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Exploration of Endothelial Cell Directed Innate Immunity in Leprosy

  • Author(s): Kibbie, Jon J.
  • Advisor(s): Modlin, Robert L
  • et al.
Abstract

As an initial point of contact with circulating innate immune precursor cells, the endothelium is poised to deliver instructive signals that influence innate immune cell activation and differentiation. In an attempt to study the endothelial innate immune interaction during an inflammatory state we developed a novel bioassay that identified activated endothelium by its capacity to trigger macrophage inflammatory protein 1 beta (MIP1b from primary monocytes. After screening a small molecule library consisting of 642 compounds, we identified two structurally unique chemical families that were able to specifically activate the endothelium. Structure-function analysis combined with transcriptional profiling identified inflammatory gene networks induced exclusively by the active compounds and allowed us to further identify important regulators of endothelial activation.

With the discovery of these unique endothelial activators we sought to further characterize the CD209 positive macrophage populations arising from this interaction. As seen in human leprosy, a stark spatial distribution of CD209 positive macrophage (MF) subsets is

linked to the fate of the host and pathogen. We recapitulated divergent CD209 positive MF subsets through primary cell co-culture phenotypic screens, identifying perturbations that licensed the endothelial microenvironment to skew monocytes towards the CD209 positive and CD163 negative MF; subset that is equipped for host defense. Transcriptional profiling of endothelial cells polarized by these structurally diverse activators revealed a subset of mutually regulated genes, and integration with the transcriptome profiles from leprosy lesions led to the discovery that jagged1 (JAG1) expression strongly correlates with the spatial distribution of CD209 positive MF; subsets at the site of disease. These findings suggest that soluble JAG1 may facilitate antimycobacterial human innate immune responses.

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