The immunoproteasome regulates ILC2 responses by modulating mitochondrial capacity

Area of Science:

• Immunology
• Cell Biology
• Metabolic pathways

Background:

• Type 2 innate lymphoid cells (ILC2s) are crucial for type 2 immunity.
• ILC2s are implicated in inflammatory conditions like asthma and airway inflammation.
• The immunoproteasome (i-20S) is known for protein degradation.

Purpose of the Study:

• To investigate the role of the immunoproteasome (i-20S) in ILC2 function.
• To explore the impact of i-20S inhibition on ILC2 mitochondrial capacity and metabolism.
• To assess the therapeutic potential of targeting i-20S in type 2 inflammatory diseases.

Main Methods:

• Analysis of proteasome subunit composition in human ILC2s (hILC2s).
• Pharmacological inhibition of i-20S (specifically β5i/LMP7) in hILC2s and assessment of mitochondrial function, ROS production, ATP levels, and activation.
• Evaluation of proteasome inhibition effects on ILC2s in mouse models of IL33-induced airway inflammation and house dust mite-induced asthma.

Main Results:

• Human ILC2s predominantly express the immuno- (β5i) proteasome subunit.
• Selective i-20S inhibition in hILC2s led to ROS production, inhibited aconitase, reduced ATP, and impaired ILC2 activation and cytokine secretion without causing cell death.
• Proteasome inhibition in mice similarly blocked ILC2 mitochondrial function and activation, effectively preventing airway inflammation and asthma.

Conclusions:

• The immunoproteasome (i-20S) is essential for maintaining ILC2 mitochondrial function and metabolic status.
• Selective, reversible inhibition of i-20S offers a potential strategy to modulate ILC2 activity in type 2 inflammatory diseases.
• Targeting i-20S impacts immune cell metabolism, providing a novel therapeutic approach for conditions like asthma.