A Neutrophil Timer Coordinates Immune Defense and Vascular Protection

被引：305

作者：

Adrover, Jose M. ^{[1
]}

del Fresno, Carlos ^{[2
]}

Crainiciuc, Georgiana ^{[1
]}

Isabel Cuartero, Maria ^{[3
,4
]}

Casanova-Acebes, Maria ^{[1
,16
]}

Weiss, Linnea A. ^{[1
,17
]}

Huerga-Encabo, Hector ^{[5
]}

Silvestre-Roig, Carlos ^{[6
,7
]}

Rossaint, Jan ^{[8
]}

Cossio, Itziar ^{[1
]}

Lechuga-Vieco, Ana V. ^{[2
]}

Garcia-Prieto, Jaime ^{[2
]}

Gomez-Parrizas, Monica ^{[2
]}

Quintana, Juan A. ^{[1
]}

Ballesteros, Ivan ^{[1
]}

Martin-Salamanca, Sandra ^{[1
]}

Aroca-Crevillen, Alejandra ^{[1
]}

Chong, Shu Zhen ^{[9
]}

Evrard, Maximilien ^{[9
]}

Balabanian, Karl ^{[10
]}

Lopez, Jorge ^{[11
]}

Bidzhekov, Kiril ^{[6
]}

Bachelerie, Frangoise ^{[10
]}

Abad-Santos, Francisco ^{[12
]}

Munoz-Calleja, Cecilia ^{[11
]}

Zarbock, Alexander ^{[8
]}

Soehnlein, Oliver ^{[6
,7
]}

Weber, Christian ^{[6
,13
]}

Ng, Lai Guan ^{[9
]}

Lopez-Rodriguez, Cristina ^{[5
]}

Sancho, David ^{[2
]}

Moro, Maria A. ^{[3
,4
]}

Ibanez, Borja ^{[2
,14
,15
]}

Hidalgo, Andres ^{[1
,6
]}

机构：

[1] Ctr Nacl Invest Cardiovasc Carlos III CNIC, Area Dev & Cell Biol, Madrid, Spain

[2] Ctr Nacl Invest Cardiovasc Carlos III CNIC, Area Myocardial Pathophysiol, Madrid, Spain

[3] Univ Complutense, Fac Med, Dept Pharmacol, Unidad Invest Neurovasc, Madrid, Spain

[4] Inst Invest Hosp 12 Octubre I 12, Madrid, Spain

[5] Pompeu Fabra Univ, Dept Expt & Hlth Sci, Immunol Unit, Barcelona, Spain

[6] Ludwig Maximillians Univ Munchen, Inst Cardiovasc Prevent IPEK, Munich, Germany

[7] German Ctr Cardiovasc Res DZHK, Partner Site Munich Heart Alliance, Munich, Germany

[8] Univ Munster, Dept Anesthesiol Intens Care & Pain Med, Munster, Germany

[9] ASTAR, Singapore Immunol Network SIgN, Singapore, Singapore

[10] Univ Paris Sud, Lab Excellence Res Medicat & Innovat Therapeut, Inserm Unite Mixte Rech UMR S996, Clamart, France

[11] Hosp Univ La Princesa, Inst Invest Sanitaria Princesa, Dept Immunol, Madrid, Spain

[12] Hosp Univ La Princesa, Inst Invest Sanitaria Princesa, Inst Teofilo Hernando, Dept Clin Pharmacol, Madrid, Spain

[13] Maastricht Univ, Cardiovasc Res Inst Maastricht CARIM, Dept Biochem, Maastricht, Netherlands

[14] GIBER Enfermedades Cardiovasc CIBERCV, Madrid, Spain

[15] Fdn Jimenez Diaz, IIS, Dept Cardiol, Madrid, Spain

[16] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA

[17] Ctr Nacl Biotecnol, Madrid, Spain

来源：

IMMUNITY | 2019年 / 50卷 / 02期

基金：

欧洲研究理事会; 欧盟地平线“2020”;

关键词：

FLUORESCENT PROTEIN; LEUKOCYTE ADHESION; BONE-MARROW; CXCR4; SELECTIN; INFLAMMATION; MODULATION; OSCILLATIONS; EXPRESSION; RELEASE;

D O I：

10.1016/j.immuni.2019.01.002

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Neutrophils eliminate pathogens efficiently but can inflict severe damage to the host if they over-activate within blood vessels. It is unclear how immunity solves the dilemma of mounting an efficient anti-microbial defense while preserving vascular health. Here, we identify a neutrophil-intrinsic program that enabled both. The gene Bmal1 regulated expression of the chemokine CXCL2 to induce chemokine receptor CXCR2-dependent diurnal changes in the transcriptional and migratory properties of circulating neutrophils. These diurnal alterations, referred to as neutrophil aging, were antagonized by CXCR4 (C-X-C chemokine receptor type 4) and regulated the outer topology of neutrophils to favor homeostatic egress from blood vessels at night, resulting in boosted anti-microbial activity in tissues. Mice engineered for constitutive neutrophil aging became resistant to infection, but the persistence of intravascular aged neutrophils predisposed them to thrombo-inflammation and death. Thus, diurnal compartmentalization of neutrophils, driven by an internal timer, coordinates immune defense and vascular protection.

引用

页码：390 / +

页数：23

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