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Originally published online as doi:10.1189/jlb.0703347 on January 14, 2004

Published online before print January 14, 2004
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(Journal of Leukocyte Biology. 2004;75:731-737.)
© 2004 by Society for Leukocyte Biology

Receptor tyrosine kinases and the regulation of macrophage activation

P. H. Correll1, A. C. Morrison and M. A. Lutz

Department of Veterinary Science, The Pennsylvania State University, University Park

1Correspondence: Department of Veterinary Science, 115 Henning Building, The Pennsylvania State University, University Park, PA 16802-3500. E-mail: phc7{at}psu.edu

Key Words: STK/RON • Mer/Axl/Tyro3


   INTRODUCTION
TOP
 INTRODUCTION
REFERENCES
 
It is becoming increasingly clear that macrophages are a diverse and dynamic population of cells that can be activated down a number of distinct developmental pathways (recently reviewed in refs. [1 , 2 ]). These cells have the capacity to perform a wide range of critical functions including the recognition, phagocytosis, and clearance of invading pathogens through the expression of pattern recognition receptors (PRRs) and the up-regulation of cytotoxic molecules; immune modulation through the production of cytokines and chemokines, antigen presentation, and the regulation of T cell activation and differentiation; and the resolution of inflammation and the promotion of healing through induction of matrix synthesis, fibroblast proliferation, angiogenesis, and the clearance of cellular debris. To perform these disparate tasks, macrophages must be capable of inducing the expression of specific subsets of genes in a coordinated manner in response to environmental stimuli. The basal activity of tissue resident macrophages as well as their ability to respond to environmental stimuli vary considerably. This response must be tightly controlled to stimulate immunity to infection and at the same time, protecting host tissues from inflammatory damage and promoting normal tissue homeostasis. Here, we propose that receptor tyrosine kinases (RTKs) play a role in fine-tuning this system.

Expression of at least three distinct families of RTKs has been reported in the monocyte/macrophage lineage. The receptor for macrophage colony-stimulating factor 1 (M-CSF-1R; c-fms) is widely expressed in the monocyte/macrophage lineage [3 ] and is required for the development of a number of tissue-resident macrophage populations [4 ]. This receptor is a member of the platelet-derived growth factor receptor (PDGFR) superfamily of RTKs, containing five immunoglobulin (Ig)-like domains in the extracellular portion of the receptor and a split kinase domain (Fig. 1A ). In contrast, the Axl/Tyro3/Mer family of receptors [5 , 6 ] contains two Ig-like domains and two fibronectin type III repeats in the ectodomain and a contiguous kinase domain with two tandem tyrosines in the activation loop. The murine STK/human RON receptor [7 , 8 ], a member of the MET family of RTKs, is closely related to the Tyro3 family and shares a similar kinase structure. The ectodomain of STK, however, is composed of a disulfide-linked extracellular {alpha} chain and transmembrane ß chain, the structure of which is poorly characterized. Recent studies using the MET receptor suggest that the c-terminal half of the extracellular domain contains four atypical Ig domains, and the N-terminal ligand-binding region adopts a ß-propeller fold similar to that displayed by the {alpha}V integrin [9 ]. Although M-CSF has been implicated in the proliferation but not the activity of terminally differentiated macrophages [10 ], the Tyro3 family of receptors and STK appear to play a role in regulating the activation of these cells in response to environmental stimuli [11 , 12 ].



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  		Figure 1. RTKs expressed in the monocyte/macrophage lineage. (A) Cartoon of the conserved structural features of the RON/Src tyrosine kinase (STK), Axl/Tyro3/Mer, and c-fms receptors and their family members. Green and light blue bars represent the kinase domain and fibronectin-like repeats, respectively. Half circles, Ig domains. Y, tyrosine residues. (B) Expression of the murine STK receptor in various cells of the monocyte/macrophage lineage. LPS, Lipopolysaccharide.

