Differentiation

Abstract

As circulating monocytes enter the site of disease, the local microenvironment instructs their differentiation into tissue macrophages (M Φ ). To identify mechanisms that regulate M Φ differentiation, we studied human leprosy as a model, since M1-type antimicrobial M Φ predominate in lesions in the self-limited form, whereas M2-type phagocytic M Φ are charac-teristic of the lesions in the progressive form. Using a heterotypic co-culture model, we found that unstimulated endothelial cells (EC) trigger monocytes to become M2 M Φ . How-ever, biochemical screens identified that IFN- γ and two families of small molecules activated EC to induce monocytes to differentiate into M1 M Φ . The gene expression profiles induced in these activated EC, when overlapped with the transcriptomes of human leprosy lesions, identified Jagged1 (JAG1) as a potential regulator of M Φ differentiation. JAG1 protein was preferentially expressed in the lesions from the self-limited form of leprosy, and localized to the vascular endothelium. The ability of activated EC to induce M1 M Φ was JAG1-dependent and the addition tuberculoid leprosy. These differences in the immune response can be characterized by the phenotype and activation state of the macrophage. We illustrate how the local endothelial microenvironment can “ educate ” macrophages, identifying Jagged1 and select small molecules that can regulate this pathway. Therefore, these studies identify a potential strategy to intervene in infection and inflammation, by targeting macrophage instruction at the site of disease. Through the integration of in vitro modeling and gene expression profiles at the site of disease, we found that Jagged 1 harnesses the endothelial microenvironment to instruct antimicrobial macrophage responses in leprosy.