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Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase 23, 24 that senses and integrates a myriad of stimuli and plays a critical role in many biological processes, such as cell growth, proliferation, survival, and immune cell activation 25, 26. However, the molecular mechanisms by which LSECtin senses apoptotic cells and restores tissue homeostasis in macrophages have not been fully elucidated. Findings from our recent study revealed that LSECtin, which is located on intestinal macrophages, promotes macrophage phagocytosis of apoptotic cells, contributing to tissue homeostasis in colitis 12. Similar to DC-SIGN and L-SIGN, LSECtin functions as an endocytic receptor and mediates the binding and internalization of relevant apoptotic cells and viruses 14, 22. LSECtin acts as a coinhibitory molecule and limits T cell immunity to promote hepatitis B virus tolerance 20, 21. LSECtin (encoded by Clec4g), which belongs to the CLR superfamily, is a type II transmembrane protein that has been previously detected on liver-resident macrophages called Kupffer cells (KCs) and intestinal macrophages 12, 19, 20. The signaling pathways and functional outcomes of downstream CLRs, which sense apoptotic cells, are not understood. Apoptotic cells are generally considered to be immunologically silent in control of immunity and homeostasis 16, 17, 18. More is known about the signaling by receptors of necrotic cells and their functional consequences of uptake 14, 15. These CLRs detect molecules released from dying cells or exposed by cell corpses and can integrate signaling that either suppresses or induces inflammation 11, 12, 13. Myeloid C-type lectin receptors (CLRs) are particularly involved in the clearance of dying cells and cell debris 10.
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However, the molecular mechanisms of macrophages confer protection during intestinal disease and how macrophages might be targeted therapeutically are not yet fully understood. Therefore, macrophages represent a potential therapeutic target in IBD 4. Then macrophages undergo a functional switch, produce anti-inflammatory/tissue growth factors that are essential for mucosal healing, and return to homeostasis 6, 7, 8, 9. Macrophages engulf apoptotic cells that were produced by tissue damage. Increasing evidence suggests that macrophages have protective functions in intestinal health and disease 4, 5, 6. Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract caused by impairment of the intestinal epithelial cell (IEC) layers 1, 2, 3. Collectively, our findings suggest that LSECtin-dependent apoptotic cell clearance by macrophages activates mTORC1, and thus contributes to intestinal regeneration and the remission of colitis. Elevated mTORC1 signaling triggers macrophages to produce anti-inflammatory/tissue growth factors that contribute to the proliferation of epithelial cells and promote the reestablishment of tissue homeostasis. Mechanistically, apoptotic cells enhance the interaction between LSECtin and mTOR, and increase the activation of mTORC1 induced by LSECtin in macrophages. Here, using immunoprecipitation in combination with mass spectrometry to identify LSECtin-interacting proteins, we found that LSECtin interacted with mTOR, exhibiting a role in activating mTORC1. However, the mechanisms by which the phagocytosis of apoptotic cells triggers the pro-repair function of macrophages remain largely undefined. The C-type lectin receptor family member LSECtin promotes apoptotic cell clearance by macrophages and induces the production of anti-inflammatory/tissue growth factors, which direct intestinal repair in experimental colitis. Damage to intestinal epithelial cells and the induction of cellular apoptosis are characteristics of inflammatory bowel disease.