 
Consistent with the activation of nearly all RTKs, the ligands for the Tyro3 family of RTKs (Gas6 and protein S [13 14 15 ]) and STK [macrophage-stimulating protein (MSP); ref. 16 ] bind to the extracellular domain of their respective receptors, resulting in the up-regulation of kinase activity. However, RTKs also appear to participate in the recognition of a wide range of exogenous and endogenous ligands. Listeria monocytogenes has been shown to gain entry into hepatocytes through the interaction of InlB with the Met receptor [17 ]. In addition, Tyro3 receptors play a direct role in the recognition of apoptotic cells through the interaction of Gas6 with phosphatidyl serine on the surface of apoptotic cells, and macrophages from Mer knockout (KO) mice are defective in the clearance of apoptotic thymocytes [18 ]. Alternatively, these RTKs can also regulate the expression or activity of classic PRRs. For example, signaling through the STK receptor regulates the activation of the {alpha}Mß2 integrin, complement receptor 3 (CR3), which recognizes a variety of exogenous and endogenous ligands, including C3bi, intercellular adhesion molecule-1 (ICAM-1), LPS, and zymosan. CR3 activation by the MSP/STK signaling pathway results in the phagocytosis of C3bi-coated erythrocytes and enhanced macrophage binding to ICAM-1 via a phosphatidylinositol-3 kinase (PI-3K)/protein kinase C-{zeta}-dependent mechanism [19 ]. In addition, MSP stimulation of primary peritoneal macrophages induces the expression of scavenger receptor A [20 ], which recognizes the exogenous ligands lipid A and lipoteichoic acid as well as oxidized low-density lipoprotein and apoptotic cells, resulting in enhanced uptake of acetylated LDL by these cells.

Although the Tyro3 family of receptors is reported to be widely expressed by monocytes and their derivatives, expression of the STK receptor by monocyte/macrophage populations is highly regulated. STK/RON is not expressed on circulating monocytes, bone marrow-derived macrophages, splenic red pulp macrophages, or alveolar macrophages but is expressed on a number of specialized tissue macrophage populations (Fig. 1B) , including peritoneal macrophages, osteoclasts, mesangial cells, Kupffer cells, dermal macrophages, and marginal zone macrophages in the spleen [21 22 23 ] (and unpublished observations). Futhermore, LPS stimulation of macrophages in vitro or in vivo inhibits expression of STK [24 ]; however, the up-regulation of STK expression on day 3 concanavalin A-elicited peritoneal macrophages and at sites of wounding has been demonstrated [21 , 23 ]. Our unpublished data indicate that interleukin (IL)-4, glucocorticoids, and hypoxia (1% oxygen) induce the expression of STK on primary peritoneal macrophages but not bone marrow-derived macrophages in vitro, suggesting that these factors may play a role in the induction of STK on elicited macrophages in vivo in the context of the peritoneal cavity or at sites of wounding. Based on the restricted expression of STK in cells of the monocyte/macrophage lineage, we speculate that the MSP/STK signaling pathway may play a role in regulating the recognition of exogenous and endogenous ligands by tissue resident macrophages as well as regulating the response of varying macrophage populations to these and other environmental stimuli.

Kupffer cells account for 80–90% of total fixed tissue macrophages in the body. These cells reside primarily in the lumen of hepatic sinusoids attached to endothelial cells, where they clear bacteria and endotoxin from the blood transported from the gastrointestinal tract via the portal vein. Effective clearance of L. monocytogenes is dependent on Kupffer cells, as evidenced by increased Listeria in the blood of Kupffer cell-depleted mice. Futhermore, this clearance is dependent on the interaction between Kupffer cells and neutrophils in an ICAM-1/CR3-dependent manner [25 ]. Mice with a targeted deletion in the gene encoding STK are more susceptible to infection with L. monocytogenes, harboring increased bacterial counts in the liver but not the spleen [26 ]. As an intracellular pathogen, Listeria avoids detection by the innate-immune system by residing in hepatocytes. Therefore, the initial rapid clearance of these invaders by macrophages is essential in preventing infection. STK may enhance initial clearance of Listeria by Kupffer cells through promoting the uptake of complement-opsonized bacterial products as well as augmenting CR3/ICAM-1-dependent interactions with neutrophils. Alternatively, STK may enhance clearance of Listeria through the activation of other PRRs, such as SR-A, which has been shown to be critical in the innate response to infection with Listeria [27 ]. Subsequently, Kupffer cells lacking STK may be unable to efficiently control the initial infection, thus allowing for the dissemination of Listeria into the liver.

