A Neutrophil Timer Coordinates Immune Defense and Vascular Protection

Adrover JM; {Del Fresno} C; Crainiciuc G; Cuartero MI; Casanova-Acebes M; Weiss LA; Huerga-Encabo H; Silvestre-Roig C; Rossaint J; Cossío I; Lechuga-Vieco AV; García-Prieto J; Gómez-Parrizas M; Quintana JA; Ballesteros I; Martin-Salamanca S; Aroca-Crevillen A; Chong SZ; Evrard M; Balabanian K; López J; Bidzhekov K; Bachelerie F; Abad-Santos F; Mu{ñ}oz-Calleja C; Zarbock A; Soehnlein O; Weber C; Ng LG; Lopez-Rodriguez C; Sancho D; Moro MA; Ibá{ñ}ez B; Hidalgo A

Zusammenfassung

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.

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