Background: BTB and CNC homolog 1 (Bach1) is a transcriptional repressor of heme oxygenase-1 (HO-1), which plays an important role in the protection of cells and tissues against acute and chronic inflammation. However, the role of Bach1 in the gastrointestinal mucosal defense system remains little understood. HO-1 supports the suppression of experimental colitis and localizes mainly in macrophages in colonic mucosa. This study was undertaken to elucidate the Bach1/HO-1 system's effects on the pathogenesis of experimental colitis.
Methods: This study used C57BL/6 (wild-type) and homozygous Bach1-deficient C57BL/6 mice in which colonic damage was induced by the administration of an enema of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Subsequently, they were evaluated macroscopically, histologically, and biochemically. Peritoneal macrophages from the respective mice were isolated and analyzed. Then, wild-type mice were injected with peritoneal macrophages from the respective mice. Acute colitis was induced similarly.
Results: TNBS-induced colitis was inhibited in Bach1-deficient mice. TNBS administration increased the expression of HO-1 messenger RNA and protein in colonic mucosa in Bach1-deficient mice. The expression of HO-1 mainly localized in F4/80-immunopositive and CD11b-immunopositive macrophages. Isolated peritoneal macrophages from Bach1-deficient mice highly expressed HO-1 and also manifested M2 macrophage markers, such as Arginase-1, Fizz-1, Ym1, and MRC1. Furthermore, TNBS-induced colitis was inhibited by the transfer of Bach1-deficient macrophages into wild-type mice.
Conclusions: Deficiency of Bach1 ameliorated TNBS-induced colitis. Bach1-deficient macrophages played a key role in protection against colitis. Targeting of this mechanism is applicable to cell therapy for human inflammatory bowel disease.
Article first published online 26 February 2013
*Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
†Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe-City, Japan
‡Department of Biochemistry, Tohoku University School of Medicine and CREST, Japan Science and Technology Agency, Sendai, Japan.
Reprints: Yuji Naito, MD, PhD, Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan (e-mail: firstname.lastname@example.org).
Supported by Grants-in-Aid for Scientific Research (B) to T. Yoshikawa (no. 21390184), (C) to Y. Naito (no. 22590705), and (C) to T. Takagi (no. 22590706) from the Japan Society for the Promotion of Science, and by a City Area Program to T. Yoshikawa and Y. Naito from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and by an Adaptable and Seamless Technology Transfer Program through target-driven R&D to Y. Naito from the Japan Science and Technology Agency.
The authors have no conflicts of interest to disclose.
Received June 21, 2012
Accepted July 05, 2012