Although MSP, the ligand for STK, was originally isolated from serum as a result of its ability to induce chemotaxis and complement-mediated phagocytosis by primary peritoneal macrophages, studies in recent years have highlighted a pivotal role for the MSP/STK signaling pathway in regulating the effector functions of macrophages. MSP stimulation of primary peritoneal macrophages inhibits the production of nitric oxide (NO) [28 , 29 ] and prostaglandin E2 [30 ] in response to proinflammatory cytokines and LPS, as a result of an inhibition of the expression of inducible NO synthase (iNOS) and cyclooxygenase-2, respectively. This inhibition is associated with a decrease in the activation of nuclear factor (NF)-{kappa}B in response to LPS in the presence of MSP/STK [29 , 30 ]. STK-deficient mice exhibit increased susceptibility to LPS-induced septic shock [31 32 33 ] and enhanced inflammation in response to nickel-induced lung injury associated with increased serum nitrite levels and pulmonary tyrosine nitrosylation [34 ]. MSP is a serum protein that is produced primarily in the liver and circulates in the serum in an inactive form. The active form of MSP is generated by proteolytic cleavage by members of the coagulation cascade [35 ] and is found in the serum of patients with septic shock. However, mice with a targeted deletion in MSP do not exhibit enhanced susceptibility to endotoxic shock [36 ], suggesting the presence of alternative ligands or ligand-independent activation of STK in vivo. A deletion in the tyrosine kinase domain of the closely related Mer RTK also results in enhanced sensitivity to endotoxic shock, and macrophages from these animals produce elevated levels of tumor necrosis factor {alpha} (TNF-{alpha}) and display increased activation of NF-{kappa}B in response to stimulation with LPS [37 ]. Taken together, these data suggest that RTK expression on tissue-resident and exudate macrophages limits the activation of NF-{kappa}B and the production of inflammatory mediators, including NO, by these cells in response to environmental stimuli, thus protecting host tissues from inflammatory damage.

In addition to its regulation at the level of iNOS transcription, NO production by activated macrophages is also regulated through substrate availability. L-arginine is a substrate for iNOS and arginase, which drives the production of ornithine, a precursor for polyamine and proline synthesis. Although the effects of NO are primarily cytotoxic, production of ornithine by macrophages promotes cell proliferation and matrix synthesis. IL-4, a potent inhibitor of NO production, accomplishes this task by up-regulating arginase expression through the activation of signal transducer and activator of transcription (Stat)6 and limiting the amount of L-arginine available to iNOS [38 ]. We have shown that MSP induces expression of arginase I in primary peritoneal macrophages [20 ] and cooperates with IL-4 to enhance arginase activity in a Stat6-dependent manner (Caleph Wilson and P. H. Correll, submitted). However, unlike IL-4, MSP inhibition of NO is independent of L-arginine availability, suggesting that the MSP/STK signaling pathway independently regulates iNOS and arginase expression. MSP-induced arginase I expression is dependent on the PI-3K and p38 mitogen-activated protein kinase signaling pathways (A. C. Morrison and P. H. Correll, unpublished). It is interesting that resident peritoneal macrophages but not bone marrow-derived macrophages, harvested from mice with a targeted mutation in the lipid phosphatase, Src homology 2 domain-containing inositol phosphatase-1, express elevated levels of arginase [39 ]. The ability of STK and PI-3K to induce arginase I expression in resident macrophages suggests a potential dual role for RTK signaling in limiting tissue-destructive inflammation and promoting the wound-healing process by tipping the balance of arginine metabolism in macrophages (Fig. 2 ).



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  		Figure 2. Activation of STK by MSP tips the balance of arginine metabolism toward ornithine. Although proinflammatory cytokines and LPS induce expression of iNOS, resulting in the metabolism of arginine to NO, T helper cell type 2 (Th2) cytokines induce expression of arginase, resulting in the production of ornithine. MSP stimulation of the STK receptor inhibits iNOS expression in response to interferon-{gamma} (IFN-{gamma}) and LPS and induces the expression of arginase, thus favoring the metabolism of arginine to ornithine.

