Kidney Week

Abstract: SA-PO723

Pharmacologic Activation of CD11b Suppresses TLR7-Driven Proinflammatory Myeloid Signaling and Protects against Lupus Nephritis

Session Information

• Glomerular Diseases: Therapeutic Strategies
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Li, Xiaobo, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States

Xiaobo Li, MD, PhD

• Jimenez, Viviana, Rush University, Chicago, Illinois, United States

Viviana Jimenez

• Nguyen, Billy, Rush University, Chicago, Illinois, United States

Billy Nguyen

• Ranjan, Nishant, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States

Nishant Ranjan, MSc, PhD

• Cimbaluk, David J., Rush University Medical Center, Chicago, Illinois, United States

David J. Cimbaluk, MD

• Reiser, Jochen, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States

Jochen Reiser, MD, PhD

• Gupta, Vineet, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States

Vineet Gupta, PhD

Background

Lupus Nephritis (LN) is a severe complication of Systemic Lupus Erythematosus (SLE) and occurs in approx. 50% of all patients. Single nucleotide polymorphisms (SNPs) in ITGAM gene, coding for CD11b, shows a high correlation with risk for SLE and LN. We previously showed that ITGAM SNPs that result in less functional protein show heightened inflammatory signaling via toll-like receptors (TLRs), resulting in enhanced systemic immunity. However, how these are linked to increased kidney disease is unclear.

Methods

Human PBMCs from LN patients, primary macrophages, RAW264.7 cells, MRL/lpr genetic and humanized mouse model were utilized in our study. Two orthogonal approaches, genetic and pharmacologic, were utilized to activate CD11b and to measure its effect on TLR7-dependent inflammatory signaling in myeloid cells in vitro and in LN in vivo.

Results

We found that LN patients carrying ITGAM SNPs have significantly elevated serum suPAR levels, suggesting a strong link between the variants and kidney disease. TLR7-stimulation increased suPAR, IFN I, IL-6 and other pro-inflammatory markers in myeloid cells and absence of CD11b exacerbated this response. Conversely, CD11b activation using an oral allosteric agonist called Ontegimod or a gain-of-function point mutation in CD11b (constitutively active) significantly reduced serum suPAR, pro-inflammatory markers, anti-dsDNA antibodies, and ameliorated proteinuria and glomerulonephritis. CD11b activation also reduced splenomegaly and CD11b⁺ cells infiltration in kidney. Mechanistically, CD11b activation reduced TLR7-dependent NF-kB and IFN-I signaling to suppress suPAR generation, demonstrating therapeutic modality for LN.

Conclusion

CD11b activation reduced TLR7-dependent suPAR levels in LN models. This study provides pre-clinical evidence supporting CD11b activation as a promising therapeutic for treating SLE and LN.

Funding

• NIDDK Support