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
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.
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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 -