Abstract
Conventional Ly6Chi monocytes have developmental plasticity for a spectrum of differentiated phagocytes. Here we show, using conditional deletion strategies in a mouse model of Toll-like receptor (TLR) 7-induced inflammation, that the spectrum of developmental cell fates of Ly6Chi monocytes, and the resultant inflammation, is coordinately regulated by TLR and Notch signaling. Cell-intrinsic Notch2 and TLR7-Myd88 pathways independently and synergistically promote Ly6Clo patrolling monocyte development from Ly6Chi monocytes under inflammatory conditions, while impairment in either signaling axis impairs Ly6Clo monocyte development. At the same time, TLR7 stimulation in the absence of functional Notch2 signaling promotes resident tissue macrophage gene expression signatures in monocytes in the blood and ectopic differentiation of Ly6Chi monocytes into macrophages and dendritic cells, which infiltrate the spleen and major blood vessels and are accompanied by aberrant systemic inflammation. Thus, Notch2 is a master regulator of Ly6Chi monocyte cell fate and inflammation in response to TLR signaling.
Highlights
Infectious agents or tissue injury trigger an inflammatory response that aims to eliminate the inciting stressor and restore internal homeostasis (J. Bonnardel & Guilliams, 2018)
Toll-like receptor 7 (TLR7) stimulation in the absence of functional Notch2 signaling promotes resident tissue macrophage gene expression signatures in monocytes and ectopic differentiation of Ly6Chi monocytes into macrophages and dendritic cells, which appear in the blood stream and infiltrate the spleen and major blood vessels, resulting in unrestrained systemic inflammation
Our data present a spectrum of developmental cell fates of Ly6Chi monocytes and their coordinated regulation by Toll-like receptor (TLR) and Notch signaling during inflammation
Summary
Infectious agents or tissue injury trigger an inflammatory response that aims to eliminate the inciting stressor and restore internal homeostasis (J. Bonnardel & Guilliams, 2018). Ly6Chi monocytes can convert to a second, minor subpopulation of monocytes with blood vessel patrolling behavior, in mice called Ly6Clo monocytes (Gamrekelashvili et al, 2016; Patel et al, 2017; Varol et al, 2007; Yona et al, 2013). These monocytes have a long lifespan and remain mostly within blood vessels, where they crawl along the luminal side of blood vessels to monitor endothelial integrity and to orchestrate endothelial repair (Auffray et al, 2007; Carlin et al, 2013; Getzin et al, 2018). We show that Notch signaling restrains TLR-driven inflammation by modulating Ly6Clo monocyte vs. macrophage cell fate decisions in inflammation
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