[HTML][HTML] CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus
MH Faridi, SQ Khan, W Zhao, HW Lee… - The Journal of …, 2017 - Am Soc Clin Investig
MH Faridi, SQ Khan, W Zhao, HW Lee, MM Altintas, K Zhang, V Kumar, AR Armstrong…
The Journal of clinical investigation, 2017•Am Soc Clin InvestigGenetic variations in the ITGAM gene (encoding CD11b) strongly associate with risk for
systemic lupus erythematosus (SLE). Here we have shown that 3 nonsynonymous ITGAM
variants that produce defective CD11b associate with elevated levels of type I interferon (IFN-
I) in lupus, suggesting a direct link between reduced CD11b activity and the chronically
increased inflammatory status in patients. Treatment with the small-molecule CD11b agonist
LA1 led to partial integrin activation, reduced IFN-I responses in WT but not CD11b-deficient …
systemic lupus erythematosus (SLE). Here we have shown that 3 nonsynonymous ITGAM
variants that produce defective CD11b associate with elevated levels of type I interferon (IFN-
I) in lupus, suggesting a direct link between reduced CD11b activity and the chronically
increased inflammatory status in patients. Treatment with the small-molecule CD11b agonist
LA1 led to partial integrin activation, reduced IFN-I responses in WT but not CD11b-deficient …
Genetic variations in the ITGAM gene (encoding CD11b) strongly associate with risk for systemic lupus erythematosus (SLE). Here we have shown that 3 nonsynonymous ITGAM variants that produce defective CD11b associate with elevated levels of type I interferon (IFN-I) in lupus, suggesting a direct link between reduced CD11b activity and the chronically increased inflammatory status in patients. Treatment with the small-molecule CD11b agonist LA1 led to partial integrin activation, reduced IFN-I responses in WT but not CD11b-deficient mice, and protected lupus-prone MRL/Lpr mice from end-organ injury. CD11b activation reduced TLR-dependent proinflammatory signaling in leukocytes and suppressed IFN-I signaling via an AKT/FOXO3/IFN regulatory factor 3/7 pathway. TLR-stimulated macrophages from CD11B SNP carriers showed increased basal expression of IFN regulatory factor 7 (IRF7) and IFN-β, as well as increased nuclear exclusion of FOXO3, which was suppressed by LA1-dependent activation of CD11b. This suggests that pharmacologic activation of CD11b could be a potential mechanism for developing SLE therapeutics.
The Journal of Clinical Investigation