Sulfur metabolic response in macrophage limits excessive inflammatory response by creating a negative feedback loop

Area of Science:

• Immunology
• Metabolomics
• Cell Biology

Background:

• Macrophage inflammatory responses are critical in disease pathogenesis.
• Metabolic alterations, particularly in amino acid metabolism, regulate macrophage inflammatory phenotypes.

Purpose of the Study:

• To investigate novel metabolic pathways regulating macrophage inflammatory responses.
• To explore the role of cysteine metabolism in modulating inflammation.

Main Methods:

• Metabolome analysis of mouse peritoneal macrophages stimulated with lipopolysaccharide (LPS).
• Assessment of inflammatory gene expression in Slc7a11 knockout (xCT-KO) macrophages.
• Analysis of sulfur metabolites and supersulfide levels.
• Effect of supersulfide donor (NAC-S2) on inflammatory gene expression.

Main Results:

• LPS stimulation increased cysteine and related metabolites, indicating heightened cysteine demand.
• Slc7a11 (xCT) upregulation facilitates cysteine supply during inflammation.
• xCT-KO macrophages showed prolonged pro-inflammatory gene upregulation, similar to cystine-depleted wild-type macrophages.
• Activated macrophages produce supersulfides, which were reduced in xCT-KO cells.
• Supersulfide donor (NAC-S2) attenuated pro-inflammatory gene expression in xCT-KO macrophages.

Conclusions:

• Activated macrophages increase cystine uptake via xCT, leading to supersulfide production.
• Supersulfides act in a negative feedback loop to limit excessive inflammation.
• Sulfur metabolism plays a crucial role in the finely tuned regulation of macrophage inflammatory responses.