Date Published: August 17, 2016
Publisher: Public Library of Science
Author(s): Jon Kibbie, Rosane M. B. Teles, Zhiming Wang, Patrick Hong, Dennis Montoya, Stephan Krutzik, Seung Lee, Ohyun Kwon, Robert L. Modlin, Daniel Cruz, Christopher M. Sassetti.
As circulating monocytes enter the site of disease, the local microenvironment instructs their differentiation into tissue macrophages (MΦ). To identify mechanisms that regulate MΦ differentiation, we studied human leprosy as a model, since M1-type antimicrobial MΦ predominate in lesions in the self-limited form, whereas M2-type phagocytic MΦ are characteristic 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 MΦ. However, biochemical screens identified that IFN-γ and two families of small molecules activated EC to induce monocytes to differentiate into M1 MΦ. 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 MΦ 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 MΦ was JAG1-dependent and the addition of JAG1 to quiescent EC facilitated monocyte differentiation into M1 MΦ with antimicrobial activity against M. leprae. Our findings indicate a potential role for the IFN-γ-JAG1 axis in instructing MΦ differentiation as part of the host defense response at the site of disease in human leprosy.
When circulating monocytes enter the site of disease, local cues from the tissue microenvironment direct their differentiation into specialized MΦ equipped for diverse tasks [1–3]. While classically activated M1 MΦ with antimicrobial activity promote host defense against intracellular pathogens, alternatively activated (M2) MΦ perform homeostatic functions including phagocytosis critical to tissue remodeling [1–6]. In leprosy, the divergence of MΦ functional programs correlate with the clinical disease spectrum [7–9]. In the self-limited, tuberculoid (T-lep) form of leprosy, disease lesions contain well-organized granulomas with M1 MΦ, expressing the MΦ marker CD209, but negative for the haptoglobin receptor CD163, yet armed with antimicrobial effector function . By contrast, in the progressive, lepromatous (L-lep) form of leprosy, patient lesions are characterized by disorganized granulomas containing MΦ which co-express CD209 and CD163 but lack antimicrobial activity. Instead, these MΦ are programmed with phagocytic function, which results in the accumulation of host-derived lipids and favors mycobacterial growth [10, 11], and are therefore referred to as M2 MΦ. These data raise the question regarding the mechanisms by which clues from the microenvironment influence MΦ programming at the site of infection.
Given the critical role the microvasculature plays in the transmigration of circulating leukocytes, it is poised to deliver instructive cues to monocytes entering the site of disease [12, 14, 15]. To investigate how the microvasculature, specifically EC, influence MΦ differentiation, we chose leprosy as a model, focusing on M1 and M2 MΦ that expressed CD209, and the relative expression of CD163, either low and high, reflecting the major MΦ phenotypes at the site of disease and endowed with distinct functional programs. We hypothesized that a resting microenvironment leads EC to instruct monocyte differentiation into M2 MΦ with phagocytic function; whereas, perturbations in the local microenvironment may direct monocytes to differentiate into M1 MΦ with antimicrobial activity (Fig 1A).
Our understanding of MΦ immunobiology has been significantly advanced through understanding of the pathways by which microbial ligands and/or cytokines program monocytes to differentiate into M1 and M2 MΦ [27, 28]. However, it is not clear how local tissue signals can differentially program the MΦ response. Signals from endothelium are involved; this default pathway triggers M2 MΦ differentiation . However, the mechanisms by which monocytes, upon entering the site of disease via the endothelium, are instructed to differentiate into M1 MΦ remain elusive [1–3]. Here, we hypothesized that if EC were to encounter the proper signals, the EC microenvironment would instruct monocytes to differentiate into M1 MΦ, equipped for host defense against intracellular pathogens at the site of disease. By studying leprosy as a model, we provide evidence that upregulation of JAG1 on endothelium instructs monocytes to differentiate into M1 MΦ with antimicrobial activity.