[PDF][PDF] A neutrophil timer coordinates immune defense and vascular protection

JM Adrover, C Del Fresno, G Crainiciuc, MI Cuartero… - Immunity, 2019 - cell.com
JM Adrover, C Del Fresno, G Crainiciuc, MI Cuartero, M Casanova-Acebes, LA Weiss…
Immunity, 2019cell.com
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 …
Summary
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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