Uncovering the Impact of S1PR1 Mutation in the Cystic Fibrosis

Background. Predicting the outcomes of Pseudomonas aeruginosa infections in people with cystic fibrosis (CF) is challenging due to their variable severity, ranging from mild to life-threatening pulmonary conditions. To address this variability and explore genetic modifiers beyond CFTR, our prior research in a genetically diverse mouse population identified sphingosine 1-phosphate receptor 1 (S1PR1) as a promising candidate associated with P. aeruginosa infection. Here, we uncover the impact of S1PR1 in the CF airway epithelium. Methods. We established a novel model system through CRISPR/Cas9 gene editing of S1PR1 in bronchial cell lines, both in the presence (C38) and absence of CFTR mutations (IB3-1). We examined the impact of S1PR1 on cytotoxicity and inflammatory responses. Our findings were validated by assessing lungs of people with CF in comparison with non-CF subjects. Results. Stimulation with P. aeruginosa exoproducts resulted in decreased cell survival in both C38-CFTR+/+ and IB3-1-CFTR-/- cell lines. The presence of CFTR mutation significantly influenced these differences, with S1PR1 exacerbating the effect. Mutation of S1PR1, in conjunction with a CFTR mutation, caused the protein to be relocated within the peri-nuclear cytoplasmic region. Immunohistochemistry analysis further demonstrated a substantial reduction in S1PR1 protein expression in the lungs of people with CF compared to non-CF. Conclusions. These findings implicate S1PR1 as involved in CF.