enhanced Treg expansion dependent on FAO through FA transport and mitochondrial synthesis, which are mTOR-dependent. 47 CPT1, as one of the rate-limiting enzymes, has been checked or modulated for FAO studies.…”

“…Fang et al found that tetrandrine induced Treg differentiation and enhanced FAO. Further mechanistic studies revealed that enhances the acetylation of H3K27 in the promoter and CNS1 regions of Foxp3 through the acetyl‐CoA derived from FAO 9,46 . AMPK activators enhanced Treg expansion dependent on FAO through FA transport and mitochondrial synthesis, which are mTOR‐dependent 47 .…”

“…Lipid metabolism that supports Treg survival and suppressive function has been observed 8 . Naïve T cells can barely differentiate into Treg when carnitine palmitoyltransferase (CPT1), a key enzyme of FAO, is knocked down 9 . However, the relationship between metabolism modulation and Treg differentiation remains unclear.…”

“…8 Naïve T cells can barely differentiate into Treg when carnitine palmitoyltransferase (CPT1), a key enzyme of FAO, is knocked down. 9 However, the relationship between metabolism modulation and Treg differentiation remains unclear. S1P-S1PR are also critical in developing metabolic diseases that are related to modulating lipolysis, glucose uptake and mitochondrial biogenesis of metabolic tissues.…”

Mitochondrial fusion induced by transforming growth factor-β1 serves as a switch that governs the metabolic reprogramming during differentiation of regulatory T cells

“…In addition, targeting metabolic abnormalities in immune cells may help to improve autoimmune symptoms [ [31] , [32] , [33] ]. The aryl hydrocarbon receptor agonists inhibited glycolysis and enhanced FAO-induced Treg cell generation, improving symptoms of colitis and arthritis in mice [ 34 , 35 ]. The present results demonstrated that enhanced mitochondrial fusion could induce Treg cell generation and alleviate disease symptoms in mice.…”