Mohd Hafeez Faridi,¹ Samia Q. Khan,¹ Wenpu Zhao,² Ha Won Lee,¹ Mehmet M. Altintas,¹ Kun Zhang,³ Vinay Kumar,⁴ Andrew R. Armstrong,¹ Carmelo Carmona-Rivera,² Jessica M. Dorschner,⁵ Abigail M. Schnaith,⁵ Xiaobo Li,¹ Yogita Ghodke-Puranik,⁵ Erica Moore,² Monica Purmalek,² Jorge Irizarry-Caro,² Tingting Zhang,⁶ Rachael Day,⁷ Darren Stoub,⁷ Victoria Hoffmann,⁸ Shehryar Jehangir Khaliqdina,¹ Prachal Bhargava,¹ Ana M. Santander,⁹ Marta Torroella-Kouri,⁹ Biju Issac,⁹ David J. Cimbaluk,¹⁰ Andrew Zloza,¹¹ Rajeev Prabhakar,⁶ Shashank Deep,⁴ Meenakshi Jolly,¹² Kwi Hye Koh,¹ Jonathan S. Reichner,¹³ Elizabeth M. Bradshaw,¹⁴ JianFeng Chen,³ Luis F. Moita,¹⁵ Peter S. Yuen,¹⁶ Wanxia Li Tsai,¹⁷ Bhupinder Singh,¹⁸ Jochen Reiser,¹ Swapan K. Nath,¹⁸ Timothy B. Niewold,⁵ Roberto I. Vazquez-Padron,¹⁹ Mariana J. Kaplan,² and Vineet Gupta<sup>1

1</sup>Drug Discovery Center, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA. ²Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland, USA. ³State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. ⁴Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, India. ⁵Division of Rheumatology, Mayo Clinic, Rochester, Minnesota, USA. ⁶Department of Chemistry, University of Miami, Coral Gables, Florida, USA. ⁷Department of Chemistry and Biochemistry, Dordt College, Sioux Center, Iowa, USA. ⁸Pathology Branch, Division of Veterinary Resources, Office of the Director, NIH, Bethesda, Maryland, USA. ⁹Sylvester Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA. ¹⁰Department of Pathology, Rush University Medical School, Chicago, Illinois, USA. ¹¹Section of Surgical Oncology Research, Rutgers Cancer Institute of New Jersey, and Department of Surgery, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, USA. ¹²Division of Rheumatology, Department of Internal Medicine, Rush University Medical School, Chicago, Illinois, USA. ¹³Division of Surgical Research, Department of Surgery, Rhode Island Hospital, Providence, Rhode Island, USA. ¹⁴Division of Immunology, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA. ¹⁵Innate Immune and Inflammation Laboratory, Instituto Gulbenkian de Ciencia, Oeiras, Portugal. ¹⁶National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA. ¹⁷Office of Science and echnology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland, USA. ¹⁸Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA. ¹⁹Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA.

Authorship note: MHF, SQK, WZ, HWL, and MMA contributed equally to this work.

Address correspondence to: Vineet Gupta, Cohn Building, Suite 222, 1735 W. Harrison Avenue, Rush University Medical Center, Chicago, Illinois 60612, USA. Or to: Mariana J. Kaplan, 9000 Rockville Pike, Building 10, Room 6D47D, Systemic Autoimmunity Branch, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland 20892, USA. Or to: Roberto I. Vazquez-Padron, Department of Surgery and Vascular Biology Institute, University of Miami Miller School of Medicine, 1600 NW 10th Avenue, Rosenstiel Medical School Building, Room 1048, Miami, Florida 33136, USA.

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.