Studying Macrophage Phenotype and Function in Slowly Progressing Models of PKD

Background: Macrophages have been associated with the progression of polycystic kidney disease (PKD) for several decades. While data suggest that macrophages promote cyst progression through the production of pro-inflammatory cytokines, the majority of data supporting this paradigm were collected using rapidly progressing mouse models of disease. The phenotype and function of macrophages in slowly progressing forms of the disease remain poorly understood. Methods: To understand how the rate of PKD progression impacts macrophage phenotype and function, we generated a comprehensive single-cell RNA sequencing (scRNAseq) atlas of kidney resident macrophages (KRM) isolated from slowly and rapidly progressing models of PKD as well as non-cystic controls. Results: Using single-cell RNA sequencing (scRNAseq), our lab identified a subset of kidney resident macrophages (KRM), termed Trem2+ cyst associated macrophages (CAM), that were highly enriched in slowly progressing mouse models when compared to rapidly progressing models and non-cystic controls. Trem2+ CAM had an enrichment of genes associated with phagocytosis and the lysosome. Functional analyses indicate that Trem2+ CAM also had enriched lysosomal activity compared to total KRM and were located adjacent to apoptotic cystic epithelium, suggesting these cells may be restricting PKD progression through phagocytosis and lysosomal degradation of the apoptotic cystic epithelium (efferocytosis). To test this hypothesis, we crossed two PKD mouse models (Ift88 and Pkd1RC/RC) to the Trem2-/- background. Analysis of preliminary data indicate that loss of Trem2 significantly worsened cystic disease as measured by 2KW/BW and BUN. Further, loss of Trem2 resulted in increased apoptotic cystic epithelium. Conclusion: Collectively, our data suggest that Trem2+ CAM restrict cyst progression through phagocytosis and lysosomal degradation of the apoptotic cystic epithelium. Funding: NIDDK Support, Private Foundation Support