ASCT2-mediated glutamine uptake promotes Th1 differentiation via ROS-EGR1-PAC1 pathway in oral lichen planus

by Selleckchem | Nov 11 2023

Oral lichen planus (OLP) is a T cell-mediated autoimmune disease of oral mucosa concerning with the redox imbalance. Although glutamine uptake mediated by alanine-serine-cysteine transporter 2 (ASCT2) is critical to T cell differentiation, the exact mechanism remains ambiguous. Here, we elucidate a novel regulatory mechanism of ASCT2-mediated uptake in the differentiation and proliferation of T cells through maintaining redox balance in OLP. The results of immunohistochemistry (IHC) showed that both ASCT2 and glutaminase (GLS) were obviously upregulated compared to controls in OLP. Moreover, correlation analyses indicated that ASCT2 expression was significantly related to GLS level. Interestingly, the upregulation of glutamine metabolism in epithelial layer was consistent with that in lamina propria. Functional assays in vitro revealed the positive association between glutamine metabolism and lymphocytes infiltration. Additionally, multiplex immunohistochemistry (mIHC) uncovered a stronger colocalization among ASCT2 and CD4 and IFN-γ, which was further demonstrated by human Th1 differentiation assay in vitro. Mechanistically, targeting glutamine uptake through interference with ASCT2 using L-γ-Glutamyl-p-nitroanilide (GPNA) decreased the glutamine uptake of T cells and leaded to the accumulation of intracellular reactive oxygen species (ROS), which promoted dual specificity phosphatase 2 (DUSP2/PAC1) expression through activation of early growth response 1 (EGR1) to induce dephosphorylation of signal transducer and activator of transcription 3 (STAT3) and inhibit Th1 differentiation in turn. These results demonstrated that glutamine uptake mediated by ASCT2 induced Th1 differentiation by ROS-EGR1-PAC1 pathway, and restoring the redox dynamic balance through targeting ASCT2 may be a potential treatment for T cell-mediated autoimmune diseases.

Comments:

The passage you've provided discusses a research study that investigates the role of glutamine uptake mediated by alanine-serine-cysteine transporter 2 (ASCT2) in the differentiation and proliferation of T cells in the context of oral lichen planus (OLP), which is described as a T cell-mediated autoimmune disease of the oral mucosa with implications for redox balance.

Here's a breakdown of the key findings and implications of this study:

1. **Upregulation of ASCT2 and Glutaminase (GLS):** The study found that both ASCT2 and GLS were significantly upregulated in OLP patients compared to controls. This suggests that there is an increased utilization of glutamine in OLP.

2. **Correlation between ASCT2 and GLS:** The study indicates that there is a significant correlation between the expression levels of ASCT2 and GLS, implying a coordinated role in glutamine metabolism.

3. **Glutamine Metabolism in Epithelial Layer and Lamina Propria:** The increased glutamine metabolism was observed not only in the epithelial layer but also in the lamina propria of OLP patients, suggesting a widespread impact on T cell function.

4. **Lymphocyte Infiltration:** Functional assays conducted in vitro demonstrated a positive association between glutamine metabolism and lymphocyte infiltration, which suggests a role for glutamine in promoting T cell activity.

5. **Colocalization of ASCT2 with CD4 and IFN-γ:** Multiplex immunohistochemistry revealed a strong colocalization between ASCT2 and CD4, as well as IFN-γ, indicating a potential role of ASCT2 in the differentiation of Th1 cells, a subset of T cells involved in immune responses.

6. **Mechanistic Insights:** The study provides insights into the mechanism by which glutamine uptake via ASCT2 promotes Th1 differentiation. It suggests that inhibiting glutamine uptake with L-γ-Glutamyl-p-nitroanilide (GPNA) leads to the accumulation of intracellular reactive oxygen species (ROS). This, in turn, promotes the expression of dual specificity phosphatase 2 (DUSP2/PAC1) through activation of early growth response 1 (EGR1). DUSP2/PAC1 then dephosphorylates signal transducer and activator of transcription 3 (STAT3), inhibiting Th1 differentiation.

7. **Potential Therapeutic Implications:** The study concludes that targeting ASCT2 to modulate glutamine uptake may be a potential therapeutic strategy for T cell-mediated autoimmune diseases, by restoring redox balance and inhibiting Th1 differentiation.

In summary, this research provides valuable insights into the role of ASCT2-mediated glutamine uptake in T cell differentiation, particularly in the context of oral lichen planus. It suggests a potential avenue for therapeutic intervention by targeting ASCT2 to restore redox balance and inhibit the differentiation of Th1 cells, which are associated with autoimmune responses.