Editors' ChoiceIMMUNITY

Leukocyte Recruitment: Getting on Inflammation’s Nerves

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Science Translational Medicine  29 Aug 2012:
Vol. 4, Issue 149, pp. 149ec156
DOI: 10.1126/scitranslmed.3004810

A prevailing paradigm is that local tissue environments govern leukocyte recruitment under basal and inflammatory conditions. However, new evidence from Scheiermann et al. reveals that leukocyte recruitment can be regulated from a distance by the adrenergic nervous system, which acts to coordinate a rhythmic pattern of adhesion molecule and chemokine expression.

Leukocytes were found during unstimulated conditions to recruit to both the bone marrow and skeletal muscle with 24-hour temporal fluctuations according to the circadian clock. Using intravital microscopy to directly visualize inflamed tissue in vivo confirmed circadian differences in cell adhesion. Interestingly, the circadian changes in adhesion only occurred in neutrophils and monocytes, not in lymphocytes. These changes were governed by oscillating expression of the endothelial adhesion protein ICAM-1 and the chemokine CCL2 in muscle, with changes in the adhesion molecules P-selectin, E-selectin, and VCAM-1 on bone marrow endothelial cells. Surprisingly, the local circadian recruitment oscillations were regulated distantly through the sympathetic nervous system, and denervation resulted in the loss of circadian leukocyte adhesion rhythms. In addition, inhibiting the neurotransmission of adrenaline eliminated circadian adhesion-molecule and cell recruitment oscillations, whereas provoking adrenergic nerves increased adhesion molecule expression and recruitment. Importantly, these oscillations had functional consequences: The mortality of mice increased when experimental sepsis was induced at night compared with the day. Last, the authors demonstrated that this circadian system was exploitable for clinical use because lethally irradiated mice, mimicking a patient requiring a marrow transplant, had improved marrow transplantation when given at night or when the sympathetic nervous system was stimulated.

This study reveals new insights into the regulation of leukocyte recruitment via the nervous system. These new mechanisms are far-reaching in terms of informing us about inflammatory diseases and reveal new pathways to target that may modify the inflammatory response. For humans requiring bone marrow transplantation, success may be improved by altering the time of transplantation or by potentially pretreating the patient to condition their molecular internal clock to be more accepting of the transplant.

C. Scheiermann et al., Adrenergic nerves govern circadian leukocyte recruitment to tissues. Immunity 37, 1–12 (2012). [Abstract]

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