1. CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus.
- Author
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Faridi MH, Khan SQ, Zhao W, Lee HW, Altintas MM, Zhang K, Kumar V, Armstrong AR, Carmona-Rivera C, Dorschner JM, Schnaith AM, Li X, Ghodke-Puranik Y, Moore E, Purmalek M, Irizarry-Caro J, Zhang T, Day R, Stoub D, Hoffmann V, Khaliqdina SJ, Bhargava P, Santander AM, Torroella-Kouri M, Issac B, Cimbaluk DJ, Zloza A, Prabhakar R, Deep S, Jolly M, Koh KH, Reichner JS, Bradshaw EM, Chen J, Moita LF, Yuen PS, Li Tsai W, Singh B, Reiser J, Nath SK, Niewold TB, Vazquez-Padron RI, Kaplan MJ, and Gupta V
- Subjects
- Animals, CD11b Antigen genetics, Female, Forkhead Box Protein O3 genetics, Forkhead Box Protein O3 immunology, Humans, 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 Erythematosus, Systemic genetics, Lupus Erythematosus, Systemic pathology, Macrophages pathology, Male, Mice, Mice, Inbred MRL lpr, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt immunology, Toll-Like Receptors genetics, CD11b Antigen immunology, Lupus Erythematosus, Systemic immunology, Macrophages immunology, Toll-Like Receptors immunology
- 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.
- Published
- 2017
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