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

被引：93

作者：

Faridi, Mohd Hafeez ^{[1
]}

Khan, Samia Q. ^{[1
]}

Zhao, Wenpu ^{[2
]}

Lee, Ha Won ^{[1
]}

Altintas, Mehmet M. ^{[1
]}

Zhang, Kun ^{[3
]}

Kumar, Vinay ^{[4
]}

Armstrong, Andrew R. ^{[1
]}

Carmona-Rivera, Carmelo ^{[2
]}

Dorschner, Jessica M. ^{[5
]}

Schnaith, Abigail M. ^{[5
]}

Li, Xiaobo ^{[1
]}

Ghodke-Puranik, Yogita ^{[5
]}

Moore, Erica ^{[2
]}

Purmalek, Monica ^{[2
]}

Irizarry-Caro, Jorge ^{[2
]}

Zhang, Tingting ^{[6
]}

Day, Rachael ^{[7
]}

Stoub, Darren ^{[7
]}

Hoffmann, Victoria ^{[8
]}

Khaliqdina, Shehryar Jehangir ^{[1
]}

Bhargava, Prachal ^{[1
]}

Santander, Ana M. ^{[9
]}

Torroella-Kouri, Marta ^{[9
]}

Issac, Biju ^{[9
]}

Cimbaluk, David J. ^{[10
]}

Zloza, Andrew ^{[11
,12
]}

Prabhakar, Rajeev ^{[6
]}

Deep, Shashank ^{[4
]}

Jolly, Meenakshi ^{[13
]}

Koh, Kwi Hye ^{[1
]}

Reichner, Jonathan S. ^{[14
]}

Bradshaw, Elizabeth M. ^{[15
]}

Chen, JianFeng ^{[3
]}

Moita, Luis F. ^{[16
]}

Yuen, Peter S. ^{[17
]}

Tsai, Wanxia Li ^{[18
]}

Singh, Bhupinder ^{[19
]}

Reiser, Jochen ^{[1
]}

Nath, Swapan K. ^{[19
]}

Niewold, Timothy B. ^{[5
]}

Vazquez-Padron, Roberto I. ^{[20
]}

Kaplan, Mariana J. ^{[2
]}

Gupta, Vineet ^{[1
,20
]}

机构：

[1] Rush Univ, Med Ctr, Dept Internal Med, Ctr Drug Discovery, Chicago, IL 60612 USA

[2] NIAMSD, System Autoimmun Branch, NIH, Bethesda, MD 20892 USA

[3] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, CAS Ctr Excellence Mol Cell Sci,State Key Lab Cel, Shanghai, Peoples R China

[4] Indian Inst Technol Delhi, Dept Chem, New Delhi, India

[5] Mayo Clin, Div Rheumatol, Rochester, MN USA

[6] Univ Miami, Dept Chem, Coral Gables, FL 33124 USA

[7] Dordt Coll, Dept Chem & Biochem, Sioux Ctr, IA USA

[8] NIH, Pathol Branch, Div Vet Resources, Off Director, Bldg 10, Bethesda, MD 20892 USA

[9] Univ Miami, Miller Sch Med, Sylvester Canc Ctr, Miami, FL 33136 USA

[10] Rush Univ, Sch Med, Dept Pathol, Chicago, IL 60612 USA

[11] Rutgers State Univ, Sect Surg Oncol Res, Rutgers Canc Inst New Jersey, Robert Wood Johnson Med Sch, New Brunswick, NJ USA

[12] Rutgers State Univ, Dept Surg, Robert Wood Johnson Med Sch, New Brunswick, NJ USA

[13] Rush Univ, Sch Med, Dept Internal Med, Div Rheumatol, Chicago, IL 60612 USA

[14] Rhode Isl Hosp, Dept Surg, Div Surg Res, Providence, RI USA

[15] Brigham & Womens Hosp, Dept Med, Div Immunol, 75 Francis St, Boston, MA 02115 USA

[16] Inst Gulbenkian Ciencias, Innate Immune & Inflammat Lab, Oeiras, Portugal

[17] NIDDK, NIH, Bethesda, MD 20892 USA

[18] NIAMSD, Off Sci & Technol, NIH, Bethesda, MD 20892 USA

[19] Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA

[20] Univ Miami, Miller Sch Med, Dept Surg, 1600 NW 10th Ave,Rosenstiel Med Sch Bldg,Room 104, Miami, FL 33136 USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2017年 / 127卷 / 04期

基金：

欧洲研究理事会;

关键词：

KAPPA-B PATHWAY; MACROPHAGE RESPONSES; INTEGRIN CD11B/CD18; BETA(2) INTEGRINS; LIGAND-BINDING; RS1143679; R77H; ANIMAL-MODELS; MURINE LUPUS; I INTERFERON; MAC-1;

D O I：

10.1172/JCI88442

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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-beta, 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.

引用

页码：1271 / 1283

页数：13

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