CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus
Mohd Hafeez Faridi, … , Mariana J. Kaplan, Vineet Gupta
Mohd Hafeez Faridi, … , Mariana J. Kaplan, Vineet Gupta
Published March 6, 2017
Citation Information: J Clin Invest. 2017;127(4):1271-1283. https://doi.org/10.1172/JCI88442.
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Research Article Autoimmunity Inflammation

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

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

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Figure 6

LA1 improves vasorelaxation in mice.

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LA1 improves vasorelaxation in mice. (A) Quantification of acetylcholine...
(A) Quantification of acetylcholine-dependent (Ach-dependent) relaxation after phenylephrine (PE) precontraction in aortic rings from 19-week-old MRL/Lpr mice after 10-week treatment with LA1 or vehicle. Control data are from MRL/Mpj. Data are mean ± SEM (n = 7 LA1-treated, n = 8 vehicle-treated). (*P < 0.05, **P < 0.01, ***P < 0.001, comparing LA1 vs. controls.) Curves were first analyzed using an asymmetric (5 parameters) logistic equation; significance was determined by 2-way ANOVA. (B) Representative photomicrographs of balloon-injured arteries from rats treated with vehicle or LA1. Images of arteries stained with Evans blue vital staining in situ before sacrifice are shown at the top. Photomicrograph of cross section of arteries stained with anti-vWF antibody to label the endothelium (arrow) is presented below. Scale bars: 50 μm. (C) Quantification of the amount of Evans blue extracted from the balloon-injured arteries from rats treated with vehicle or LA1 (as in B). Data are mean ± SEM (n = 7 vehicle-treated, n = 8 LA1-treated). (D) Quantification of the extent of reendothelialization 7 days after balloon injury from the balloon-injured arteries from rats treated with vehicle or LA1 after staining with anti-vWF antibody (as in B). Data shown are mean ± SEM (n = 7 vehicle-treated, n = 8 LA1-treated) (C and D, *P < 0.05, Student’s t test).