Abstract: FR-PO686

IRAK4 Inactivation Eliminates Disease Phenotype in a Murine Model of Lupus/Lupus Nephritis

Session Information

Category: Glomerular

  • 1001 Glomerular: Basic/Experimental Immunology and Inflammation

Authors

  • Horne, Barry K., Boston University School of Medicine, South Weymouth, Massachusetts, United States
  • Rifkin, Ian R., Boston University School of Medicine, South Weymouth, Massachusetts, United States
  • Bonegio, Ramon G., Boston University School of Medicine, South Weymouth, Massachusetts, United States
Background

Toll-like Receptor (TLR) signaling has been shown to play a major role in the progression of lupus and lupus nephritis (LN). Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) is a protein kinase that is critical to mammalian TLR signaling. Humans with homozygous loss-of-function (LOF) mutations in IRAK4 lead relatively normal lives upon reaching adulthood. Attempts at specific in vivo inactivation of kinases in other human diseases have met with great success, and they are currently considered attractive targets for the development of new therapeutics. Thus, we hypothesized that inactivation of IRAK4 would ameliorate disease in our murine model of lupus / LN, and validate it as a potential therapeutic.

Methods

We crossed lupus prone Yaa, FcγRIIb-/- mice to mice with inactive IRAK4 kinase to allow the comparison of lupus prone mice with (IRAK4+/+) or without (IRAK4KD/KD) functional IRAK4. We conducted a survival study, and analyzed the groups for markers of the lupus phenotype: body weight, spleen weight, cervical lymph node weight, perigonadal fat weight, and proteinuria.

Results

IRAK4+/+ mice developed severe lupus and lupus nephritis, and died at a median age of 27 weeks (range: 22 to 28 weeks). In contrast, IRAK4KD/KD mice had a dramatic survival advantage (p<0.001), and mice analyzed at 1 year of age had no evidence of lupus. They exhibited no signs of nephritis, lacked proteinuria, and had normal spleen, cervical lymph node, and fat weights.

Conclusion

IRAK4 kinase activity is indispensable for the development of lupus and lupus nephritis in the Yaa, FcγRIIb-/- mice, indicating that the IRAK4 signaling pathway is an attractive therapeutic target.

Funding

  • NIDDK Support