Oxidative Phosphorylation Regulates B Cell Effector Cytokines and Promotes Inflammation in Multiple Sclerosis

Oxidative Phosphorylation Regulates B Cell Effector Cytokines and Promotes Inflammation in Multiple Sclerosis

Background Introduction

In recent years, the antibody-independent functions of B cells in health and disease have become a research hotspot, particularly their ability to secrete different cytokines that can activate or downregulate local immune responses. Studies have shown that dysregulation of B cell cytokines is one of the causes of various immune-mediated diseases, including Multiple Sclerosis (MS). However, the mechanisms regulating B cell cytokine expression are still not well understood. This paper explores how the secretion of pro-inflammatory (e.g., GM-CSF expression) and anti-inflammatory (e.g., IL-10 expression) B cell cytokines is regulated, with a particular focus on the role of Oxidative Phosphorylation (OxPhos).

Research Origin

This study was conducted by Rui Li and his team, with authors from the University of Pennsylvania, the First Affiliated Hospital of Fujian Medical University, Harbin Medical University, among others. The findings were published on May 3, 2024, in the journal Science Immunology under the title “Oxidative phosphorylation regulates B cell effector cytokines and promotes inflammation in multiple sclerosis”.

Research Methods

The study explores the mechanisms regulating the secretion of pro-inflammatory and anti-inflammatory cytokines in B cells, with a particular focus on the role of OxPhos.

Research Procedure

  1. Sample Preparation and RNA Sequencing

    • B cells isolated from peripheral blood were used. Using a recently developed “Cytokine Secretion Assay”, B cells secreting IL-10 and GM-CSF were isolated and subjected to bulk RNA sequencing.
    • Principal Component Analysis (PCA) was used to distinguish the transcriptomic features of GM-CSF+ B cells from IL-10+ B cells.
  2. Metabolic Pathway Analysis

    • Gene Set Enrichment Analysis (GSEA) showed that GM-CSF+ B cells were enriched for several pathways controlling cellular metabolic activities, such as OxPhos, glycolysis, and the PI3K-mTOR pathway.
    • GM-CSF+ B cells exhibited higher mitochondrial mass compared to IL-10+ B cells.
  3. In Vitro B Cell Metabolic Activity Experiments

    • B cells were activated using various known stimulation methods that induce different B cell cytokine responses, and their mitochondrial respiration and glycolytic activities were measured.
    • The results indicated that stimuli inducing GM-CSF led to higher metabolic activity and mitochondrial mass.
  4. Partial Inhibition of OxPhos

    • By inhibiting mTOR signaling and using a Complex I inhibitor (Rotenone) or a glycolysis inhibitor (2-DG), it was found that partial inhibition of OxPhos can reduce GM-CSF expression and increase IL-10 expression, shifting towards an anti-inflammatory phenotype.
  5. In Vivo B Cell Metabolic Activity

    • The cytokine responses of B cells were compared between patients with rare mitochondrial respiratory chain mutations and healthy controls, revealing that B cells from patients with mutations showed significantly reduced cytokine responses.

Data Analysis and Results

  1. Transcriptome Analysis

    • PCA and GSEA results demonstrated transcriptomic differences between GM-CSF+ and IL-10+ B cells.
    • GM-CSF+ B cells were enriched for OxPhos and glycolysis-related pathways.
  2. Experimental Results

    • Partial OxPhos inhibition reduced the secretion of pro-inflammatory cytokines (such as GM-CSF) by B cells, while increasing the secretion of anti-inflammatory cytokines (such as IL-10).
    • In vitro experiments linked B cell metabolic activity to their cytokine secretion.
  3. In Vivo Verification

    • B cells from patients with mitochondrial mutations showed reduced metabolic activity and cytokine secretion.
    • Further validation in animal models found that lowering mitochondrial respiration in B cells can reduce neuroinflammation.

Research Conclusion

This study found that OxPhos plays a crucial role in regulating the secretion of pro-inflammatory and anti-inflammatory cytokines in B cells. Partial inhibition of OxPhos can reverse the cytokine imbalance in B cells from multiple sclerosis patients, suggesting potential for restoring cytokine balance by regulating B cell metabolism.

Research Highlights

  • The study reveals the metabolic regulation mechanisms of B cell cytokine expression.
  • OxPhos is more active in pro-inflammatory B cells than in anti-inflammatory B cells.
  • Partial inhibition of OxPhos promotes a shift towards an anti-inflammatory B cell phenotype, providing a theoretical basis for the development of new non-depleting B cell-targeted therapies.

Research Significance

This study not only expands our understanding of B cell functions and regulatory mechanisms but also offers new potential strategies for treating various autoimmune diseases, including multiple sclerosis. By regulating B cell metabolism, it is possible to intervene in cytokine dysregulation and improve disease conditions. This finding provides new directions for future development of therapies targeting metabolic pathways.