Receptor tyrosine kinases and the regulation of macrophage activation.

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 chain and transmembrane 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 ligandbinding region adopts a -propeller fold similar to that displayed by the 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]. Consistent with the activation of nearly all RTKs, the ligands for the Tyro3 family of RTKs (Gas6 and protein S [13–15]) 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 M 2 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-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