Osteopontin Deficiency Accelerates Spontaneous Colitis in Mice with Disrupted Gut Microbiota and Macrophage Phagocytic Activity.
BACKGROUND
Osteopontin (OPN) is a multifunctional protein expressed in a variety of tissues and cells. Recent studies revealed increased OPN expression in the inflamed intestinal tissues of patients with inflammatory bowel disease (IBD). The role of OPN in the pathophysiology of IBD, however, remains unclear.


OBJECTIVE
To investigate the role of OPN in the development of intestinal inflammation using a murine model of IBD, interleukin-10 knock out (IL-10 KO) mice.


METHODS
We compared the development of colitis between IL-10 KO and OPN/IL-10 double KO (DKO) mice. OPN expression in the colonic tissues of IL-10 KO mice was examined by fluorescence in situ hybridization (FISH) analysis. Enteric microbiota were compared between IL-10 KO and OPN/IL-10 DKO mice by terminal restriction fragment length polymorphism analysis. The effect of OPN on macrophage phagocytic function was evaluated by phagocytosis assay.


RESULTS
OPN/IL-10 DKO mice had an accelerated onset of colitis compared to IL-10 KO mice. FISH analysis revealed enhanced OPN synthesis in the colonic epithelial cells of IL-10 KO mice. OPN/IL-10 DKO mice had a distinctly different enteric bacterial profile with a significantly lower abundance of Clostridium subcluster XIVa and a greater abundance of Clostridium cluster XVIII compared to IL-10 KO mice. Intracellular OPN deletion in macrophages impaired phagocytosis of fluorescence particle-conjugated Escherichia coli in vitro. Exogenous OPN enhanced phagocytosis by OPN-deleted macrophages when administered at doses of 1 to 100 ng/ml, but not 1000 ng/ml.


CONCLUSIONS
OPN deficiency accelerated the spontaneous development of colitis in mice with disrupted gut microbiota and macrophage phagocytic activity.
Department of Gastroenterology and Hepatology, Kansai Medical University, Hirakata, Osaka, Japan.
Takahiko
T
Toyonaga
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
Hiroshi
H
Nakase
Department of Internal medicine, Takashima Municipal Hospital, Takashima, Shiga, Japan.
Satoru
S
Ueno
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
Minoru
M
Matsuura
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
Takuya
T
Yoshino
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
Yusuke
Y
Honzawa
Nutritional Science Institute, Morinaga Milk Industry Co., Ltd, Zama, Kanagawa, Japan.
Ayako
A
Itou
Nutritional Science Institute, Morinaga Milk Industry Co., Ltd, Zama, Kanagawa, Japan.
Kazuyoshi
K
Namba
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
Naoki
N
Minami
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
Satoshi
S
Yamada
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
Yorimitsu
Y
Koshikawa
Department of Matrix Medicine, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.
Toshimitsu
T
Uede
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
Tsutomu
T
Chiba
Department of Gastroenterology and Hepatology, Kansai Medical University, Hirakata, Osaka, Japan.
Kazuichi
K
Okazaki
D000818:Animals; D003092:Colitis / Q000209:etiology* / Q000382:microbiology; D004195:Disease Models, Animal; D000069196:Gastrointestinal Microbiome / Q000235:genetics*; D015212:Inflammatory Bowel Diseases / Q000209:etiology; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000502:physiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053495:Osteopontin / Q000172:deficiency* / Q000378:metabolism; D010587:Phagocytosis
C556062:IL10 protein, mouse; C506896:Spp1 protein, mouse; D053495:Osteopontin; D016753:Interleukin-10