Abstract: FR-PO691

CD11b Activation Reduces Inflammation in Lupus Nephritis by Downregulating TLR Pathways

Session Information

Category: Glomerular

  • 1001 Glomerular: Basic/Experimental Immunology and Inflammation

Authors

  • Khan, Samia, Rush University Medical Center, Chicago, Illinois, United States
  • Faridi, Mohd Hafeez, Rush University Medical Center, Chicago, Illinois, United States
  • Lee, Ha Won, Rush University Medical Center, Chicago, Illinois, United States
  • Altintas, Mehmet M., Rush University Medical Center, Chicago, Illinois, United States
  • Khaliqdina, Shehryar J., Rush University Medical Center, Chicago, Illinois, United States
  • Cimbaluk, David J., Rush University Medical Center, Chicago, Illinois, United States
  • Gupta, Vineet, Rush University Medical Center, Chicago, Illinois, United States
Background

Single nucleotide polymorphisms (SNPs) in the ITGAM gene, coding for CD11b subunit of the integrin CD11b/CD18, produce defective protein and confers a strong predisposition to systemic lupus erythematosus (SLE, lupus) and lupus nephritis. Elevated levels of IFN I in circulation is a heritable risk factor for SLE and play a pathogenic role and are likely driven by a combination of genetic variations and environmental stress. Here we investigate if variations in ITGAM are linked to high IFN I and whether pharmacological CD11b activation could be a therapeutic strategy.

Methods

To test for a direct link between ITGAM SNPs and the TLR induced IFN-I pathways, we measured serum IFN I activity in 171 SLE patients and determined their ITGAM genotype. Since ITGAM SNPs result in functionally deficient CD11b, we tested whether partial CD11b activation with small molecule agonist, leukadherin-1 (LA1) can suppress IFN-I pathways and determined TLR signaling components that are regulated by CD11b activation. To test the efficacy of LA1 in a lupus model, we used the MRL/lpr mice that develop IFN I-dependent multi-organ lupus similar to human lupus with renal inflammation.

Results

We report that SLE subjects carrying ITGAM SNPs have significantly elevated serum IFN-I activity indicating a direct link between reduced CD11b activity and elevated inflammation in patients. LA1 treatment reduced IFN I responses and protected lupus-prone MRL/lpr mice from kidney injury. LA1-treated mice had reduced glomerular damage, proteinuria, and IgG renal immune complex deposition as compared to vehicle-treated controls. CD11b agonist LA1 suppressed proinflammatory cytokine secretion by TLR-activated leukocytes and suppressed IFN I signaling, via an AKT-FOXO3-IRF7 pathway. TLR-stimulated macrophages from CD11b SNP carriers showed increased expression of IRF7 and IFNB, as well as increased nuclear exclusion of FOXO3, which was reversed by LA1.

Conclusion

LA1 suppresses TLR-induced cytokine production that has been directly linked to exacerbation of lupus nephritis. Hence pharmacological CD11b activation is a promising potential novel therapeutic target, particularly in patients identified as carriers of ITGAM variants.

Funding

  • NIDDK Support