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- W4313382092 abstract "Abstract Genetic variations in the ITGAM gene (coding for CD11b) produce defective CD11b and associate with a risk for systemic lupus erythematosus (SLE, lupus). Elevated level of IFN I in circulation plays a pathogenic role and is a heritable risk factor for SLE. Whether variations in ITGAM are linked to high IFN I and whether CD11b activation could be a therapeutic strategy is unknown and is explored here. We measured serum IFN I activity in 171 SLE patients and report that three ITGAM variants significantly associate with elevated levels of IFN I in lupus, suggesting a direct link between reduced CD11b activity and elevated inflammation in patients. Given that ITGAM SNPs result in functionally deficient CD11b, we tested whether partial CD11b activation with small molecule agonist, leukadherin-1 (LA1) reduces IFN I responses and determined the underlying mechanistic pathways. CD11b activation with LA1 reduced TLR-dependent pro-inflammatory signaling in leukocytes and suppressed IFN I signaling via an AKT-FOXO3-IRF7 pathway. TLR-stimulated macrophages from CD11b SNP carriers showed increased basal expression of IRF7 and IFNB, as well as increased nuclear exclusion of FOXO3, which was suppressed by LA1. To test the efficacy of LA1 in vivo, we used the MRL/lpr mice that develop IFN I-dependent multi-organ lupus. LA1 treatment reduced IFN I responses and protected lupus-prone MRL/lpr mice from kidney injury. LA1-treated mice had reduced proteinuria, IgG renal immune complex deposition, and glomerular damage as compared to controls. LA1 suppresses TLR-stimulated overproduction of cytokines in vivo, which drives lupus pathogenesis. These findings suggest that pharmacological CD11b activation is a promising therapeutic strategy in human SLE." @default.
- W4313382092 created "2023-01-06" @default.
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- W4313382092 date "2017-05-01" @default.
- W4313382092 modified "2023-09-23" @default.
- W4313382092 title "CD11b activation protects against lupus nephritis by suppressing TLR-dependent IFN responses via AKT-FOXO3-IRF7" @default.
- W4313382092 doi "https://doi.org/10.4049/jimmunol.198.supp.217.5" @default.
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