CD11b activation suppresses TLR-dependent... : Journal of Clinical Investigation (original) (raw)

CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus

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

Journal of Clinical Investigation

127

(

)

1271

1283

April 3, 2017

| DOI: 10.1172/JCI88442

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.