Leukocyte ADAM17 regulates acute pulmonary inflammation

Area of Science:

• Immunology
• Molecular Biology
• Pulmonary Medicine

Background:

• ADAM17 (a disintegrin and metalloproteinase domain-17) is a transmembrane protease regulating inflammatory protein shedding.
• Its specific substrates and role in pulmonary inflammation remain largely uncharacterized in vivo.

Purpose of the Study:

• To investigate the role of leukocyte ADAM17 in acute lung inflammation using a conditional knock-out mouse model.
• To identify ADAM17's in vivo substrates and its contribution to neutrophil recruitment and chemokine expression in the lung.

Main Methods:

• Utilized conditional ADAM17 knock-out mice to specifically delete the protease in leukocytes.
• Administered lipopolysaccharide (LPS) to induce acute lung inflammation.
• Quantified levels of TNF-α, IL-6R, L-selectin, and neutrophil-tropic chemokines (CXCL1, CXCL5) in alveolar lavage fluid.
• Assessed neutrophil infiltration into the alveolar compartment.

Main Results:

• ADAM17-null mice showed a significant reduction (>95%) in alveolar TNF-α and L-selectin shedding after LPS administration.
• Alveolar IL-6R levels were only modestly reduced (≈25%), suggesting ADAM17 is not the primary sheddase for IL-6R.
• Overall neutrophil infiltration and lung inflammation were reduced in ADAM17-null mice.
• Interestingly, neutrophil recruitment occurred earlier in ADAM17-null mice, accompanied by diminished CXCL1 and CXCL5 levels.

Conclusions:

• Leukocyte ADAM17 plays a significant role in promoting acute lung inflammation.
• ADAM17 regulates key inflammatory mediators like TNF-α and influences neutrophil recruitment via chemokines.
• ADAM17 emerges as a potential therapeutic target for acute lung injury and inflammatory lung diseases.