Fth1-mScarlet Reports Monocyte State during Lipopolysaccharide-induced Lung Inflammation

Abstract

Monocytes and macrophages are central to host defense but also contribute to inflammation-associated pathology. Efforts to manipulate monocyte and macrophage function are limited by our ability to effectively quantify the functional programs of these cells. We identified the gene Fth1, which encodes the ferritin H chain, as highly predictive of alveolar macrophage transcriptomic states during LPS-induced lung inflammation and developed an Fth1-mScarlet reporter mouse. In the steady-state lung, high Fth1-mScarlet expression is restricted to alveolar macrophages. In response to LPS-induced lung inflammation, Fth1 reporter activity is robustly increased in monocytes, with its expression reporting genes that are differentially expressed in monocytes versus macrophages. Consistent with this reporter-associated gene profile, within the Lyz2-GFP+CD11b+Ly6C+ gate, the highest Fth1 reporter expression was observed in CD11c+ cells, indicative of monocyte-to-macrophage differentiation. Although Fth1-mScarlet was induced in monocytes responding to either TLR4 ligation or M-CSF-induced macrophage differentiation in vitro, TLR4-dependent expression occurred with greater speed and magnitude. Considering this, we suggest that Fth1-mScarlet expression reports monocyte-to-macrophage differentiation, with increased expression in proinflammatory states. Dissecting macrophage differentiation from inflammatory programs will be enhanced when combining Fth1-mScarlet with other reporter systems. Thus, the Fth1-mScarlet model addresses an important lack of tools to report the diverse spectrum of monocyte and macrophage states in vivo.