Panoply™ Human MERTK Over-expressing Stable Cell Line

Acute-on-chronic liver failure (ACLF) is a severe disease with a very high mortality rate. Macrophage-related inflammation plays a crucial role in the development and progression of ACLF. Previous studies have shown that mesenchymal stem cell (MSC) therapy is beneficial for ACLF; however, the underlying mechanisms remain unclear. Therefore, researchers treated an ACLF mouse model with murine bone marrow-derived mesenchymal stem cells or co-cultured them with LPS-stimulated RAW264.7/J774A.1 macrophages. They analyzed histological and serological indicators as well as survival rates to evaluate the efficacy. The researchers also examined changes in Mer tyrosine kinase (Mertk), JAK1/STAT6, inflammatory cytokines, and macrophage polarization markers in vitro and in vivo. In ACLF mice, MSCs improved liver function, increased the 48-hour survival rate of ACLF mice, and alleviated inflammatory damage by promoting M2 macrophage polarization and increasing the expression level of Mertk in macrophages. This is significant because Mertk regulates M2 macrophage polarization through the JAK1/STAT6 signaling pathway.

To elucidate the relationship between Mertk and macrophage polarization, researchers constructed Mertk-overexpressing RAW264.7 cells. The results showed an increased protein expression level of the M2 marker Arg-1 (Figure 1A-C). Furthermore, Mertk expression was positively correlated with the expression of anti-inflammatory cytokines (such as TGF-β and IL-10) (Figure 1D) and negatively correlated with the expression of pro-inflammatory cytokines (such as INF-γ, TNF-α, IL-1β, and IL-6) (Figure 1D). Therefore, Mertk promotes M2 macrophage polarization. Next, the researchers evaluated the mechanism by which Mertk regulates this polarization. Bioinformatics analysis indicated that the JAK/STAT signaling pathway might play a key role. Previous studies have shown that TAM receptor activation may be related to the phosphorylation of Jak1. They detected the protein phosphorylation levels of JAK1, JAK2, JAK3, STAT1, STAT2, STAT3, STAT4, STAT5, and STAT6, as well as the mRNA expression levels of JAK2, JAK3, and Tyk2, and found that Mertk expression was positively correlated with the expression of pJAK1 and pSTAT6 (Figure 1E-G). Subsequently, the researchers intervened by adding a JAK1 inhibitor to Mertk-overexpressing RAW264.7 cells, and the cytokine levels did not change significantly. This indicates that Mertk regulates M2 macrophage polarization through the JAK1/STAT6 signaling pathway (Figure 1D).

Figure 1. Mertk promotes M2 macrophage polarization via Mertk/JAK1/STAT6 signaling in cultured cells. (Li Z H, et al., 2023)