Active CD11b Targets TLR7-Driven Inflammation to Reduce suPAR Levels and Kidney Damage in Lupus Nephritis
- Glomerular Diseases: From Inflammation to Fibrosis - I
November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: From Inflammation to Fibrosis
- Jimenez, Viviana, Rush University Medical Center, Chicago, Illinois, United States
- Villanueva, Veronica, Rush University Medical Center, Chicago, Illinois, United States
- Li, Xiaobo, Rush University Medical Center, Chicago, Illinois, United States
- Alzahrani, Khulood, Rush University Medical Center, Chicago, Illinois, United States
- Faridi, Hafeez, Chicago State University College of Pharmacy, Chicago, Illinois, United States
- Gupta, Vineet, Rush University Medical Center, Chicago, Illinois, United States
Lupus nephritis (LN) is a common end-organ injury resulting from systemic lupus erythematosus (SLE). CD11b heterodimerizes with b2 integrin to form the CD11b/CD18 receptor on surface of leukocytes that is essential for their normal functions. Genome-wide association studies revealed a number of single nucleotide polymorphisms (SNPs) in the ITGAM gene, that codes for CD11b, associate with SLE and LN. Prior studies have shown that several coding SNPs in CD11b reduce integrin function and increase Toll like receptor (TLR)-dependent inflammatory signaling. However, it is not clear if ITGAM SNPs also correlate with various kidney disease biomarkers, such as suPAR, and what the underlying mechanism could be. Additionally, it is not known if activation of CD11b would be able to reduce these biomarkers and kidney injury in vivo.
We used a combination of in vitro and in vivo assays. A macrophage cell line as well as primary macrophages were utilized and treated with TLR7 agonists. Two orthogonal approaches, genetic and pharmacologic, were utilized to activate CD11b and measure its effect on TLR7-dependent inflammatory signaling in myeloid cells in vitro and in LN models in vivo.
Additionally, we utilized the MRL/lpr mice, a genetic model which shares many features and organ pathology with SLE, and a newly developed humanized mouse model of LN to mechanistically define role of CD11b activation in disease control.
TLR7-stimulation increased suPAR levels in wild type cells in vitro and in vivo. Absence of CD11b (using CD11b knock out) exacerbated response. Conversely, CD11b activation using an oral agonist or a genetic mutation in CD11b significantly reduced suPAR and reduced proteinuria and LN pathology. CD11b activation also reduced splenomegaly and infiltration of CD11b+ inflammatory cells in the kidney. Mechanistically, CD11b activation reduced TLR7-dependent activation of NFkB to suppress suPAR generation.
We demonstrate that CD11b activation reduced TLR7-dependent suPAR levels in models of LN. These studies provide further support for CD11b activation as a therapeutic strategy for LN.
- NIDDK Support