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Abstract: PO1667

CD11b Activation Suppresses Pro-Inflammatory suPAR in Myeloid Cells and Reduces Lupus Nephritis in Mice

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Villanueva, Veronica, Rush University Medical Center, Chicago, Illinois, United States
  • Li, Xiaobo, Rush University Medical Center, Chicago, Illinois, United States
  • Khan, Samia Qamar, Rush University Medical Center, Chicago, Illinois, United States
  • Sever, Sanja, Harvard Medical School, Boston, Massachusetts, United States
  • Reiser, Jochen, Rush University Medical Center, Chicago, Illinois, United States
  • Gupta, Vineet, Rush University Medical Center, Chicago, Illinois, United States
Background

Lupus nephritis (LN) is a debilitating glomerular disease and a comorbidity of systemic lupus erythematosus (SLE). CD11b, the alpha-chain of integrin CD11b/CD18, plays a critical role in cell signaling. Several mutations in the gene ITGAM, encoding CD11b, are associated with SLE and LN, these mutations are reported to reduce integrin function. suPAR is produced by myeloid cells upon pro-inflammatory activation and is a circulating risk factor for glomerular diseases. suPAR is downstream of Toll-like receptor signaling, where TLR-activation increases suPAR levels. We previously showed that activation of CD11b suppresses TLR-dependent pro-inflammatory signaling. Here, we investigate if this mechanism includes control of suPAR levels, which may provide novel therapeutic options for LN.

Methods

To investigate TLR-dependent signaling affected by CD11b activation, we utilized in vitro assays using primary macrophages and genetically engineered K562 cells expressing CD11b and CD18. K562 cells were developed to express either wild type CD11b or CD11b carrying mutations commonly found in LN patients. These cells were treated with TLR agonists or LN patient sera and level of suPAR in cell supernatants was assessed by ELISA. For complementary in vivo studies, we utilized our newly generated mouse model, where we incorporated a constitutively active CD11b point mutation (I332G) globally in mice to generate a model for CD11b activation – CD11b knock-in model. C57BL/6 wild type mice, the CD11b knock-out and the CD11b knock-in mice were used in models of SLE and LN to determine the effect of CD11b activation on circulating suPAR levels and course of the disease.

Results

TLR-stimulation increased suPAR levels in vitro and in vivo. Importantly, CD11b activation resulted in significantly reduced suPAR levels in both systems, suggesting a novel mechanism for controlling glomerular diseases. Additional mechanistic studies are on-going to define the exact molecular mechanism of action.

Conclusion

Using these models, we have identified a possible link between CD11b activation and suPAR levels in myeloid cells. These studies will provide understanding of the influence CD11b has on signaling pathways and inflammation associated with LN.

Funding

  • NIDDK Support