RORα Induces KLF4-Mediated M2 Polarization in the Liver Macrophages that Protect against Nonalcoholic Steatohepatitis

Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Yong-Hyun Han, Hyeon-Ji Kim, Hyelin Na, Min-Woo Nam, Ju-Yeon Kim, Jun-Seok Kim, Seung-Hoi Koo, Mi-Ock Lee
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.

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Teaser

Han et al. find that RORα is a key regulator of M1/M2 polarization in liver macrophages. Myeloid-specific knockout of RORα display decreased M2/M1 ratio in Kupffer cells and enhanced susceptibility to nonalcoholic steatohepatitis. This function of RORα may suggest therapeutic strategies for nonalcoholic steatohepatitis.


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