The fate and lifespan of human monocyte subsets in steady state and systemic inflammation.

Amit A Patel,Becca Asquith,Richard A Flavell,Yan Zhang,Simon Yona,Venetia Bigley,Derek Macallan,Lies Boelen,James N Fullerton,Derek W Gilroy,Anthony Rongvaux,Alexander A Maini

doi:10.1084/jem.20170355

Abstract

In humans, the monocyte pool comprises three subsets (classical, intermediate, and nonclassical) that circulate in dynamic equilibrium. The kinetics underlying their generation, differentiation, and disappearance are critical to understanding both steady-state homeostasis and inflammatory responses. Here, using human in vivo deuterium labeling, we demonstrate that classical monocytes emerge first from marrow, after a postmitotic interval of 1.6 d, and circulate for a day. Subsequent labeling of intermediate and nonclassical monocytes is consistent with a model of sequential transition. Intermediate and nonclassical monocytes have longer circulating lifespans (∼4 and ∼7 d, respectively). In a human experimental endotoxemia model, a transient but profound monocytopenia was observed; restoration of circulating monocytes was achieved by the early release of classical monocytes from bone marrow. The sequence of repopulation recapitulated the order of maturation in healthy homeostasis. This developmental relationship between monocyte subsets was verified by fate mapping grafted human classical monocytes into humanized mice, which were able to differentiate sequentially into intermediate and nonclassical cells.

Highlights

The mononuclear phagocyte system comprises three types of cells: monocytes, macrophages, and DCs, as well as their committed bone marrow progenitors
Characterization of human monocyte subset kinetics under steady state The literature has not always clearly distinguished between monocyte subsets, making interpretation confusing.We chose to follow a systematic strategy to identify the three conventional monocyte subsets of interest
In addition to CD14 and CD16 expression, we confirmed additional membrane marker expression between monocyte subsets (Fig. 1 b and Fig.S1 a;Ingersoll et al.,2010).Interestingly,these data demonstrate the discrete nature of monocyte subsets is a continuum of more than just CD14 and CD16 expression

Summary

Introduction

The mononuclear phagocyte system comprises three types of cells: monocytes, macrophages, and DCs, as well as their committed bone marrow progenitors (van Furth et al, 1972; Yona and Gordon, 2015).

Results

Conclusion