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Tyro3, Axl, and Mertk receptor signaling in inflammatory bowel disease and colitis-associated cancer
Carla V Rothlin1, Jonathan A Leighton, Sourav Ghosh
1*Department of Immunobiology, School of Medicine, Yale University, New Haven, Connecticut; †Division of Gastroenterology, Mayo Clinic, Scottsdale, Arizona; and ‡Department of Cellular and Molecular Medicine and Arizona Cancer Center, University of Arizona, Tucson, Arizona.
Abstract:
Three receptor tyrosine kinases, Tyro3, Axl, and Mertk (TAM) and their ligands Gas6 and Protein S, have emerged as potent negative regulators of innate immune responses. 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. In light of the key role of TAMs in controlling inflammatory responses, here, we review the recent advances on TAM research vis-à-vis the resolution of intestinal inflammation. Targeted activation of TAM receptor tyrosine kinases may represent a potent therapeutic opportunity in inflammatory bowel disease.
Insights
The TAM receptor tyrosine kinases (Tyro3, Axl, Mertk) regulate immune responses and apoptotic cell clearance. Their targeted activation offers a potential therapeutic strategy for inflammatory bowel disease by reducing inflammation.
Area of Science:
- Immunology
- Molecular Biology
- Gastroenterology
Background:
- The TAM receptor tyrosine kinases (Tyro3, Axl, Mertk) and their ligands (Gas6, Protein S) are key regulators of innate immunity.
- TAM signaling dampens pro-inflammatory cytokine production and facilitates the clearance of apoptotic cells, preventing excessive inflammation.
Purpose of the Study:
- To review recent advances in TAM receptor research concerning the resolution of intestinal inflammation.
- To explore the therapeutic potential of TAM receptor activation in inflammatory bowel disease (IBD).
Main Methods:
- Review of existing literature on TAM receptor signaling in immune responses.
- Analysis of studies investigating TAM function in mouse models of inflammation.
- Examination of the role of TAMs in apoptotic cell clearance and tissue repair.
Main Results:
- TAM signaling is crucial for resolving inflammation and removing apoptotic cells during immune responses.
- Dysregulation of TAM pathways may contribute to the pathogenesis of inflammatory bowel disease.
- Targeted activation of TAM receptors shows promise for managing intestinal inflammation.
Conclusions:
- The TAM pathway plays a significant role in controlling inflammatory responses within the intestine.
- Targeted activation of TAM receptor tyrosine kinases presents a potential therapeutic avenue for inflammatory bowel disease.
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