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Abstract: PO1426

CD11b Activation Suppresses Pro-Inflammatory IL-1β in Myeloid Cells and Protects Against Lupus Nephritis

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Villanueva, Veronica, Rush University Graduate College, Chicago, Illinois, United States
  • Li, Xiaobo, Rush University Graduate College, Chicago, Illinois, United States
  • Jimenez, Viviana, Rush University Graduate College, Chicago, Illinois, United States
  • Gupta, Vineet, Rush University Graduate College, 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. Mutations in the ITGAM gene, encoding CD11b, are associated with LN and reduce integrin function. Interleukin-1β (IL-1β) is produced by myeloid cells as a proprotein and cleaved by caspase-1 where it mediates the inflammatory response. IL-1β is downstream of toll-like receptor and IL-1β receptor signaling. We previously showed that activation of CD11b suppresses TLR-dependent pro-inflammatory signaling. Here, we investigate if this mechanism includes control of IL-1β and/or if CD11b influences IL-1β by another mechanism, which may provide novel therapeutic options for proinflammatory diseases.

Methods

To investigate TLR-dependent signaling affected by CD11b activation, we utilized in vitro assays using primary macrophages. Cells were treated with TLR agonists, IL-1β protein, or IL-1β antibody and changes in protein expression was assessed by western blot and proinflammatory cytokine levels were 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, CD11b knock-out, and CD11b knock-in mice were used to determine the effect of CD11b activation on circulating IL-1β levels.

Results

TLR-stimulation increased IL-1β levels in vitro and in vivo. Importantly, CD11b activation resulted in significantly reduced IL-1β levels in both systems, suggesting a novel mechanism for controlling inflammation in glomerular diseases. Additional mechanistic studies are on-going to define the exact molecular mechanism of action. Murine models of SLE and LN display significant decreases in IL-1β when CD11b is activated, both genetically or pharmacologically, showing potential protection against LN.

Conclusion

Using these models, we have identified a possible link between CD11b activation and IL-1β secretion in myeloid cells. These studies will provide understanding of the influence CD11b has on signaling pathways and inflammation associated with inflammatory diseases such as LN.

Funding

  • NIDDK Support