Circadian Features of Neutrophil Biology

Abstract

Rhythms in immunity manifest in multiple ways, but perhaps most prominently by the recurrent onset of inflammation at specific times of day. These patterns are of importance to understand human disease and are caused, in many instances, by the action of neutrophils, a myeloid leukocyte with striking circadian features. The neutrophil's short life, marked diurnal variations in number, and changes in phenotype while in the circulation, help explain the temporal features of inflammatory disease but also uncover core features of neutrophil physiology. Here, we summarize well-established concepts and introduce recent discoveries in the biology of these cells as they relate to circadian rhythms. We highlight that although the circadian features of neutrophils are better known and relevant to understand disease, they may also influence important aspects of organ function even in the steady-state. Finally, we discuss the possibility of targeting these temporal features of neutrophils for therapeutic benefit.

Keywords: chronotherapy; circadian inflammation; molecular clock; neutrophil; oscillatory signals.

Figure 1

Circadian regulation of neutrophils in bone marrow and blood. Mature neutrophils are produced in the bone marrow during granulopoiesis. The transcription factors PU.1, Gfi-1, GATA-1 and different enhancer-binding proteins (C/EBPs) are involved in this process, but the existence of oscillatory changes in their expression is unknown. The sympathetic nervous system releases cues (adrenaline and noradrenaline) that act on stromal cells to generate circadian changes in CXCL12 levels. This ultimately decreases the expression of CXCL12 and promotes the circadian release of neutrophils into the bloodstream. In turn, the parasympathetic nervous system suppresses the activity of the SNS trough cholinergic signals (acetylcholine). In addition to the CXCR4/CXCL12 axis, signaling through CXCR2 by the chemokines CXCL1 and CXCL2 produced by osteoblasts and bone marrow endothelial cells, also mediates neutrophil egress, however the circadian regulation of this axis needs further investigation. Neutrophils undergo aging in circulation following circadian patterns and are finally cleared into the bone marrow and other tissues. The engulfment of aged neutrophils by macrophages activates LXR signaling, which in turn blunts expression of CXCL12 to promote the circadian egress of hematopoietic stem and progenitor cells (HSPCs). Note that cell morphologies are characteristic from mice.

Figure 2

Circadian functions of neutrophils in tissues. In homeostasis, neutrophil infiltration into most tissues is circadian, but not in the intestine or the liver. Neutrophils perform different functions in a circadian-independent manner: In the intestine, they control G-CSF production to mobilize HSC. In other tissues they regulate circadian processes, such as transcriptional programs and tumor invasion in the lung. The circadian influence in other tissues is not well-defined. For example, metabolism or detoxification control in the liver, gut microbiota regulation in the intestine, or their own re-education and immune defense in the spleen or lymph nodes, respectively. In inflammatory scenarios, neutrophil recruitment oscillates and influences disease outcome. During bacterial infection in the lung, bronchiolar cells modulate CXCL5 expression to control the oscillatory recruitment of neutrophils. In models of cardiac ischemia, increased infiltration into the heart accounts for exacerbated cardiac damage at different times depending on the type of injury performed.