CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus

• Published in: The Journal of clinical investigation Vol. 127; no. 4; pp. 1271 - 1283
• Main Authors: Faridi, Mohd Hafeez, Khan, Samia Q, Zhao, Wenpu, Lee, Ha Won, Altintas, Mehmet M, Zhang, Kun, Kumar, Vinay, Armstrong, Andrew R, Carmona-Rivera, Carmelo, Dorschner, Jessica M, Schnaith, Abigail M, Li, Xiaobo, Ghodke-Puranik, Yogita, Moore, Erica, Purmalek, Monica, Irizarry-Caro, Jorge, Zhang, Tingting, Day, Rachael, Stoub, Darren, Hoffmann, Victoria, Khaliqdina, Shehryar Jehangir, Bhargava, Prachal, Santander, Ana M, Torroella-Kouri, Marta, Issac, Biju, Cimbaluk, David J, Zloza, Andrew, Prabhakar, Rajeev, Deep, Shashank, Jolly, Meenakshi, Koh, Kwi Hye, Reichner, Jonathan S, Bradshaw, Elizabeth M, Chen, JianFeng, Moita, Luis F, Yuen, Peter S, Li Tsai, Wanxia, Singh, Bhupinder, Reiser, Jochen, Nath, Swapan K, Niewold, Timothy B, Vazquez-Padron, Roberto I, Kaplan, Mariana J, Gupta, Vineet
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.04.2017
• Subjects: Animals; Arthritis; Biomedical research; Care and treatment; CD11b Antigen - genetics; CD11b Antigen - immunology; Cellular proteins; Cytokines; Development and progression; Disease; Experiments; Female; Forkhead Box Protein O3 - genetics; Forkhead Box Protein O3 - immunology; Genetic aspects; Genotype & phenotype; Haplotypes; Health aspects; Humans; Immune response; Interferon Regulatory Factor-3 - genetics; Interferon Regulatory Factor-3 - immunology; Interferon Regulatory Factor-7 - genetics; Interferon Regulatory Factor-7 - immunology; Interferon Type I - genetics; Interferon Type I - immunology; Lupus; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - pathology; Macrophages - immunology; Macrophages - pathology; Male; Mice; Mice, Inbred MRL lpr; Mutation; Polymorphism, Single Nucleotide; Proteins; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - immunology; Skin diseases; Studies; Systemic lupus erythematosus; Toll-like receptors; Toll-Like Receptors - genetics; Toll-Like Receptors - immunology
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI88442

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.