Nonalcoholic steatohepatitis (NASH) is emerging as a leading cause of chronic liver disease. However, therapeutic options are limited by incomplete understanding of the mechanisms of NASH fibrosis, ...which is mediated by activation of hepatic stellate cells (HSCs). In humans, human genetic studies have shown that hypomorphic variations in MERTK, encoding the macrophage c-mer tyrosine kinase (MerTK) receptor, provide protection against liver fibrosis, but the mechanisms remain unknown. We now show that holo- or myeloid-specific Mertk targeting in NASH mice decreases liver fibrosis, congruent with the human genetic data. Furthermore, ADAM metallopeptidase domain 17 (ADAM17)-mediated MerTK cleavage in liver macrophages decreases during steatosis to NASH transition, and mice with a cleavage-resistant MerTK mutant have increased NASH fibrosis. Macrophage MerTK promotes an ERK-TGFβ1 pathway that activates HSCs and induces liver fibrosis. These data provide insights into the role of liver macrophages in NASH fibrosis and provide a plausible mechanism underlying MERTK as a genetic risk factor for NASH fibrosis.
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•MerTK signaling in liver macrophages promotes liver fibrosis in NASH•Macrophage MerTK activates hepatic stellate cells in NASH by inducing TGF-β1•ATRA-induced MerTK cleavage blocks the TGF-b1-fibrosis pathway in steatosis•ATRA-induced MerTK cleavage becomes defective in NASH
Genome-wide association studies have indicated that MerTK is a risk factor for liver fibrosis in NASH with an unknown mechanism. Cai et al. discovered that MerTK signaling in liver macrophages, which is enhanced in NASH owing to suppression of its cleavage by ADAM17, promotes TGF-β1 production, HSC activation, and liver fibrosis in NASH.
The immune system evolved for adequate surveillance and killing of pathogens while minimizing host damage, such as due to chronic or exaggerated inflammation and autoimmunity. This is achieved by ...negative regulators and checkpoints that limit the magnitude and time course of the immune response. Tumor cells often escape immune surveillance and killing. Therefore, disrupting the brakes built into the immune system should effectively boost the anticancer immune response. The success of anti-CTLA4, anti-PD-1 and anti-PD-L1 have firmly established this proof of concept. Since the response rate of anti-CTLA4, anti-PD-1 and anti-PD-L1 is still limited, there is an intense effort for the identification of new targets and development of approaches that can expand the benefits of immunotherapy to a larger patient pool. Additional T cell checkpoints are obvious targets; however, here we focus on the unusual suspects—cells that function to initiate and guide T cell activity. Innate immunity is both an obligate prerequisite for the initiation of adaptive immune responses and a requirement for the recruitment of activated T cells to the site of action. We discuss some of the molecules present in innate immune cells, including natural killer cells, dendritic cells, macrophages, myeloid-derived suppressor cells, endothelial cells and stromal cells, that can activate or enhance innate immune cell functions, and more importantly, the inhibitors or checkpoints present in these cells that restrain their functions. Boosting innate immunity, either by enhancing activator functions or, preferably, by blocking the inhibitors, may represent a new anticancer treatment modality or at least function as adjuvants to T cell checkpoint inhibitors.
Summary
Cancer immunotherapy utilizing T‐cell checkpoint inhibitors has shown tremendous clinical success. Yet, this mode of treatment is effective in only a subset of patients. Unresponsive patients ...tend to have non‐T‐cell‐inflamed tumors that lack markers associated with the activation of adaptive anti‐tumor immune responses. Notably, elimination of cancer cells by T cells is critically dependent on the optimal activity of innate immune cells. Therefore, identifying new targets that regulate innate immune cell function and promote the engagement of adaptive tumoricidal responses is likely to lead to the development of improved therapies against cancer. Here, we review the TAM receptor tyrosine kinases—TYRO3, AXL, and MERTK—as an emerging class of innate immune checkpoints that participate in key steps of anti‐tumoral immunity. Namely, TAM‐mediated efferocytosis, negative regulation of dendritic cell activity, and dysregulated production of chemokines collectively favor the escape of malignant cells. Hence, disabling TAM signaling may promote engagement of adaptive immunity and complement T‐cell checkpoint blockade.
TAM Receptor Signaling in Immune Homeostasis Rothlin, Carla V; Carrera-Silva, Eugenio A; Bosurgi, Lidia ...
Annual review of immunology,
01/2015, Letnik:
33, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The TAM receptor tyrosine kinases (RTKs)-
T
YRO3,
A
XL, and
M
ERTK-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.
Immunobiology of the TAM receptors Lemke, Greg; Rothlin, Carla V
Nature reviews. Immunology,
200805, 2008-May, 2008-5-00, 20080501, Letnik:
8, Številka:
5
Journal Article
Recenzirano
Odprti dostop
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.
Chronic senescence can trigger pathological inflammation. In this issue, Schloesser et al. (2022. J. Cell Biol.https://doi.org/10.1083/jcb.202207097) demonstrate that senescent cells employ "don't ...eat me" signals that inhibit the ability of macrophages to engulf them and additionally prevent macrophages from removing neighboring corpses, revealing a new mechanism by which senescence may contribute to triggering inflammation.
Cell death occurs when a pathogen invades a host organism or the organism is subjected to sterile injury. Thus, cell death is often closely associated with the induction of an immune response. ...Furthermore, cell death can occur as a consequence of the immune response and precedes the tissue renewal and repair responses that are initiated by innate immune cells during resolution of an immune response. Beyond immunity, cell death is required for development, morphogenesis and homeostasis. How can such a ubiquitous event as cell death trigger such a wide range of context-specific effector responses? Dying cells are sensed by innate immune cells using specialized receptors and phagocytosed through a process termed efferocytosis. Here, we outline a general principle whereby signals within the dead cell as well as the environment are integrated by specific efferocytes to define the appropriate effector response.
Cell death is prevalent throughout life; however, the coordinated interactions and roles of phagocytes during corpse removal in the live brain are poorly understood. We developed photochemical and ...viral methodologies to induce death in single cells and combined this with intravital optical imaging. This approach allowed us to track multicellular phagocytic interactions with precise spatiotemporal resolution. Astrocytes and microglia engaged with dying neurons in an orchestrated and synchronized fashion. Each glial cell played specialized roles: Astrocyte processes rapidly polarized and engulfed numerous small dendritic apoptotic bodies, while microglia migrated and engulfed the soma and apical dendrites. The relative involvement and phagocytic specialization of each glial cell was plastic and controlled by the receptor tyrosine kinase
. In aging, there was a marked delay in apoptotic cell removal. Thus, a precisely orchestrated response and cross-talk between glial cells during corpse removal may be critical for maintaining brain homeostasis.
The TAM receptor tyrosine kinases T yro3, A xl, and M er and their ligands Gas6 and Protein S are essential for the phagocytosis of apoptotic cells and membranes in the adult immune, nervous, and ...reproductive systems. Genetic studies indicate that this receptor-ligand system is central to apoptotic cell engulfment that is triggered by the ‘eat-me’ signal phosphatidylserine (PtdSer). At the same time, TAM signaling is normally activated by Toll-like receptor (TLR) and type I interferon signaling, as part of the innate inflammatory response in dendritic cells (DCs) and macrophages, where it inhibits this response. Deficiencies in TAM signaling result in human retinal dystrophies and may contribute to lupus and other human autoimmune diseases.
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