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Review Free to read. A number of studies using genetic ablation of TAM loci in mice have elucidated the mechanism of TAM engagement and function during the immune response and removal of apoptotic cells. Following phagocytosis of apoptotic cells or the induction of T-cell dependent adaptive immune responses, ligand-induced TAM signaling dampens proinflammatory cytokine production and thus prevents exaggerated or prolonged inflammation.
It is believed that the TAM pathway may play an important role in the pathogenesis of inflammatory bowel disease. Suppression of inflammation and removal of apoptotic cells followed by tissue repair are essential processes for disease remission and the successful management of inflammatory bowel disease.
Targeted activation of TAM receptor tyrosine kinases may represent a potent therapeutic opportunity in inflammatory bowel disease. Inflammatory bowel disease IBD refers to a group of chronic inflammatory disorders that affect mainly the gastrointestinal tract. These diseases seem to be more prevalent in the developed world including North America and Europe. Current estimates suggest that approximately 1. Aminosalicylates have traditionally been considered the first line therapy for IBD, although this concept is evolving, particularly in CD, because of their limited effectiveness in altering the natural history of the disease.
Immunomodulator therapy i. Newer therapies that target T-cell homing to the intestine such as vedolizumab 2 , 3 will add to the armamentarium but still, newer therapeutic approaches are needed.
Therapeutic efforts have been hampered by the lack of a clear understanding about the pathogenesis of IBD and a realization that the causes are multifactorial. For example, genetic predispositions can be associated with IBD and unbiased approaches such as genome-wide association studies have identified certain IBD susceptibility loci.
Some of the IBD susceptibility genes identified by genome-wide association studies, e. Therefore, identifying immunoregulatory pathways that maintain physiological mucosal immunity might provide a better understanding of the exact etiology of IBD. In this review, we discuss the current understanding of an important group of immunoregulatory molecules—the receptor tyrosine kinases RTKs Axl and Mertk and their ligands growth-arrest-specific 6 Gas6 and Protein S Pros1.
The primary mechanism of action of current, frontline IBD therapy centers on dampening the inflammatory immune response. In contrast, the Axl and Mertk signaling pathway plays a prominent role in the resolution of inflammation through the negative regulation of the innate immune response and the phagocytosis of apoptotic neutrophils. Therefore, an improved understanding of the multifunctional roles of Axl and Mertk in mucosal immunity may prove critical for designing more effective therapies for IBD.
Lai and Lemke 13 initially identified these receptors by cloning fragments encoding their intracellular domains based on homology with tyrosine kinase domains and named them Tyro3, 7, and Subsequently, full-length cDNA of these receptors were cloned in many laboratories. Full-length Axl was independently cloned by 3 groups in Janssen et al 15 termed the gene UFO in allusion to the unidentified function of the gene at that time.
Rescigno et al 16 called it Ark for adhesion-related kinase. The viral and the cellular version of avian Mertk were cloned in and , respectively, and named v-ryk and c-eyk. Lai and Lemke classified these RTKs as a unique subgroup because of sequence identity. The original classification of these RTKs, performed by nothing more than sequence gazing, remarkably withstood the test of bioinformatics-based assembly of the kinome.
The extracellular domain of these single-pass membrane-spanning receptors is composed of 2 immunoglobulin-like domains and 2 fibronectin type III-like domains Fig. Through biochemical and cell-based assays, 2 closely related proteins—Gas6 growth-arrest-specific 6 and Pros1 Protein S, named after the city where it was discovered, Seattle 23 —were identified as TAM agonists.
From N- to C-termini, Gas6 and Pros1 feature Gla domains followed by 4 Epidermal Growth Factor-like repeats and 2 tandem laminin G domains that are related to those of the sex hormone binding globulin. Schematic representation of TAM receptors and ligands protein structure. A, TAM receptors carry 2 immunoglobulin-like domains in their N-terminus, followed by 2 fibronectin type III repeats, a transmembrane region and a tyrosine kinase domain in the C-terminal intracellular region.
The 2 laminin G domains form a sex hormone binding globulin-like domain, i. Pros1 also carries a thrombin sensitive region. EGF, epidermal growth factor. TAM RTKs were originally identified using a Schwann cell cDNA library, and their discovery was speculated to support a functional role of their tyrosine kinase activity in neural development. A similar TAM function is observed in the immune system. Hence, the TAMs have been termed homeostatic regulators—their function is mostly dispensable during development but essential in maintaining physiological organ function.
A major insight into the role of TAMs in autoimmune diseases came from the generation of the TAM triple knockout mice. However, beginning at approximately 4 weeks after birth, these mice start to display dramatic splenomegaly and lymphadenopathy. Furthermore, TAM triple knockouts are characterized by high circulating amounts of autoantibodies against dsDNA and phospholipids, and display clinical features of systemic autoimmunity. Is autoimmunity in the absence of TAM function a consequence of the failure to clear apoptotic cells, or do TAMs mediate a more direct suppression of the immune response?
