Thiomyristoyl ameliorates colitis by blocking the differentiation of Th17 cells and inhibiting SIRT2-induced metabolic reprogramming

by Selleckchem | Jul 24 2023

Background: The pathogenesis of inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC) has not been fully elucidated. However, a strong correlation between IBD and high T helper 17 (Th17) levels has been found. Sirtuin 2 (SIRT2) has recently been found to play an important role in metabolic reprogramming, but its potential anti-inflammatory properties remain unclear.

Methods: The expression levels of SIRT2 and glucose metabolism-related proteins in peripheral blood mononuclear cells (PBMCs) of IBD patients and healthy volunteers were detected. Human PBMCs were differentiated into Th17 cells in vitro and were treated with TM simultaneously. The ratio of Th17 cells and apoptotic cells and the production of Interleukin (IL)-17A and the expression levels of transcription factors of classical signaling pathway related to Th17 differentiation were determined. The acetylation of LDHA and glucose metabolism was assessed. Subsequently, C57BL/6J colitis mice induced by 2.5% dextran sulfatesodiumsalt (DSS) were treated with or without TM, Disease activity index, T cell subsets in the mice spleen, relevant inflammatory cytokines in serum, specific mRNA, and proteins in mice colon were evaluated respectively.

Results: SIRT2 and glucose metabolism-related proteins in PBMCs of patients were overexpressed. Compared with the positive control group, human PBMCs treated with TM had lower levels of IL-17A, percentage of Th17 cells, levels of phospho-signal transducer and activator of transcription (p-STAT) 3 and phospho-nuclear transcription factor-κB (p-NF-κB), but higher levels of acetylated LDHA. Compared with colitis mice, TM-treated colitis mice had longer colons, reduced weight-losses, and lower disease activity index and histopathologic scores. Interestingly, although the expression levels of interferon (IFN)-γ, IL-17A, and retinoic acid receptor-related orphan receptor (ROR)-γt were inhibited in the colons of TM-treated colitis mice, the expression of forkhead box protein P3 (FOXP3) didn't change. Consistently, relative to the high percentage of splenic Th17 cells in colitis mice, the percentage of splenic Th17 cells in TM-treated colitis mice was as normal as PBS-treated mice, while the percentage of Treg cells was not affected. Additionally, the TM group had reduced levels of IL-23 and hypoxiainduciblefactor-1α (HIF-1α), and an increased level of IL-10 in the colon, compared with the colitis group.

Conclusion: Our results indicate that TM reduces UC progression by reducing metabolic reprogramming and T cell differentiation. Specifically, TM prevented Th17 differentiation by reducing the expression of related transcription factors and promoting acetylation of LDHA (weakening glycolysis). SIRT2 may be a potential target for IBD treatment.

Comments:

The study described investigates the potential role of Sirtuin 2 (SIRT2) in inflammatory bowel diseases (IBD), specifically Crohn's disease (CD) and ulcerative colitis (UC). The researchers aimed to explore the anti-inflammatory properties of SIRT2 and its effects on metabolic reprogramming and T cell differentiation.

The study involved several experiments using both human peripheral blood mononuclear cells (PBMCs) and a mouse model of colitis induced by dextran sulfate sodium salt (DSS). Here are the key findings of the study:

1. Expression of SIRT2 and glucose metabolism-related proteins: The researchers found that the expression levels of SIRT2 and glucose metabolism-related proteins were elevated in PBMCs of IBD patients compared to healthy volunteers. This suggests a potential involvement of SIRT2 in IBD pathogenesis and metabolic dysregulation.

2. Inhibition of Th17 cell differentiation: In vitro experiments using human PBMCs showed that treatment with a compound called TM (not specified in the context) reduced the levels of interleukin-17A (IL-17A) and the percentage of Th17 cells. Th17 cells are known to be involved in the inflammatory response in IBD. TM treatment also reduced the levels of phospho-signal transducer and activator of transcription 3 (p-STAT3) and phospho-nuclear transcription factor-κB (p-NF-κB), which are signaling molecules associated with Th17 differentiation.

3. Effects on glucose metabolism: TM treatment increased the acetylation of LDHA, an enzyme involved in glycolysis. This suggests that TM weakened glycolysis, a metabolic pathway that is often enhanced in inflammatory conditions, including IBD.

4. Improvement of colitis in mice: In the mouse model of colitis induced by DSS, treatment with TM resulted in several positive outcomes. TM-treated colitis mice had longer colons, reduced weight loss, lower disease activity index, and improved histopathologic scores compared to colitis mice without treatment. These findings indicate that TM attenuated the severity of colitis.

5. Effects on T cell subsets: TM treatment in colitis mice normalized the percentage of splenic Th17 cells, which was elevated in colitis mice, back to levels similar to those of healthy mice. However, the percentage of Treg cells, another subset of T cells involved in immune regulation, was not affected. This suggests a specific targeting of Th17 cells by TM.

6. Modulation of inflammatory cytokines: TM treatment in colitis mice reduced the levels of pro-inflammatory cytokine IL-23 and hypoxia-inducible factor-1α (HIF-1α) in the colon. Additionally, the level of anti-inflammatory cytokine IL-10 was increased. These changes indicate a shift towards a more balanced and regulated immune response in the colon.

In conclusion, the study suggests that SIRT2 plays a role in IBD pathogenesis and metabolic reprogramming. TM treatment attenuated the progression of UC by inhibiting Th17 cell differentiation, promoting acetylation of LDHA, and modulating inflammatory cytokines. The findings highlight the potential of SIRT2 as a therapeutic target for IBD treatment, although further research is needed to explore the specific mechanisms involved and the translational potential of these findings.