Interleukin-33 delays recovery of mucosal inflammation via downregulation of homeostatic ABCG5/8 in the colon

• Published in: Laboratory investigation 2020-03, Vol.100 (3), p.491-502
• Main Authors: Mishima, Yoshiyuki, Sonoyama, Hiroki, Ishihara, Shunji, Oshima, Naoki, Moriyama, Ichiro, Kawashima, Kousaku, Kinoshita, Yoshikazu
• Format: Article
• Language: English
• Subjects: 13/21; 38/77; 38/89; 45/61; 631/250/127/1213; 64/60; 692/699/1503/257; Animals; ATP Binding Cassette Transporter, Subfamily G, Member 5 - genetics; ATP Binding Cassette Transporter, Subfamily G, Member 5 - metabolism; ATP Binding Cassette Transporter, Subfamily G, Member 8 - genetics; ATP Binding Cassette Transporter, Subfamily G, Member 8 - metabolism; Caco-2 Cells; Cholesterol; Colon; Colon - metabolism; Colon - pathology; Cytokines; Dextran; Dextran sulfate; Dextrans; Down-Regulation; Gene expression; Homeostasis; Humans; Inflammation; Inflammation - metabolism; Inflammatory bowel disease; Interleukin 8; Interleukin-33 - genetics; Interleukin-33 - metabolism; Interleukins; Intestinal Mucosa - metabolism; Intestine; Laboratory Medicine; Lipoproteins - genetics; Lipoproteins - metabolism; Medicine; Medicine & Public Health; Mice; Mice, Inbred BALB C; Mucosa; Pathogenesis; Pathology; Recovery; siRNA; Small intestine; Therapeutic applications; Toll-like receptors; Ulcerative colitis
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/s41374-019-0329-3

Previous studies have suggested that interleukin-33 (IL-33) is involved in the pathogenesis of ulcerative colitis (UC), though the detailed mechanisms are not fully known. We investigated IL-33-mediated colonic homeostasis using a mechanistic method. Il33−/− mice were more tolerant to dextran sulfate sodium-induced acute colitis than the wild type and also showed delayed recovery from colitis with recombinant IL-33 (rIL-33) administration. Unexpectedly, microarray analysis identified significant downregulation of the Abcg5/8 genes in mouse colons following rIL-33 treatment. ABCG5/8 are known cholesterol transporters in the small intestine and liver, though their colon activities have not been elucidated, thus their role in IL-33-mediated inflammation was investigated. In vitro, toll-like receptor (TLR) stimulation upregulated ABCG5/8 mRNA expression in Caco2 and HCT-15 cells, with subsequent downregulation by rIL-33, while inhibition of ABCG5/8 along with their siRNA increased TLR-stimulated IL-8 production. Together, these results indicated that colonic ABCG5/8 play a regulatory role in TLR-induced inflammation, while histological inflammation in human UC was correlated positively with the level of mucosal IL-33 and inversely with that of colonic ABCG5/8. This is the first report of IL-33-mediated downregulation of colonic ABCG5/8 in a colitis recovery phase, indicating their involvement in UC pathogenesis and potential as a therapeutic target.