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 April 3, 2017
Citation Information: J Clin Invest. 2017;127(4):1271-1283. https://doi.org/10.1172/JCI88442.
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Categories: 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 1

ITGAM SNPs correlate with elevated IFN-I activity in SLE patients.

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ITGAM SNPs correlate with elevated IFN-I activity in SLE patients. (A) F...
(A) Functional IFN-I activity, as determined using reporter cell assay (3, 78), in serum samples from 171 SLE subjects genotyped for 3 ITGAM SNPs (rs1143678, rs1143679, and rs1143683) and its association with minor allele carriers compared with carriers of major alleles, stratified by high versus low IFN-I levels. Each dot represents a unique sample. (B) Functional association with serum IFN-I activity in patients carrying ITGAM haplotype rs1143679(G)-rs1143683(T) versus noncarriers.