 
In addition to the regulation of macrophage effector functions, there is an emerging role for RTK signaling in regulating the immunomodulatory functions of macrophages. Although simultaneous stimulation of macrophages with MSP and IFN-{gamma} with or without LPS has little effect on cytokine production by macrophages, pretreatment of primary peritoneal macrophages with MSP for 2–4 h results in the complete inhibition of IL-12 production in response to IFN-{gamma} and LPS as a result of the inhibition of IL-12 p40 expression [40 ]. This inhibition appears to result from a block in Stat1 tyrosine phosphorylation and IFN consensus sequence-binding protein up-regulation induced by IFN-{gamma}. IL-12 is a key regulator of IFN-{gamma} production by natural killer (NK) and {gamma}{delta} T cells in the early stages of an innate-immune response and serves to bridge innate and adaptive immunity by promoting the survival of Th1 cells (reviewed in ref. [41 ]). Pretreatment of macrophages with MSP also results in the inhibition of major histcompatibility complex (MHC) class II expression in response to IFN-{gamma} and IL-4 and reduced Th1/Th2 differentiation under polarizing conditions in vitro (Wilson and P. H. Correll, submitted). In vivo, STK-deficient mice exhibit increased inflammation in a Th1-mediated delayed-type hypersensitivity response [31 , 33 ]. Furthermore, macrophages and dendritic cells from triple mutant mice for the RTKs Tyro3, Axl, and Mer express elevated levels of MHC class II and the costimulatory molecule B7-2 in response to LPS and produce increased levels of IL-12 [42 ]. These data suggest that in addition to regulating innate-immune responses, the expression of RTKs on antigen-presenting cells (APC) may play a key role in modulating Th differentiation and thus regulating acquired immunity (Fig. 3 , adapted from ref. [1 ]).



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  		Figure 3. MSP/STK limits IFN-{gamma}-induced IL-12 production, MHC class II expression, and Th1 cell differentiation. IL-12 production by macrophages induces IFN-{gamma} production by NK and {gamma}{delta} T cells and supports Th1 cell differentiation. IFN-{gamma} also increases surface expression of MHC class II on macrophages, resulting in enhanced antigen presentation. MSP/STK inhibits IL-12 production and MHC class II expression, and stimulation of primary peritoneal macrophages with MSP limits the ability of these cells to support Th1 differentiation. TCR, T cell receptor.

 
Although signaling through RTKs has traditionally been shown to promote cell growth and survival, thus playing a critical role in differentiation and tumorigenesis, the studies described here have provided the first link between RTK signaling and immune regulation. However, the mechanism by which these RTKs inhibit macrophage activation remains unclear. IL-10, a potent inhibitor of classical activation, induces Stat3 phosphorylation, and mice with a tissue-specific deletion of Stat3 in macrophages develop an intestinal inflammation similar to that observed in the IL-10 KO animals and are more susceptible to septic shock [43 ]. Furthermore, microarray studies using macrophages from these mice have indicated that IL-10 exerts most, if not all, of its effects on macrophages through the activation of Stat3 [44 ]. Activation of Stat3 by a number of wild-type and mutant RTKs, including those of the MET and Tyro3 families, has also been demonstrated [45 46 47 48 49 ]. Although the effects of the MSP/STK signaling pathway on macrophage activation are similar to those observed for IL-10, we have demonstrated that STK does not enhance IL-10 production by peritoneal macrophages, alone or in combination with LPS. Futhermore, using peritoneal macrophages from IL-10 KO mice, we have shown that the induction of arginase [20 ] and the inhibition of IL-12 [40 ] by MSP are independent of IL-10. Alternatively, these signaling pathways may provide parallel but distinct functions in regulating macrophage activation during an immune response. For example, the expression of RTKs on macrophages could set a threshold that proinflammatory stimuli must overcome to induce classical macrophage activation, whereas the induction of IL-10 in response to LPS may provide an important negative-feedback mechanism for limiting the extent and/or duration of this response.

