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 2

LA1 induces intermediate-affinity conformation in CD11bA and reduces TLR-stimulated proinflammatory cytokines.

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LA1 induces intermediate-affinity conformation in CD11bA and reduces TLR...
(A) IL-1β, IL-6, TNF-α, and MCP-1 levels in primary mouse macrophage supernatants treated with vehicle DMSO (C), LA1 (20 μM), LPS (50 ng/ml), or LPS+LA1 for 8 hours (MCP-1) or 12 hours (IL-1β, IL-6, and TNF-α). Bars show mean ± SEM (n = 3) from 1 of at least 3 independent experiments. (B) IL-6 and TNF-α levels in supernatants of human macrophages treated with vehicle DMSO (C), LPS (50 ng/ml), or LPS+LA1 for 12 hours. Bars show mean ± SEM (n = 3) from 1 of at least 2 independent experiments. (C) IL-6 and TNF-α levels in supernatants of human macrophages treated with vehicle DMSO (C), R848, or R848+LA1 for 12 hours. Bars show mean ± SEM (n = 3) from 1 of 2 independent experiments. (D) IFN-β levels in the sera of WT or CD11b–/– mice treated with DMSO (C), LPS (100 ng/ml), or LPS+LA1 for 4 hours. Bars show mean ± SEM (n = 3). (E) IFN-β levels in supernatants of primary WT or CD11b–/– macrophages treated with DMSO (C), LA1 (20 μM), LPS (100 ng/ml), or LPS+LA1 for 12 hours. Bars show mean ± SEM (n = 3) from a representative experiment. #Not detectable. (F) Survival of C57BL/6 mice (n = 12) subjected to CLP and treated with vehicle (1% DMSO in saline) or LA1 (2 mg/kg/d). (G) IL-1β, IL-6, and TNF-α in plasma obtained 24 hours after C57BL/6 mice were subjected to either sham surgery (C) or CLP and treated with either vehicle (CLP+Veh) or LA1 (CLP+LA1). Bars show mean ± SEM. (H) Body weight loss (percentage of the initial weight) over 14 days in C57BL/6 mice (n = 20 per group) infected with WT H1N1 virus and treated daily with either vehicle (H1N1 + Vehicle) or LA1 (H1N1 + LA1). Weight loss in noninfected animals (control) and noninfected animals treated with LA1 (Control + LA1) is also shown. Each data point represents mean ± SEM (*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001; A–E, 1-way ANOVA, Tukey’s test; F–H, Student’s t test).