IL-22 Binding Protein Controls IL-22-Driven Bleomycin-Induced Lung Injury

Area of Science:

• Immunology
• Pulmonology
• Cell Biology

Background:

• Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) have high mortality rates, necessitating new therapeutic targets.
• Interleukin-22 (IL-22) exhibits protective and inflammatory roles in the lung, requiring regulation by IL-22 binding protein (IL-22BP).

Purpose of the Study:

• To investigate the role of IL-22BP in controlling and preventing bleomycin-induced acute lung injury.
• To elucidate the mechanisms by which IL-22BP deficiency exacerbates lung inflammation.

Main Methods:

• Utilized IL-22BP knockout (Il22ra2^-/-) and wild-type C57Bl/6 mice in a bleomycin-induced ALI model.
• Assessed lung inflammation, weight loss, mortality, and cytokine profiles.
• Investigated IL-22 signaling pathways in macrophages via IL-22 receptor alpha-1 (Il22ra1).

Main Results:

• Il22ra2^-/- mice exhibited increased sensitivity to bleomycin, characterized by significant weight loss, mortality, and acute pulmonary inflammation.
• Excess IL-22 production in knockout mice drove pathogenic IL-17A⁺ γδ T cell influx.
• Noncanonical IL-22 signaling to Il22ra1⁺ macrophages initiated inflammation, leading to the production of IL-1β, IL-6, and TGF-β1.

Conclusions:

• IL-22BP is essential for preventing excessive IL-22 activity and mitigating bleomycin-induced lung injury.
• IL-22BP restrains IL-22 signaling to macrophages, thereby reducing inflammation and improving outcomes in ALI.
• Targeting the IL-22/IL-22BP axis presents a potential therapeutic strategy for ALI/ARDS.