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 7

LA1 reduces IFN-I levels and the nuclear exclusion of FOXO3 in LPS-stimulated patient cells.

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LA1 reduces IFN-I levels and the nuclear exclusion of FOXO3 in LPS-stimu...
(A) Real-time qRT-PCR–based measurement of IFNB and IRF7 in PBMCs from normal donors carrying nonvariant or variant alleles of ITGAM. The data shown are expressed as fold change of ITGAM variant SNP carriers over noncarriers (normalized to 1). Data shown are mean ± SEM (major allele carriers, n = 5, and minor allele carriers, n = 6). (B) Representative immunofluorescence images of subcellular localization of FOXO3 (red, bottom panels) in human macrophages from donors carrying nonvariant (Noncarriers) or variant alleles (SNP carriers) of ITGAM treated with vehicle DMSO, LPS (50 ng/ml), or LPS (50 ng/ml) plus LA1 (20 μM) for 4 hours. Nuclei were stained with DAPI (blue). Scale bars: 10 μm. Bar graphs represent quantitation of the nuclear fraction of FOXO3 in cells (n = 30) from 3 unique donors in each group. Data are mean ± SEM (*P < 0.05, **P < 0.01, ****P < 0.0001, Student’s t test).