A bifunctional fusion protein protected against diabetic nephropathy by suppressing NLRP3 activation

Area of Science:

• Nephrology
• Immunology
• Molecular Biology

Background:

• Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD), linked to metabolic disorders, inflammation, and oxidative stress.
• High interleukin-17A (IL-17A) expression correlates with DN progression, but targeting it has limited effects on oxidative stress.
• Interleukin-22 (IL-22) shows potential in mitigating mitochondrial damage and inflammation.

Purpose of the Study:

• To develop and evaluate a novel bifunctional fusion protein combining anti-IL-17A antibody and IL-22.
• To investigate the therapeutic effects of this fusion protein on the immune microenvironment, oxidative stress, and inflammatory pathways in a murine DN model.

Main Methods:

• Fusion of IL-22 cytokine to an anti-IL-17A antibody to create a bifunctional molecule.
• Administration of the anti-IL17A/IL22 fusion protein in a murine model of diabetic nephropathy.
• Assessment of macrophage polarization (M1/M2), reactive oxygen species (ROS) production, mitochondrial membrane potential, and key signaling pathways (TRAF6/NF-κB, AKT/ROS/TXNIP, NLRP3).

Main Results:

• The fusion protein modulated macrophage populations, increasing M1 and decreasing M2 types, thereby improving the immune microenvironment.
• It prevented mitochondrial membrane potential loss and reduced ROS production in the DN model.
• The protein effectively blocked TRAF6/NF-κB and AKT/ROS/TXNIP signaling, leading to synergistic inhibition of NLRP3 inflammasome activation and suppression of inflammation.

Conclusions:

• The bifunctional anti-IL17A/IL22 fusion protein demonstrates significant therapeutic benefits in a murine DN model.
• This novel fusion protein improves immune regulation, reduces oxidative stress, and inhibits key inflammatory pathways, highlighting its potential as a therapeutic strategy for diabetic nephropathy.