Macrophage Stimulating Protein Is a Novel Neurotrophic Factor

Abstract

Macrophage stimulating protein (MSP), also known as hepatocyte growth factor-like, is a soluble cytokine that belongs to the family of the plasminogen-related growth factors (PRGFs). PRGFs are ␣/␤ heterodimers that bind to transmembrane tyrosine kinase receptors. MSP was originally isolated as a chemotactic factor for peritoneal macrophages. Through binding to its receptor, encoded by the RON gene, it stimulates dissociation of epithelia and works as an inflammatory mediator by repressing the production of nitric oxide (NO). Here, we identify a novel role for MSP in the central nervous system. As a paradigm to analyze this function we chose the hypoglossal system of adult mice. We demonstrate in vivo that either administration of exogenous MSP or transplantation of MSP-producing cells at the proximal stump of the resected nerve is sufficient to prevent motoneuron atrophy upon axotomy. We also show that the MSP gene is expressed in the tongue, the target of the hypoglossal nerve, and that MSP induces biosynthesis of Ron receptor in the motoneuron somata. Finally, we show that MSP suppresses NO production in the injured hypoglossal nuclei. Together, these data suggest that MSP is a novel neurotrophic factor for cranial motoneurons and, by regulating the production of NO, may have a role in brain plasticity and regeneration. INTRODUCTIONMacrophage stimulating protein (MSP;Skeel et al., 1991;Yoshimura et al., 1993), also known as hepatocyte growth factor-like (Degen et al., 1991), belongs to the family of plasminogen-related growth factors (PRGF; Donate et al., 1994), of which hepatocyte growth factor (HGF) is the prototype. These soluble cytokines share a common structure: they are heterodimeric polypeptides comprising two subunits joined by disulfide bonds, respectively, characterized by the presence of four kringle domains and a nonfunctional serine-protease-like domain (Naldini et al., 1992;Waltz et al., 1997). The PRGF receptors of MSP and HGF identified so far are Ron for MSP (Gaudino et al., 1994) and Met for HGF (Bottaro et al., 1991;Naldini et al., 1991).MSP/hepatocyte growth factor-like was originally isolated as a chemotactic factor for peritoneal macrophages Skeel, 1978, 1979), although it may also act as a mitogen or morphogen in a variety of other cell types such as osteoclasts (Kurihara et al., 1996(Kurihara et al., , 1998, epithelial cells (Medico et al., 1996), hematopoietic precursors (Broxmeyer et al., 1996), and carcinoma cells (Maggiora et al., 1998;Willett et al., 1998). It has been shown that in exudate macrophages MSP inhibits the production of nitric oxide (NO), an inflammatory mediator produced in response to treatment with bacterial lipopolysaccharide or interferon-gamma (Wang et al., 1994;Chen et al., 1998).MSP transcripts are present in the liver and, at a lower amount, in kidney and pancreas (Bezerra et al., 1993;Yoshimura et al., 1993). Transcripts of RON (also known as STK in mouse) are detectable in many different organs during murine development. Relatively late in development, hig...

RON Receptor Tyrosine Kinase, a Negative Regulator of Inflammation, Inhibits HIV-1 Transcription in Monocytes/Macrophages and Is Decreased in Brain Tissue from Patients with AIDS

“…We propose that in the brain RON is a protective barrier against inflammation, and that HIV-1 infection, either directly or indirectly, alters RON function, contributing to an inflammatory microenvironment that favors HIV-1 replication. RON and MSP are expressed in multiple cell types in the CNS (this study and data not shown) (75,76), and MSP has been suggested to act as neurotrophic factor for subsets of sensory and sympathetic neurons during development (53,75,76), although we have not seen altered MSP expression in brains from HIV patients (data not shown). However, the consistent decrease in RON protein in AIDS patients suggests that chronic HIV-1 infection alters RON protein levels.…”

Effect of BSN-MST1 locus on inflammatory bowel disease and multiple sclerosis susceptibility

“…7 Through binding to its receptor, encoded by the MST1R gene, it stimulates dissociation of epithelia and works as an inflammation modulator by repressing the production of nitric oxide and IL-12. 8,9 This multifunctional factor regulates cell adhesion and motility, growth and survival. Moreover, the MST1R-deficient mouse showed a more rapid onset after EAE (experimental autoimmune encephalitis) induction with overall worsened severity, together with exacerbated demyelization, axonal injury and neuroinflammation.…”

Regulation of cell migration and cytokine production by HGF-like protein (HLP) / macrophage stimulating protein (MSP) in primary microglia

“…In the nervous system, neuronal survival and/or neurite extension-promoting activities of HLP for sensory, sympathetic and motor neurons were revealed (5,6,24,26). While the in vivo expression of Ron in microglia of multiple sclerosis patients and mouse model was reported previously (29), any function of The number of cells in the absence of HLP was defined as 100%.…”