CSI granuloma -Cell-type specific interactions in granulomas

Granulomatous inflammation can occur in multiple organs and body parts and is characterized by compact aggregates of immune cell infiltrates. Typically, granulomas are surrounded by tissue- resident structural cells such as fibroblasts. In fact, granulomas are often circumscribed by concentric scar tissue, which is deposited by fibroblasts. This progressive tissue fibrosis and scarring can result in the disruption of organ function, thus posing a major burden to affected individuals and the healthcare system in general. Sarcoidosis is among the disorders characterized by chronic granulomatous inflammation in multiple tissues and body parts, with progression towards lung fibrosis associated with a substantial increase in morbidity and mortality of affected individuals. Accordingly, a better understanding of the fundamental mechanisms governing granulomatous inflammation is of direct clinical relevance. Despite the major influence of immune cells on granulomatous disease pathogenesis, the detrimental role of structural cells in tissues affected by granulomas is increasingly appreciated. However, due to the lack of (i) reliable granuloma models and (ii) cell interaction networks of granulomas, the role of structural cells on immune cell activation and aggregation remains to be answered. This proposal suggests a combined cell biological and immunological approach to provide a quantitative understanding of the molecular and cellular principles underlying granuloma formation and maintenance. We will focus on analyzing the prototypic cell type-specific interactions between immune cells and structural cells to identify the strongest disease-driving cell circuits using unbiased system-wide transcriptomic analyses of available biopsies from patients affected by sarcoidosis. We will then test the effect of ligand-receptor interactions on granuloma formation and maintenance in vitro to identify the key mediators of immune cell-structural cell interactions in granulomas. Technically, these questions will be addressed in a multidisciplinary approach encompassing unbiased system-wide, single-cell transcriptomic analyses combined with human tissue bioengineering and high resolution microscopy. Results of this project will generate an integrated view of how cell-cell interactions drive granulomatous inflammation and will not only impact the field of sarcoidosis research but also reach out to other granulomatous diseases and cancer.