Targeting IL-6 receptor mediated metabolic pathways to control Th17 cell differentiation and inflammatory responses

Area of Science:

• Immunology
• Cell Metabolism
• Molecular Biology

Background:

• Interleukin-6 (IL-6) is a key cytokine involved in inflammation.
• IL-6 influences T cell function, including the differentiation of CD4+ T cells into pro-inflammatory Th17 cells.
• Cellular metabolism is tightly linked to T cell function.

Purpose of the Study:

• To investigate the role of IL-6 receptor (IL-6R) signaling in Th17 cell metabolism.
• To determine if metabolic pathways regulated by IL-6R can be targeted to control Th17-mediated inflammation.

Main Methods:

• Utilized T cell-specific IL-6R conditional knockout mice and littermate controls.
• Analyzed T cell populations, differentiation, glucose uptake, glycolysis, oxygen consumption, and mitochondrial function.
• Inhibited lactate dehydrogenase (LDH) using FX11 to assess its impact on Th17 and Treg cells.

Main Results:

• IL-6R signaling regulates CD4+ and CD8+ T cell proportions and drives Th17 cell differentiation.
• IL-6R signaling is essential for Th17 cell glycolysis, reducing glucose uptake and key glycolytic enzyme expression while increasing basal oxygen consumption.
• IL-6R signaling enhances oxidative capacity and mitochondrial coupling efficiency in Th17 cells.
• FX11 selectively impaired Th17 cell differentiation with minimal impact on Treg cells.

Conclusions:

• IL-6R signaling is a critical regulator of Th17 cell metabolism, influencing both glycolytic and oxidative pathways.
• Targeting IL-6R-regulated metabolic pathways, such as by inhibiting LDH, offers a selective approach to suppress inflammatory Th17 responses.
• This provides a potential therapeutic strategy for managing IL-6-mediated inflammatory conditions.