RTK signaling could ultimately inhibit LPS-induced NF-{kappa}B activation and IFN-{gamma}-induced Stat1 tyrosine phosphorylation through the induction of classical negative-feedback pathways (Fig. 4 ). SOCS proteins constitute a family of molecules that provide a negative-feedback loop in the regulation of Jak/Stat signaling. IL-10 induces the expression of SOCS1 and SOCS3 in a Stat3-dependent manner [50 , 51 ], and studies of SOCS1–/– mice have demonstrated that SOCS1 is a critical regulator of IFN-{gamma} and LPS signaling in vivo [52 , 53 ], and SOCS3 appears to prevent IFN-{gamma}-like responses in cells stimulated with IL-6 [54 , 55 ]. Several RTKs have also been shown to induce the expression of SOCS proteins, suggesting the possibility that RTK signaling could regulate macrophage activation through the induction of SOCS1 and SOCS3. RTK signaling has been shown to activate NF-{kappa}B signaling in several cell types through the PI-3K- and Akt-dependent phosphorylation of I{kappa}B kinase [56 , 57 ]. Conversely, PI-3K has been shown to be a negative regulator of iNOS expression in macrophages through sustained activation of NF-{kappa}B [58 ], and the inhibition of iNOS by MSP has been shown to be PI-3K-dependent [59 ]. Furthermore, recent studies have demonstrated that PI-3K negatively regulates the production of IL-12 by dendritic cells and Th1 responses in vivo [60 ], and it has been suggested that PI-3K functions at the early phase of TLR signaling to modulate the magnitude of classical macrophage activation [61 ]. Negative-feedback inhibition of the NF-{kappa}B signaling pathway has also been demonstrated through the up-regulation of I{kappa}B and more recently, the p65-dependent expression of twist proteins. Twist 1 and twist 2 are basic helix-loop-helix transcription factors that are up-regulated in response to NF-{kappa}B, and studies from twist mutant mice demonstrate a role for twist 1 and 2 in the inhibition of p65 transactivation and the regulation of proinflammatory cytokine production in vivo [62 ]. It is interesting that the Met RTK has been shown to induce muscle differentiation through the up-regulation of twist 1 expression [63 ], and fibroblast growth factor 2 induces expression of twist 1 in osteoblasts [64 ].



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  		Figure 4. Potential mechanisms by which RTKs could limit the activation of macrophages by IFN-{gamma} and LPS. In other systems, RTKs have been shown to induce the tyrosine phosphorylation of Stat3, a critical negative regulator of macrophage activation, and induce expression of suppressor of cytokine signaling (SOCS)1 and SOCS3. Futhermore, RTKs have been shown to induce NF-{kappa}B activation through a PI-3K-dependent mechanism and to up-regulate the expression of twist genes. Activation of these signaling pathways could induce negative-feedback inhibition of IFN-{gamma} and LPS signaling. IFN-{gamma}R, IFN-{gamma} receptor; GF, growth factor; TLR4, Toll-like receptor 4; JAK, Janus tyrosine kinase; IkB, inhibitor of {kappa}B; P, phosphotyrosine.

 
The signals that regulate macrophage activation and function must be tightly controlled to promote immunity to infection and protect host tissues from inflammatory damage. Although these cells play a critical role in the host response to infection, macrophages are the primary effector cells in the tissue-destruction phase of autoimmunity. Cytotoxic effector molecules such as NO produced by activated macrophages have been implicated in the pathogenesis of organ-specific autoimmunity. In addition, IL-12 has been shown to play an important role in sustaining autoimmunity in several mouse models through its ability to mediate the production of IFN-{gamma} and favor a Th1 response. Changes in the threshold of macrophage activation or reduced ability to clear apoptotic cells can predispose mice to autoimmunity. The STK and Mer family of RTKs represents a new class of signaling molecules involved in the regulation of macrophages. The expression of these RTKs on distinct populations of macrophages appears to play a role in innate recognition and regulate the threshold for classical macrophage activation. In the absence of the Mer receptor, mice develop lupus-like autoimmunity [65 ] as a result, at least in part, of the inability of Mer-deficient macrophages to efficiently clear apoptotic cells, and triple mutant Mer/Axl/Tyro3 mice develop a severe lymphoproliferative disorder accompanied by autoimmunity [42 ]. Although STK-deficient mice do not develop obvious signs of autoimmunity, the absence of STK on an C3.MRLLPR background appears to exacerbate the pathogenesis of disease in these mice (Manujendra Ray and P. H. Correll, unpublished observations). As a result of the ability of RTKs to regulate innate-immune recognition, production of cytotoxic effector molecules, and Th activation by macrophages, these receptors may provide a novel target for the treatment of a wide range of autoimmune disorders.

Received July 24, 2003; revised November 20, 2003; accepted November 23, 2003.


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