title: CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus.
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.
authors.forename: Mohd Hafeez
authors.initials: MH
authors.lastname: Faridi
authors.forename: Samia Q
authors.initials: SQ
authors.lastname: Khan
authors.forename: Wenpu
authors.initials: W
authors.lastname: Zhao
authors.forename: Ha Won
authors.initials: HW
authors.lastname: Lee
authors.forename: Mehmet M
authors.initials: MM
authors.lastname: Altintas
authors.forename: Kun
authors.initials: K
authors.lastname: Zhang
authors.forename: Vinay
authors.initials: V
authors.lastname: Kumar
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Armstrong
authors.forename: Carmelo
authors.initials: C
authors.lastname: Carmona-Rivera
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Dorschner
authors.forename: Abigail M
authors.initials: AM
authors.lastname: Schnaith
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Li
authors.forename: Yogita
authors.initials: Y
authors.lastname: Ghodke-Puranik
authors.forename: Erica
authors.initials: E
authors.lastname: Moore
authors.forename: Monica
authors.initials: M
authors.lastname: Purmalek
authors.forename: Jorge
authors.initials: J
authors.lastname: Irizarry-Caro
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhang
authors.forename: Rachael
authors.initials: R
authors.lastname: Day
authors.forename: Darren
authors.initials: D
authors.lastname: Stoub
authors.forename: Victoria
authors.initials: V
authors.lastname: Hoffmann
authors.forename: Shehryar Jehangir
authors.initials: SJ
authors.lastname: Khaliqdina
authors.forename: Prachal
authors.initials: P
authors.lastname: Bhargava
authors.forename: Ana M
authors.initials: AM
authors.lastname: Santander
authors.forename: Marta
authors.initials: M
authors.lastname: Torroella-Kouri
authors.forename: Biju
authors.initials: B
authors.lastname: Issac
authors.forename: David J
authors.initials: DJ
authors.lastname: Cimbaluk
authors.forename: Andrew
authors.initials: A
authors.lastname: Zloza
authors.forename: Rajeev
authors.initials: R
authors.lastname: Prabhakar
authors.forename: Shashank
authors.initials: S
authors.lastname: Deep
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Jolly
authors.forename: Kwi Hye
authors.initials: KH
authors.lastname: Koh
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Reichner
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Bradshaw
authors.forename: JianFeng
authors.initials: J
authors.lastname: Chen
authors.forename: Luis F
authors.initials: LF
authors.lastname: Moita
authors.forename: Peter S
authors.initials: PS
authors.lastname: Yuen
authors.forename: Wanxia
authors.initials: W
authors.lastname: Li Tsai
authors.forename: Bhupinder
authors.initials: B
authors.lastname: Singh
authors.forename: Jochen
authors.initials: J
authors.lastname: Reiser
authors.forename: Swapan K
authors.initials: SK
authors.lastname: Nath
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Niewold
authors.forename: Roberto I
authors.initials: RI
authors.lastname: Vazquez-Padron
authors.forename: Mariana J
authors.initials: MJ
authors.lastname: Kaplan
authors.forename: Vineet
authors.initials: V
authors.lastname: Gupta
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000235:genetics / Q000276:immunology*; D005260:Female; D000071316:Forkhead Box Protein O3 / Q000235:genetics / Q000276:immunology; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000276:immunology; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000276:immunology; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D020641:Polymorphism, Single Nucleotide; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology*
chemical_list: D039481:CD11b Antigen; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; C474033:FoxO3 protein, mouse; C494232:IRF3 protein, human; C494234:IRF7 protein, human; C509295:ITGAM protein, human; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; C494233:Irf3 protein, mouse; C494235:Irf7 protein, mouse; D051193:Toll-Like Receptors; D051057:Proto-Oncogene Proteins c-akt