The regulation of M1/M2 polarization in liver macrophages is closely associated with the progression of nonalcoholic steatohepatitis (NASH); however, the mechanism involved in this process remains unclear. Here, we describe the orphan nuclear receptor retinoic-acid-related orphan receptor α (RORα) as a key regulator of M1/M2 polarization in hepatic residential Kupffer cells (KCs) and infiltrated monocyte-derived macrophages. RORα enhanced M2 polarization in KCs by inducing the kruppel-like factor 4. M2 polarization was defective in KCs and bone-marrow-derived macrophages of the myeloid-specific RORα null mice, and these mice were susceptible to HFD-induced NASH. We found that IL-10 played an important role in connecting the function of M2 KCs to lipid accumulation and apoptosis in hepatocytes. Importantly, M2 polarization was controlled by a RORα activator, JC1-40, which improved symptoms of NASH. Our results suggest that the M2-promoting effects of RORα in liver macrophages may provide better therapeutic strategies against NASH.
Bibliographical noteFunding Information:
This work was supported by grants from the Bio and Medical Technology Development Program (2012M3A9B6055338), the Korea Mouse Phenotyping Project (NRF-2014M3A9D5A01073556), and the National Research Foundation of Korea (2017R1A2B3011870). We thank the Institut Clinique de la Souris for establishment of the RORαfl/fl mouse mutant line.
© 2017 The Authors
- Kupffer cells
- M2 polarity
- non-alcoholic steatohepatitis
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)