Lymphocyte activation in TAM triple knockout mice was shown to be non-cell autonomous and due to the hyperactivation of antigen presenting cells APCs. Additionally, recombinant Gas6 and Pros1 potently suppressed the activation of DCs and consequent cytokine production triggered by engagement of TLR 3, 4, and 9.
TAM function as a direct negative regulator of the innate immune response is supported by the following observations in vitro. Type 1 interferons are potent inducers of DC maturation. Second, TAM engagement leads to the upregulation of pleiotropic inhibitors of innate immunity—suppressor of cytokine signaling 1 Socs1 and Socs3 Fig. Importantly, the TAM-dependent upregulation of Socs genes required type I interferon receptor and also STAT1, the very same transcription factor that drives the initial proinflammatory response.
TAM receptors are potent inhibitors of the innate immune response. A, TAM receptors are induced downstream of cytokine receptor signal i.
B, Subsequently, activation of TAM receptors in conjunction with cytokine receptors i. In a similar fashion, C phagocytosis of apoptotic cells in a TAM receptor dependent manner potently inhibits the TLR signaling cascade. Interestingly, the removal of apoptotic cells has also been associated with the suppression of inflammation during the resolution of the immune response. TAM engagement and its anti-inflammatory effect can also occur independent of apoptotic cells.
We have recently discovered that TAM activation occurs at the interface of the innate and adaptive immune response. In contrast, the initial inflammatory response is broad and if persistent or exaggerated, can cause collateral damage. Experimental evidence demonstrated that the TAM ligand Pros1 was expressed in activated, but not resting, T cells.
T-cell—specific Pros1 knockout mice showed a general increased immune response on immunization. Activated T cells transiently express intermediate levels of PtdSer on their cell surface, in comparison with apoptotic cells. This mechanism leads to the inhibition of the innate immune response and the maintenance of immune homeostasis Fig. TAM signaling is activated at the interface of the innate and adaptive immune response.
The gut microenvironment provides a particularly challenging context for the maintenance of immune homeostasis. The gut is a home to more microorganisms than cells in our own body. An extensive mucosal immune system has evolved to protect against invading pathogens, yet coexist with commensal microbiota. Exposure to infectious agents, microabrasions, and localized disruption of the epithelial barrier allow microorganisms to come in contact with the mucosal immune system. The immune system has the task to efficiently control the invading micro-organisms.
Neutrophils are the first responders to invading bacteria and are avid phagocytes. Ly6C hi monocytes are also recruited to the site of injury and differentiate into CX 3 CR1 int macrophages that secrete cytokines and contribute to the initial inflammatory response. After dealing with the threat of the pathogen, the immune system initiates the resolution of inflammation. Macrophages are endowed with the task of removal of apoptotic cells, including neutrophils.
After clearance of apoptotic debris, a switch toward tissue repair occurs. This switch coincides with a transition from the production of proinflammatory to proresolution mediators. For example, phagocytosis of apoptotic neutrophils leads to the production of PGE2, 61 and PGE2 induces the expression of lipooxygenase and the production of lipoxins. In IBD, not only is there an excessive and prolonged inflammation characterized by over-production of proinflammatory cytokines, tissue repair is also compromised.
TAM signaling in the intestinal mucosa. A, Damage to the intestinal mucosa e. Once the threat has been controlled, a tissue repair response ensues. Apoptotic neutrophils are cleared by intestinal macrophages in a TAM-dependent manner. B, Damage to the intestinal mucosa, in the absence of TAM signaling, leads to an accumulation of apoptotic neutrophils and failure of intestinal macrophages to acquire an alternative activation state that associates with severe injury.
Axl and Mertk expression have not been reported in mouse intestinal mucosa under physiological conditions. However, Axl and Mertk are readily detected in murine intestinal lamina propria macrophages on Dextran sodium sulfate DSS -induced inflammation. Axl is more broadly expressed in both hematopoietic and in nonhematopoietic cells. Murine and human DCs express significant levels of Axl.
Whether Axl has a similar repair function in the context of colitis-associated intestinal injury is not well understood.
The increased severity of colitis was also confirmed by histopathological features such as ulcerations, crypt hyperplasia, crypt loss, leukocyte infiltration, and edema. It is interesting to note that MERTK is highly expressed in response to IL in a subtype of alternatively activated human macrophages M2c macrophages and functions in the clearance of apoptotic cells.
This is consistent with the activation of the TAM pathway as a consequence of induced inflammation. The TAM ligands have also been implicated in limiting colonic inflammation.
The cellular compartment producing Gas6 to engage the TAMs within the intestinal mucosa is not well defined. However, bone marrow-transplant approaches have suggested that both radioresistant and radiosensitive cells can be the source of Gas6 during induced-inflammatory responses in the gut. The T-cell specific ablation of Pros1 in mice caused enhanced colitis in a T-cell transfer model.
It is likely that the loss of either or both of these functions may be important in the context of IBD. In fact, IBD has been associated with an increased risk of thrombosis since as early as Bargen and Barker 95 reported extensive arterial and venous thrombosis in patients with IBD. Full-length human AXL was originally cloned from primary human myeloid leukemia cells.
Tyro3 is overexpressed in multiple myeloma and acute myeloid leukemia for review see Ref.
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