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

Abstract

Diabetic nephropathy (DN), the principal pathogeny of end-stage renal disease (ESRD), is related to metabolic disorders, chronic inflammation, and oxidative stress. It was reported that high expression of interleukin-17A (IL-17A) was intimately related to the progression of DN, and targeting IL-17A exhibited regulating effects on inflammation and autoimmunity but had only limited impact on the oxidative stress damage in DN. Recent studies showed that interleukin-22 (IL-22) could inhibit mitochondrial damage and inflammatory response. Thus, the cytokine IL-22 was first fused to anti-IL-17A antibody for endowing the antibody with the anti-hyperglycemia and anti-inflammation activity. Our study demonstrated that the fusion molecule, anti-IL17A/IL22 fusion protein, could not only lead to the increase of M1 macrophages and the decrease of M2 macrophages, further improving the immune microenvironment, but also prevent the loss of mitochondrial membrane potential by reducing the production of ROS in murine DN model. In addition, the fusion protein could block TRAF6/NF-κB and AKT/ROS/TXNIP signaling pathways, further synergistically restraining the production of NLRP3, thus suppressing the inflammatory response and playing beneficial effect on slowing down the progression of DN. In conclusion, our findings demonstrated that the bifunctional IL-17A antibody and IL-22 fusion protein were of great benefit to DN, which highlighted a potential therapeutic strategy. KEY POINTS: • Anti-IL17A/IL22 fusion protein could improve the immune microenvironment and reduce the production of ROS. • Anti-IL17A/IL22 fusion protein could block TRAF6/NF-κB and AKT/ROS/TXNIP signaling pathways and then restrain the activation of NLRP3.