Macrophage Stimulating Protein (MSP)

1. Overview

Macrophage stimulating protein (MSP) is a protein produced by macrophages. Macrophages play a variety of roles in the immune defense system, including a central role in innate or natural immunity, and were first described as phagocytes by Metchnikoff in the 19th century [1-2], and are now known to exhibit a wide range of functions including phagocytosis, tumor cytotoxicity, cytokine secretion, and possibly antigen presentation [3-4]. A number of factors are known to "activate" or participate in these activities of macrophages. These include antibodies, chemotactic agents, membrane-bound and soluble receptors, and cytokines, especially IFN-γ [5]. In addition to IFN-γ, one of the more interesting molecules associated with macrophage phagocytic activity is macrophage stimulating protein (MSP) [6]. This hepatocyte growth factor-like protein may be particularly important for the earliest stages of macrophage phagocytosis, and thus may significantly influence the downstream of macrophage-influenced permissive and persistent innate immune responses.

2. Structural information

Human MSP is an 85 kDa, disulfide-linked heterodimeric glycoprotein with considerable homology to hepatocyte growth factor (HGF) [7-10]. MSP is initially synthesized as a prepropeptide. After cleavage of the signal peptide, the propeptide of 693 amino acid (aa) residues is hydrolyzed at Arg-Val, generating two polypeptide chains to form a heterodimeric protein. The protein consists of an alpha chain of 465 amino acids (55 kDa) and a beta chain of 228 amino acids (28 kDa) linked together by a disulfide bond. Structurally, the N-terminal α-chain contains four 80-amino-acid cyclic or triple disulfide-bonded structures, whereas the C-terminal β-chain contains an inactive serine protease structural domain (SPD). Thus, MSP is considered to be a member of the family of cyclic structural domain-containing serine proteases. In addition to having a cyclic structural domain and an SPD, all members of the family circulate freely, are secreted as inactive precursors, and are activated by cleavage between the cyclic structural domain and the SPD [9-12].

3.Receptors

The human MSP receptor has been cloned and is a 185 kDa, 1400 aa transmembrane protein with intrinsic tyrosine kinase activity [13-14]. Named RON (Recepturd Origine Nantaise), this receptor has significant homology to the HGF receptor MET and is classified as a type IV protein tyrosine kinase [15]. Mouse stem cell-derived tyrosine kinases have also been cloned and found to share 74% identity with human RON at the aa sequence level [16]. Cells known to express RON include macrophages, keratinocytes, columnar epithelial cells, osteoblasts, neutrophils, megakaryocytes, chromaffin cells of the adrenal medulla, respiratory ciliated columnar epithelial cells and spermatozoa.

4. Biological Activity

Much of the activity of MSP involves effects on macrophage phagocytosis. It was recognized early that MSP increases phagocytosis of immunoglobulin-coated erythrocytes and is required for macrophages to respond to complement in a chemotactic manner [17]. Subsequent studies have shown that MSP does affect C5a receptor and C3b receptor (CR1) activity and that MSP (in vitro) promotes complement-driven phagocytosis. Once phagocytosis occurs, MSP prevents the production of nitric oxide and related intermediates, molecules that are often considered central to bactericidal activity [18]. Nitric oxide conducts macrophage apoptosis, downregulates superoxide activity, and inhibits cellular respiration, a function that is enhanced by phagocytosis. Thus, overall, inhibition of nitric oxide may actually promote phagocytosis throughout [19].

Although MSP appears to affect some aspects of chemotaxis, it does not stimulate monocyte migration from the bloodstream. In fact, we do not even know if monocytes express the MSP receptor RON [20]. MSP is not thought to circulate in a biologically active form as a disulfide-linked heterodimer. Instead, the biologically inactive proMSP is thought to be produced by hepatocyte constitutive phenotypes, circulates freely throughout the body, and is activated by proteolytic cleavage only on the surface of target cells. Thus, macrophage activity may be the limiting factor for MSP bioactivity [21-25]. MSP is also thought to play a role in embryogenesis, particularly in the development of myenteric segments and the induction of the floor plate. In addition, MSP may enhance megakaryocyte maturation by stimulating IL-6 production [26].

References

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