CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus
Year: 2017
Type: article
Abstract: 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.
DOI: 10.1172/jci88442
Authors: Mohd Hafeez Faridi, Samia Q. Khan, Wenpu Zhao, Ha Won Lee, Mehmet M. Altintas, Kun Zhang, Vinay Kumar, Andrew R. Armstrong, Carmelo Carmona-Rivera, Jessica M. Dorschner, Abigail M. Schnaith, Xiaobo Li, Yogita Ghodke-Puranik, Erica Moore, Monica Purmalek, Jorge Irizarry-Caro, Tingting Zhang, Rachael Day, Darren Stoub, Victoria Hoffmann, Shehryar Jehangir Khaliqdina, Prachal Bhargava, Ana M. Santander, Marta Torroella-Kouri, Biju Issac, David J. Cimbaluk, Andrew Zloza, Rajeev Prabhakar, Shashank Deep, Meenakshi Jolly, Kwi Hye Koh, Jonathan S. Reichner, Elizabeth M. Bradshaw, JianFeng Chen, Luis F. Moita, Peter S. Yuen, Wanxia Li Tsai, Bhupinder Singh, Jochen Reiser, Swapan K. Nath, Timothy B. Niewold, Roberto I. Vazquez-Padron, Mariana J. Kaplan, Vineet Gupta
Institutions: Rush University Medical Center, National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Chinese Academy of Sciences, Shanghai Institutes for Biological Sciences, Center for Excellence in Molecular Cell Science, State Key Laboratory of Cell Biology, Indian Institute of Technology Delhi, Mayo Clinic, University of Miami, Dordt University, Office of the Director, Sylvester Comprehensive Cancer Center, Rush University, Rutgers, The State University of New Jersey, Rutgers Cancer Institute, Rhode Island Hospital, Brigham and Women's Hospital, Instituto Gulbenkian de Ciência, National Institute of Diabetes and Digestive and Kidney Diseases, Oklahoma Medical Research Foundation
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: American Heart Association, University of Miami, Helsingin Yliopisto, Rush University, National Institutes of Health, Office of Science, Leonard M. Miller School of Medicine, National Key Research and Development Program of China, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute on Minority Health and Health Disparities
Awards: G2017721657, Mechanistic Characterization of GWAS Loci in SLE, G2356214010, Role of obesity and breast fat tissue inflammation in breast cancer promotion., Podocyte-based HCS assays for discovering therapeutics against kidney diseases, Leukadherins as novel compounds for treating restenosis, G9000066859, Translating oral CD11b agonist as a novel therapeutic for lupus nephritis
OpenAlex ID: W2593962829