MSP-RON Pathway: Potential Regulator of Inflammation and Innate Immunity

Abstract

Macrophage-stimulating protein (MSP), a soluble protein mainly synthesized by the liver, is the only known ligand for recepteur d'origine nantais (RON), which is a member of the MET proto-oncogene family. Recent studies show that the MSP-RON signaling pathway not only was important in tumor behavior but also participates in the occurrence or development of many immune system diseases. Activation of RON in macrophages results in the inhibition of nitric oxide synthesis as well as lipopolysaccharide (LPS)-induced inflammatory response. MSP-RON is also associated with chronic inflammatory responses, especially chronic liver inflammation, and might serve as a novel regulator of inflammation, which may affect the metabolism in the body. Another study provided evidence of the relationship between MSP-RON and autoimmune diseases, suggesting a potential role for MSP-RON in the development of drugs for autoimmune diseases. Moreover, MSP-RON plays an important role in maintaining the stability of the tissue microenvironment and contributes to immune escape in the tumor immune microenvironment. Here, we summarize the role of MSP-RON in immunity, based on recent findings, and lay the foundation for further research.

Keywords: MSP; RON; autoimmune disease; inflammation; innate immunity; macrophage.

Figure 1

Timeline. In this figure, we illustrate the timeline of MSP-RON discovery and its role in inflammation and innate immunity.

Figure 2

Signaling pathways activated by MSP and RON. MSP induces RON dimerization and activates downstream pathways (13). In macrophages, the activation of RON inhibits iNOS through the AKT pathway and reduces NO synthesis (10). RON activation stimulates SHP expression through the MAPK and AMPK pathways, which can antagonize the TLR4 pathway by inhibiting TRAF6 ubiquitination and preventing NF-κB from entering the nucleus, thus reducing cytokine production (39). Besides, increased expression of SHP through activation of the MSP-RON pathway can inhibit NLRP3 inflammasome activation, thereby inhibiting cleavage of pro-IL-1β into activated IL-1β (40). MSP-RON activation also inhibits CIITA transcription and, thus, MHC II expression via the MAPK pathway (41).