A Neutrophil Timer Coordinates Immune Defense and Vascular Protection

Neutrophil Diversity in Health and Disease

“…Further complicating our understanding of neutrophil identities, the phenotype of circulating mature neutrophils appears to vary over the course of their lifespan [3,6,8,9]. Similarly to what has been consistently published in papers utilizing mouse models (see below), diurnal oscillations of C-X-C chemokine receptor type 4 (CXCR4) expression have been found in circulating neutrophils from healthy subjects, and these were proposed to correlate with neutrophil maturation and aging [36,37]. Moreover, as shown by flow cytometry analysis performed at different times of the day, the proportion of CXCR4 − CD62L + young and CXCR4 + CD62L − aged neutrophil populations among circulating neutrophils from healthy individuals has been shown to be regulated by circadian oscillations [37] (Figure 1).…”

“…In this mouse model, B cell depletion reduced apoptosis of aged neutrophils which then accumulated in the lung and induced interstitial inflammation and fibrosis [42]. Of note, this aging process is necessary for the circadian control of hematopoietic niche function and progenitor mobilization [41], while also enhancing neutrophil antimicrobial activity during host defense in a mouse model of Candida albicans infection [37]. Thus, neutrophil aging can favor migration to the tissue at night-time, and enhance the antimicrobial properties of neutrophils at the time of the day when mice are exposed to pathogens.…”

“…Under resting conditions, only terminally differentiated neutrophils are released into the circulation and recovered as normal-density neutrophils (NDNs) (Box 1) [54]. Current evidence suggests that different neutrophil subpopulations, defined by the indicated markers, are present in human blood under homeostatic conditions [5,6,8,21,30,36,37]. Under resting conditions, neutrophils are also marginated in pools within the lungs, spleen, and liver, but the phenotypes and functions of these cells remain poorly defined [5,6,9].…”

“…distinct subpopulations, namely preNeu (proliferative neutrophil precursor), immature, and mature neutrophils [33]. As observed in humans, based on differential surface marker expression, circulating mouse neutrophils exhibit heterogeneity that associates with distinct effector activities [5,37,[40][41][42][43]. In mice as in humans, neutrophils not only marginate in the spleen, liver, and lung vasculature but also transit and reside in other organs such as muscle, skin, lymph nodes, and intestine [44].…”

“…Similarly, the neutrophil 'aging' process is better documented in mice than in humans. After mobilization from the BM, circulating aged neutrophils upregulate CXCR4 and CD11b, and lose CD62L, before homing back to the BM, spleen, or liver for clearance [37,41] (Figure 1). Aged neutrophils are also retained in the lung, where they become apoptotic by interacting with B cells, a process that precedes their clearance by tissueresident macrophages [42].…”