MSP-RON Signaling Pathway

A basic requirement of the immune response is that the host must be able to clear infections efficiently while minimizing damage caused to host tissues. Regulation of macrophage activity in response to inflammatory stimuli must be finely tuned to promote an effective immune response. Macrophage Stimulating Protein (MSP) acts through the transmembrane receptor kinase RON Protein Tyrosine Kinase/Receptor d'origine nantais to play a role in inflammation in response to tissue injury. The MSP protein has two receptor binding sites of different affinities: one on the α-chain and one on the β-chain. The receptor binding site on the α-chain of MSP interacts with the β-chain of RON receptor and stimulates ciliary motility in these cells.MSP is secreted by the liver into the blood as proMSP, an inactive precursor form which is then activated by tissue clotting factors such as FXIA, FXIIA and Klk. Binding of activated MSP to RON expressed on macrophages, monocytes and keratinocytes stimulates various second messenger pathways. Macrophages respond to MSP with changes in cell shape and motility, whereas keratinocytes respond by proliferating. LPS from gram negative bacteria and lipoteichoic acid from gram positive bacteria are recognized by the TLR4 and TLR2 receptors, respectively. Once activated, these receptors located on macrophages and neutrophils lead to the release of NO. Peritoneal neutrophils also produce superoxide which leads to liver cell injury. This phenomenon of Kupffer cell damage by NO or superoxide is known as 'peroxynitrite-induced liver damage'. MSP inhibits the expression of iNOS leading to the inhibition of NO and superoxide production. Thus liver damage is prevented.

MSP-induced complement mediated phagocytosis requires RON and the CR3 receptor(Integrin αM and Integrin β2). MSP stimulation of macrophages results in PI3K activity leading to activation of the atypical PKC-ζ. PKC-ζ is also activated by the CR3 receptor leading to MSP-induced CR3 mediated phagocytosis which is dependent on F-actin re-organization and phagocytic activity. MSP binding to RON also activates the RON Kinase function through auto-phosphorylation. Subsequently, pp90 is activated, bypassing JAK2 leading to morphological changes. MSP and RON receptor interaction also leads to the production of cytokines such as IL-12 and IFN-γ. These cytokines in turn activate NK cells and T cells resulting in phagocytic activity.