Sympathetic nerves regulate rhythmic leukocyte recruitment to arteries and veins

Abstract

Recent evidence points to a critical role of the time‐of‐day in the regulation of leukocyte recruitment to tissues. Using in vivo quantitative imaging analyses across the day in inflammatory scenarios, we observed circadian (~24h) leukocyte recruitment in arteries and veins of the macro‐ and microvasculature. Interestingly however, while in arteries the number of adherent cells peaked in the morning, in veins it peaked at night. These differences were functionally associated with a vessel‐type‐specific oscillatory pattern in the expression of the adhesion molecule ICAM‐1 but not of other promigratory molecules or clock genes. ICAM‐1‐deficient mice lacked rhythmic leukocyte adhesion in both arteries and veins, which was also observed in studies using functional ICAM‐1‐blocking antibodies. Since the sympathetic nervous system (SNS) is an important orchestrator of rhythmicity in peripheral tissues, we disrupted the SNS systemically by 6‐OHDA treatment. This resulted in a lack of oscillations in both arteries and veins. To assess the functional role of direct sympathetic innervation in this process, we surgically denervated sympathetic input to vessels locally by unilaterally cutting the superior cervical ganglion. While the contralateral, nerve‐intact sides still exhibited rhythmicity in both leukocyte adhesion and ICAM‐1 expression, local denervation resulted in a loss of oscillations. Similar results were obtained by administration of beta adrenergic receptor antagonists. Interestingly, when using Ng2Cre x Bmal1flox/flox mice, in which the core clock gene Bmal1 and thus rhythmicity was selectively deleted in arteriolar Ng2+‐pericytes, an ablation of the oscillations was observed in both arteries and veins. Thus, using pharmacological, surgical and genetic approaches, our data point to an important role of arteries in regulating rhythmic leukocyte recruitment to veins.Support or Funding InformationFunded by the German Research Foundation (Emmy Noether SCHE 1645/2‐1 and SFB914 projects B09 and Z03) and the European Research Council (CIRCODE, 635872)