TY - JOUR
T1 - CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus
AU - Faridi, Mohd Hafeez
AU - Khan, Samia Q.
AU - Zhao, Wenpu
AU - Lee, Ha Won
AU - Altintas, Mehmet M.
AU - Zhang, Kun
AU - Kumar, Vinay
AU - Armstrong, Andrew R.
AU - Carmona-Rivera, Carmelo
AU - Dorschner, Jessica M.
AU - Schnaith, Abigail M.
AU - Li, Xiaobo
AU - Ghodke-Puranik, Yogita
AU - Moore, Erica
AU - Purmalek, Monica
AU - Irizarry-Caro, Jorge
AU - Zhang, Tingting
AU - Day, Rachael
AU - Stoub, Darren
AU - Hoffmann, Victoria
AU - Khaliqdina, Shehryar Jehangir
AU - Bhargava, Prachal
AU - Santander, Ana M.
AU - Torroella-Kouri, Marta
AU - Issac, Biju
AU - Cimbaluk, David J.
AU - Zloza, Andrew
AU - Prabhakar, Rajeev
AU - Deep, Shashank
AU - Jolly, Meenakshi
AU - Koh, Kwi Hye
AU - Reichner, Jonathan S.
AU - Bradshaw, Elizabeth M.
AU - Chen, Jianfeng
AU - Moita, Luis F.
AU - Yuen, Peter S.
AU - Tsai, Wanxia Li
AU - Singh, Bhupinder
AU - Reiser, Jochen
AU - Nath, Swapan K.
AU - Niewold, Timothy B.
AU - Vazquez-Padron, Roberto I.
AU - Kaplan, Mariana J.
AU - Gupta, Vineet
N1 - Funding Information:
Acknowledgments We thank Dony Maiguel, Nicholas J. Tardy, Hatem Elshabrawy, Yuntao Wei, and Dania Mateu for generous technical help and help-ful discussions. We also thank Tanya Mayadas for valuable input and discussions. We thank S. Fagerholm (University of Helsinki, Helsinki, Finland) for providing the CD11b R77H plasmid. This work was supported in part by grants from the NIH (R01DK084195, R01DK106512, and R21CA176055 to VG; R01HL109582 to VG and RIVP; R01AR060366 to SN), a postdoctoral fellowship from the American Heart Association to SQK, and resources from the Rush University Medical Center. This work was also supported in part by the Intramural Research Program at the National Institute of Arthritis and Musculoskeletal and Skin Diseases/NIH (1ZIAAR041199 to MJK and by the Office of Science and Technology), the European Research Council (ERC-2014-CoG 647888-iPROTECTION to LFM), and the National Basic Research Program of China (2014CB541905).
PY - 2017/4/3
Y1 - 2017/4/3
N2 - 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-?, 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.
AB - 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-?, 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.
UR - http://www.scopus.com/inward/record.url?scp=85018666210&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85018666210&partnerID=8YFLogxK
U2 - 10.1172/JCI88442
DO - 10.1172/JCI88442
M3 - Article
C2 - 28263189
AN - SCOPUS:85018666210
SN - 0021-9738
VL - 127
SP - 1271
EP - 1283
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 4
ER -