Tissue-specific regulatory role of Sorting Nexin 27 in the intestinal inflammation

Abstract

The sorting nexin (SNX) family involves in endocytosis and protein trafficking. SNX27 specifically binds and directs the sorting transmembrane proteins containing PDZ-binding motif and is critical in protein-protein interactions in various organs. While SNX27 has been studied in neurological disorders, the tissue-specific role of SNX27 in intestinal health and disease remains unexplored. We conditionally deleted the SNX27 gene from intestine epithelial cells (SNX27 ΔIEC ) and myeloid cells (SNX27 ΔLyz ) by crossing the SNX27 Loxp mice with Villin-cre mice and Lyz-cre mice, respectively. The basic phenotypes and functional alterations were evaluated. To investigate their susceptibility to inflammations and colitis-associated cancer, mice were challenged in dextran sulfate sodium (DSS)-induced colitis and azoxymethane (AOM)/DSS-induced cancer models. We validated the loss of SNX27 in these cells by PCR and Western blots. We established the conditional deletion of SNX27 from the IECs and myeloid cells in mice, which is the first report to our knowledge. At the basal level, the SNX27 ΔIEC and SNX27 ΔLyz mice (10 weeks old) showed slightly lower body weight compared to the SNX27 Loxp mice, but no intestinal pathological symptoms, e.g., diarrhea and bloody stools. SNX27 ΔLyz mice (24-week old) had significantly longer colon and small intestine, heavier liver and spleen, compared with the age-matched SNX27 Loxp mice. Abnormal secretory cells, Paneth cells and Goblet cells, were observed in the small intestine of SNX27 ΔIEC mice, indicated by the low expression of Lysozyme and Muc-2. More importantly, the inflammatory responses of two mouse models were different. The SNX27 ΔIEC mice were more susceptible to DSS-induced colitis. DSS-SNX27 ΔIEC mice showed significantly more bodyweight loss, shorter colon and small intestine, and higher intestine permeability. In contrast, SNX27 ΔLyz mice were more resistant to the DSS treatment, compared with the SNX27 ΔIEC and SNX27 Loxp mice. In the AOM/DSS model, more tumors and bodyweight loss were found in SNX27 ΔIEC mice. The experiment ended early (11 weeks post-treatment) due to earlier onset of tumors and death in SNX27 ΔIEC mice (18-19 weeks old). The AOM/DSS-SNX27 ΔLyz mice showed less sensitivity compared to the SNX27 ΔIEC mice. Larger tumors were developed in SNX27 ΔLyz mice, compared to the SNX27 Loxp mice at 16 weeks post-treatment. A significantly larger spleen and liver were found in the SNX27 ΔLyz mice, indicating the importance of SNX27 in the immune system. The susceptibility of SNX27 ΔIEC mice to inflammations and colitis-associated colon may be due to the important role for SNX27 in intestinal barriers through epithelial tight junctions and secretory cells. Here, we highlight the different tissue-specific roles of SNX27 in maintaining intestinal homeostasis and preventing inflammation and colon cancer. Our study will provide new insights into the functions of a sorting nexin protein in intestinal disorders. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.