Potential Role of Heme Oxygenase-1 in the Resolution of Experimentally Induced Colitis through Regulation of Macrophage Polarization
Shin-Young Gwak,
Su-Jung Kim,
Jeongmin Park,
Seung Hyeon Kim,
Yeonsoo Joe,
Ha-Na Lee,
Wonki Kim,
Ishrat Aklima Muna,
Hye-Kyung Na,
Hun Taeg Chung,
Young-Joon Surh
Affiliations
Shin-Young Gwak
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul, Korea
Su-Jung Kim
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea
Jeongmin Park
Department of Biological Sciences, University of Ulsan, Ulsan, Korea
Seung Hyeon Kim
Cancer Research Institute, Seoul National University, Seoul, Korea
Yeonsoo Joe
Department of Biological Sciences, University of Ulsan, Ulsan, Korea
Ha-Na Lee
Laboratory of Immunology, Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD,
Wonki Kim
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea
Ishrat Aklima Muna
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea
Hye-Kyung Na
Department of Food Science and Biotechnology, College of Knowledge-Based Services Engineering, Sungshin Women’s University, Seoul, Korea
Hun Taeg Chung
Department of Biological Sciences, University of Ulsan, Ulsan, Korea
Young-Joon Surh
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul, Korea
Background/Aims: Heme oxygenase-1 (HO-1) plays a central role in cellular defense against inflammatory insults, and its induction in macrophages potentiates their efferocytic activity. In this study, we explored the potential role of macrophage HO-1 in the resolution of experimentally induced colitis. Methods: To induce colitis, male C57BL/6 mice were treated with 2% dextran sulfate sodium (DSS) in the drinking water for 7 days. To investigate efferocytosis, apoptotic colon epithelial CCD 841 CoN cells were coincubated with bone marrow-derived macrophages (BMDMs). Results: Administration of the HO-1 inhibitor zinc protoporphyrin IX (ZnPP) blunted the resolution of DSS-induced intestinal inflammation and expression of the proresolving M2 macrophage marker CD206. BMDMs treated with apoptotic colonic epithelial cells showed significantly elevated expression of HO-1 and its regulator Nrf2. Under the same experimental conditions, the proportion of CD206-expressing macrophages was also enhanced. ZnPP treatment abrogated the upregulation of CD206 expression in BMDMs engulfing apoptotic colonic epithelial cells. This result was verified with BMDMs isolated from HO-1-knockout mice. BMDMs, when stimulated with lipopolysaccharide, exhibited increased expression of CD86, a marker of M1 macrophages. Coculture of lipopolysaccharide-stimulated BMDMs with apoptotic colonic epithelial cell debris dampened the expression of CD86 as well as the pro-inflammatory cytokines in an HO-1-dependent manner. Genetic ablation as well as pharmacologic inhibition of HO-1 significantly reduced the proportion of efferocytic BMDMs expressing the scavenger receptor CD36. Conclusions: HO-1 plays a key role in the resolution of experimentally induced colitis by modulating the polarization of macrophages.
