Colonic epithelial exposure to heavy metals results in a chemokine response to recruit monocytes and macrophages 4306

Abstract Description Background The intestinal epithelium and lamina propria immune system must work in concert to respond to luminal cues, infection or injury to maintain intestinal homeostasis. One example is the recruitment of immune cells to the site of injury in part through the secretion of chemokines by the gut epithelium. Given uranium is detectable in two-thirds of the US community water system, we set out to understand the effects of heavy metals on the colonic epithelium using human intestinal organoids. Here, we report how uranium links colonic epithelial cells to the mucosal immune environment via the production of chemokines. STUDY DESIGN: Human colonic organoids from three biologically distinct donors were generated from endoscopic biopsies. Organoids were acutely exposed to uranium then digested for single cell RNA sequencing (scRNA-seq). Further downstream analysis was performed using Cytosig to define the molecular changes in chemokine and cytokine responses. Validation in colonic organoids were assessed using morphological and imaging techniques. Results scRNA-seq and Cytosig analysis revealed uranium exposures results in the increased expression of CCL2 (Monocyte Chemoattractant Protein-1) and CCL7 (Monocyte Chemoattractant Protein-3). This was further validated by immunofluorescence. Conclusion Our findings indicate uranium exposures promotes the upregulation of the chemokines CCL2 and CCL7 that likely recruits monocytes and macrophages for wound healing. Funding Sources NIH 1R01ES034400-01A1, 5P42ES025589-08 9941, 2K12GM088021-16 Topic Categories Mucosal and Regional Immunology (MUC)