The activation of Toll-like receptors (TLRs) in dendritic cells (DCs) triggers a rapid inflammatory response to pathogens. However, this response must be tightly regulated because unrestrained TLR signaling generates a chronic inflammatory milieu that often leads to autoimmunity. We have found that the TAM receptor tyrosine kinases-Tyro3, Axl, and Mer-broadly inhibit both TLR and TLR-induced cytokine-receptor cascades. Remarkably, TAM inhibition of inflammation is transduced through an essential stimulator of inflammation-the type I interferon receptor (IFNAR)-and its associated transcription factor STAT1. TLR induction of IFNAR-STAT1 signaling upregulates the TAM system, which in turn usurps the IFNAR-STAT1 cassette to induce the cytokine and TLR suppressors SOCS1 and SOCS3. These results illuminate a self-regulating cycle of inflammation, in which the obligatory, cytokine-dependent activation of TAM signaling hijacks a proinflammatory pathway to provide an intrinsic feedback inhibitor of both TLR- and cytokine-driven immune responses.

We report the cloning and characterization of rat ␣10, a previously unidentified member of the nicotinic acetylcholine receptor (nAChR) subunit gene family. The protein encoded by the ␣10 nAChR subunit gene is most similar to the rat ␣9 nAChR, and both ␣9 and ␣10 subunit genes are transcribed in adult rat mechanosensory hair cells. Injection of Xenopus laevis oocytes with ␣10 cRNA alone or in pairwise combinations with either ␣2-␣6 or ␤2-␤4 subunit cRNAs yielded no detectable ACh-gated currents. However, coinjection of ␣9 and ␣10 cRNAs resulted in the appearance of an unusual nAChR subtype. Compared with homomeric ␣9 channels, the ␣9␣10 nAChR subtype displays faster and more extensive agonist-mediated desensitization, a distinct currentvoltage relationship, and a biphasic response to changes in extracellular Ca 2؉ ions. The pharmacological profiles of homomeric ␣9 and heteromeric ␣9␣10 nAChRs are essentially indistinguishable and closely resemble those reported for endogenous cholinergic eceptors found in vertebrate hair cells. Our data suggest that efferent modulation of hair cell function occurs, at least in part, through heteromeric nAChRs assembled from both ␣9 and ␣10 subunits.

Recent studies have revealed that the TAM receptor protein tyrosine kinases -TYRO3, AXL and MER -have pivotal roles in innate immunity. They inhibit inflammation in dendritic cells and macrophages, promote the phagocytosis of apoptotic cells and membranous organelles, and stimulate the maturation of natural killer cells. Each of these phenomena may depend on a cooperative interaction between TAM receptor and cytokine receptor signalling systems. Although its importance was previously unrecognized, TAM signalling promises to have an increasingly prominent role in studies of innate immune regulation.Receptor protein tyrosine kinases (PTKs) are cell-surface transmembrane receptors that contain a regulated PTK activity within their cytoplasmic domains. They function as sensors for extracellular ligands, the binding of which triggers receptor dimerization and activation of the receptor's kinase. This leads to the recruitment, phosphorylation and activation of multiple downstream signalling proteins, which ultimately change the physiology of cells. Although there are only 58 receptor PTK genes in the human genome 1 (see the human kinome website), the signal transduction cascades initiated by receptor PTK activation control diverse cellular processes -from cell differentiation to cell death. Well-known receptor PTK subfamilies include the ERBB receptors, which have essential roles in cardiac and neural development and the progression of some forms of breast cancer 2 ; and the ephrin receptors, which are required for tissue morphogenesis and the patterning of neuronal connections in the developing brain 3 .The focus of this Review, the TAM group, was among the last receptor PTK subfamilies to be identified, and the biological roles of its three members -TYRO3, AXL and MERremained uncharacterized for several years. Largely through the analysis of engineered lossof-function mutants in mice, these roles have become increasingly apparent. They reflect a specific requirement for TAM signalling in settings in which fully differentiated cells, tissues and organs must be maintained in the face of continuous challenge, turnover and renewal. In humans, ongoing homeostatic regulation of this sort must be carried out, frequently on a daily basis, for decades. Although an essential role for TAM regulation of tissue homeostasis is evident in the adult nervous, reproductive and vascular systems, it is in In this Review, we highlight the central roles that TAM signalling has in the intrinsic inhibition of the inflammatory response to pathogens by dendritic cells (DCs) and macrophages; during phagocytosis of apoptotic cells by these same cells; and in the maturation and killing activity of natural killer (NK) cells. We also discuss how, in many or all of these settings, TAM receptors depend on and interact with cytokine receptors. TAM receptors and ligandsThe three TAM receptors, TYRO3, AXL and MER, were identified as a distinct receptor PTK subfamily in 1991 (REFS 4,5 ). Subsequent cloning of full-length cDNAs by multiple labo...

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Microglia are damage sensors for the central nervous system (CNS), and the phagocytes responsible for the routine non-inflammatory clearance of dead brain cells1. Here we show that the TAM receptor tyrosine kinases Mer and Axl2 regulate these microglial functions. We find that mice deficient in microglial Mer and Axl exhibit a marked accumulation of apoptotic cells (ACs) specifically in neurogenic regions of the adult CNS, and that microglial phagocytosis of the ACs generated during adult neurogenesis3,4 is normally driven by both TAM receptor ligands – Gas6 and Protein S5. Live two-photon imaging demonstrates that the microglial response to brain damage is also TAM-regulated, as TAM-deficient microglia display reduced process motility and delayed convergence to sites of injury. Finally, we show that microglial expression of Axl is prominently up-regulated in the inflammatory environment that develops in a mouse model of Parkinson’s disease6. Together, these results establish TAM receptors as both controllers of microglial physiology and potential targets for therapeutic intervention in CNS disease.

The TAM receptor tyrosine kinases (RTKs)—TYRO3, AXL, and MERTK—together with their cognate agonists GAS6 and PROS1 play an essential role in the resolution of inflammation. Deficiencies in TAM signaling have been associated with chronic inflammatory and autoimmune diseases. Three processes regulated by TAM signaling may contribute, either independently or collectively, to immune homeostasis: the negative regulation of the innate immune response, the phagocytosis of apoptotic cells, and the restoration of vascular integrity. Recent studies have also revealed the function of TAMs in infectious diseases and cancer. Here, we review the important milestones in the discovery of these RTKs and their ligands and the studies that underscore the functional importance of this signaling pathway in physiological immune settings and disease.

Tissue repair is a subset of a broad repertoire of interleukin-4 (IL-4)- and IL-13-dependent host responses during helminth infection. Here we show that IL-4 or IL-13 alone was not sufficient, but IL-4 or IL-13 together with apoptotic cells induced the tissue repair program in macrophages. Genetic ablation of sensors of apoptotic cells impaired the proliferation of tissue-resident macrophages and the induction of anti-inflammatory and tissue repair genes in the lungs after helminth infection or in the gut after induction of colitis. By contrast, the recognition of apoptotic cells was dispensable for cytokine-dependent induction of pattern recognition receptor, cell adhesion, or chemotaxis genes in macrophages. Detection of apoptotic cells can therefore spatially compartmentalize or prevent premature or ectopic activity of pleiotropic, soluble cytokines such as IL-4 or IL-13.

Highlights d Cardiomyocytes release subcellular particles called exophers d Cardiac exophers transport defective mitochondria for elimination d cMacs capture and eliminate exophers though Mertk