MSP-RON Signaling
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MSP-RON Signaling

One of the basic aspects of the immune response is that the host must be able to clear infections efficiently, while minimizing damage caused to host tissues and regulation of macrophage activities in response to inflammatory stimuli must be finely tuned to promote an effective immune response. MSP (Macrophage Stimulating Protein) acts through the transmembrane receptor kinase RON (RON Protein Tyrosine Kinase/Receptor d’origine nantais) to play a role in inflammation, in response to tissue injury (Ref.1 & 2). RON is expressed on the ciliated epithelia of the mucociliary transport apparatus of the liver (Kupffer cells) and MSP binds to the Beta-chain of RON receptor. However, the MSP protein have two receptor binding sites of different affinity, one on the Alpha-chain and one on the Beta-chain. The Alpha-chain of MSP interacts with the Beta-chain of RON receptor and stimulates ciliary motility in these cells by activating RON (Ref.3).

Upon stimulation by LPS (Lipopolysaccharide) of Gram-negative bacteria, tissue injury or Gram-positive cocci; MSP is secreted by the liver into the blood as ProMSP, an inactive precursor form. On all antigen processing cells TLR4 (Toll-Like Receptor-4) and TLR2 recognize LPS and Gram-positive bacterial infections, respectively. MSP remains associated to tissue clotting factors (like Factor-XIA, Factor-XIIA and Klk (Kallikrein)) and is activated by proteolytic cleavage of ProMSP. Binding of activated MSP heterodimer to RON expressed on macrophages, monocytes and keratinocytes stimulates second messenger pathways, including PI3K (Phosphatidylinositde-3 Kinase). Kupffer cells, macrophages respond to MSP with changes in cell shape and motility, whereas, keratinocytes respond by proliferation. MSP-RON activation also inhibits Nitric Oxide production induced by the Gram-positive bacteria and Ifn-Gamma (Interferon-Gamma) in peritoneal macrophages. Peritoneal neutrophils also produce Superoxide which leads to liver cell injury. Such a phenomenon of Kupffer cell damage by Nitric Oxide or Superoxide is known as “Peroxynitrite-Induced Liver Damage”. The interaction of MSP and macrophages at sites of inflammation also depends on chemotactic factors such as MCP1 (Monocyte Chemotactic Protein-1) and inflammatory cytokines such as IL-1Beta (Interleukin-1-Beta) and TNF-Alpha (Tumor Necrosis Factor-Alpha) that attract and activate immune cells in the affected tissue. MCP1 plays a role in the recruitment of monocytes to sites of injury and infection. MCP1 influences both innate immunity, through effects on monocytes, and adaptive immunity, through control of T-Helper cell polarization. Infections of Gram-positive cocci induce mast cells to initiate TNF-Alpha production which in turn activates MCP1. MCP1 further interact with granulocyte progenitor cells to induce monocyte cell proliferation via CCR2 (Chemokine CC-Motif Receptor-2) (Ref.4). Monocytes release cytokines like M-CSF (Macrophage Colony Stimulating Factors) which helps in macrophage proliferation. MSP and RON receptor interaction leads to the production of cytokines like IL-12 and IL-18 and these cytokines inturn activate the Natural Killer cells and T-cells. In general, MSP inhibits the expression of iNOS (Inducible NO Synthase) leading to the seizure of Nitric Oxide and Superoxide production. Thus liver damage is prevented (Ref.5 & 6).

MSP-induced complement-mediated phagocytosis requires the RON receptor tyrosine kinase and the CR3 Receptor (Itg-AlphaM (Integrin-Alpha-M) and Itg-Beta2 (Integrin-Beta-2)). CR3 occurs in erytrocytes, monocytes, macrophages, eosinophlis, dendritic cells, B-cells and T-cells. MSP stimulation of macrophages results in Tyrosine phosphorylation and Akt (v-Akt Murine Thymoma Viral Oncogene Homolog) activation. Tyrosine kinase and PI3K activity as well as activity of the atypical PKC-Zeta (Protein Kinase-C Isoform-Zeta), is localized to MSP-induced phagosomes containing Complement Receptors. Additionally, MSP augments the ability of peritoneal macrophages to bind to ICAM1 (Intercellular Adhesion Molecule-1) via the CR3 Receptor. MSP-induced ICAM1 adhesion is also dependent on Tyrosine kinase activity, PI3K and PKC-Zeta, indicating that these signaling requirements are upstream of CR3 activation. Activation of the RON receptor by MSP leads to the activation of multiple signaling pathways, PI3K and MAPK (Mitogen-Activated Protein Kinase) cascades, through phosphorylation of a two tyrosine-docking site in the C-terminal tail. The ability of MSP to down-regulate Nitric Oxide production and iNOS expression in response to cytokine and LPS stimulation is dependent on RON-mediated activation of the PI3K pathway. The activation of CR3-mediated phagocytosis and ICAM1 binding by MSP-RON provide insight into infectious diseases. MSP-induced CR3-mediated phagocytosis is dependent on F-Actin re-organization. When MSP binds to its receptor RON, RON Kinase is activated through auto-phosphorylation. Subsequently, activated RON phosphorylates Beta-Chain and pp90 without activation of JAK2 (Janus Kinase-2), leading to morphological changes. In contrast to IL-3, MSP stimulation does not activate JAK2 and induces modest cell growth probably due to two Tyrosine residues in the multi-functional docking site of RON (Ref.7 & 8). Macrophages along with digestive enzymes and reactive oxygen intermediates produce high levels of Nitric Oxide to kill pathogens. These cytotoxic functions mediated by Nitric Oxide are carried out at the expense of inflammatory damage to host cells and tissues and is dependant on iNOS up-regulation. The MSP-RON interaction minimizes this Nitric Oxide production to required level in order to bring out effective killing of pathogens. While it remains speculative, the ability of MSP to induce genes associated with alternative activation in macrophages, it may play a role in its ability to regulate septic shock (Ref.9 & 10).