PMC:7572937 / 5411-11490 JSONTXT

{"project":"MyTest","denotations":[{"id":"33082511-27317359-29997544","span":{"begin":753,"end":754},"obj":"27317359"},{"id":"33082511-2542118-29997545","span":{"begin":1171,"end":1172},"obj":"2542118"},{"id":"33082511-25395303-29997545","span":{"begin":1171,"end":1172},"obj":"25395303"},{"id":"33082511-18056353-29997545","span":{"begin":1171,"end":1172},"obj":"18056353"},{"id":"33082511-30930024-29997545","span":{"begin":1171,"end":1172},"obj":"30930024"},{"id":"33082511-2542118-29997546","span":{"begin":1321,"end":1322},"obj":"2542118"},{"id":"33082511-25395303-29997547","span":{"begin":1415,"end":1416},"obj":"25395303"},{"id":"33082511-28857501-29997548","span":{"begin":1836,"end":1838},"obj":"28857501"},{"id":"33082511-22383080-29997549","span":{"begin":2028,"end":2030},"obj":"22383080"},{"id":"33082511-30711419-29997550","span":{"begin":2359,"end":2361},"obj":"30711419"},{"id":"33082511-24034617-29997551","span":{"begin":2823,"end":2825},"obj":"24034617"},{"id":"33082511-4061566-29997552","span":{"begin":4095,"end":4097},"obj":"4061566"},{"id":"33082511-3278869-29997553","span":{"begin":4098,"end":4100},"obj":"3278869"},{"id":"33082511-23281402-29997554","span":{"begin":4363,"end":4365},"obj":"23281402"},{"id":"33082511-19692643-29997554","span":{"begin":4363,"end":4365},"obj":"19692643"},{"id":"33082511-19692643-29997555","span":{"begin":4656,"end":4659},"obj":"19692643"},{"id":"33082511-18056353-29997556","span":{"begin":4799,"end":4801},"obj":"18056353"},{"id":"33082511-28153961-29997557","span":{"begin":4895,"end":4896},"obj":"28153961"},{"id":"33082511-19498085-29997558","span":{"begin":5006,"end":5007},"obj":"19498085"},{"id":"33082511-23281402-29997559","span":{"begin":5421,"end":5423},"obj":"23281402"},{"id":"33082511-21921027-29997560","span":{"begin":5617,"end":5620},"obj":"21921027"},{"id":"33082511-24192910-29997561","span":{"begin":5621,"end":5623},"obj":"24192910"}],"namespaces":[{"prefix":"_base","uri":"https://www.uniprot.org/uniprot/testbase"},{"prefix":"UniProtKB","uri":"https://www.uniprot.org/uniprot/"},{"prefix":"uniprot","uri":"https://www.uniprot.org/uniprotkb/"}],"text":"FPRs in the GI tract\nThe GI tract is also referred to as the digestive tract and constitutes the organ system that connects the mouth to the anus. The GI tract contains the mouth, esophagus, stomach, small intestine, large intestine, and anus. Due to the characteristics of the digestive system, many external stimuli, such as food antigens and bacteria, may affect cellular activities in this region. In particular, the gut of human adults contains over ten times more bacterial cells than human cells. These bacteria build their ecosystem in the gut and maintain homeostasis with epithelial cells and immune cells via mutual interaction. Recently, increased interest in the microbiota has revealed that dysbiosis correlates with various human diseases4. In addition, the study of the functional roles of PRRs such as FPRs in the GI tract has attracted interest because many ligands of FPRs, including formylated peptides and lipid metabolites, exist in the GI track.\n\nFPR1 in the GI tract\nFPR1 recognizes formyl peptides with high affinity and is highly expressed in neutrophils. FPR1 is expressed not only in immune cells but also in IECs and intestinal neuronal cells8–11. Several reports show that FPR1 is associated with IBD pathogenesis. Crohn’s disease patients have a high expression level of FPR1 in neutrophils8, and ulcerative colitis (UC) patients exhibit further activation of FPR1 in their intestines9. FPR1 activation in immune cells can induce directional migration of these cells into the inflamed intestinal region. Gliadin, a food antigen that binds to FPR1, decreases intestinal integrity and induces neutrophil migration12.\nNeutrophils are the first immune cells that migrate into inflamed tissues, and the most dominant pathological characteristic of IBD is the migration of neutrophils into the intestinal mucosa13. Despite the lack of a major chemotactic receptor, neutrophils with Fpr1 knockout can still migrate into inflamed intestinal mucosa in the dextran sulfate sodium (DSS)-induced colitis model14. In DSS-induced colitis, neutrophil migration is induced by other chemokines, such as CXCL2, and FPR1 affects the resolution and recovery of the intestinal barrier. Another report showed that Fpr1 deletion elicits decreased leukocyte migration into the inflamed intestine in a trinitrobenzene sulfonic acid-induced colitis model15. Blocking bacterial dissemination in the intestinal epithelium is a critical factor in regulating the resolution of inflammation. During Toxoplasma gondii infection, neutrophils form a ‘cast’ in the gut lumen to separate bacteria from the epithelium and to regulate the bacterial population (Fig. 1a). Neutrophils with Fpr1 knockout are able to migrate into the lamina propria but cannot migrate into the gut lumen, where they can regulate bacterial containment16.\nFig. 1 Functional roles of FPRs in the regulation of immune responses in the GI tract.\na Neutrophils migrate into the inflamed GI tract toward various chemoattractants. In the case of Toxoplasma gondii and bacterial infection, neutrophils migrate to the gut lumen in an FPR1-dependent manner to regulate bacterial containment and to separate luminal contents from the epithelium. Neutrophils activated by FPR1 remove microenvironmental oxygen by NOX2-mediated ROS generation, resulting in local enrichment of an anaerobic bacterial consortium. In particular, Akkermansia muciniphila facilitates epithelial wound healing through an epithelial NOX1-dependent mechanism. Monocytes, which facilitate epithelial remodeling during wound closure, migrate into the inflamed site via the CCL20-CCR6 axis. FPR2 expression is related to the expression of CCR6 in monocytes. b M cells and DCs in Peyer’s patches recognize LL-37 via FPR2, promoting DC activation with increased phagocytosis, expression of CD40, and production of IL-6 and IL-12. Follicular DCs express CXCL13 and B cell-activating factor, supporting germinal center B cell activation in Peyer’s patches via FPR2 signaling.\nThere are some reports demonstrating that introduction of fMLP into the gut induces colitis17,18. However, the dose used in these models was extremely high compared to physiological concentrations. Other studies have shown that not only fMLP but also various ligands of FPR1, such as AnxA1, and commensal bacteria, elicit epithelial barrier-protective effects19–22. IECs express Hsp27 via FPR1 stimulation, which has an epithelial-protective effect21. fMLP decreases TNF-α-induced NF-κB signaling and proinflammatory cytokine production and induces IEC migration. Moreover, fMLP can promote gastric epithelial cell proliferation by interacting with FPR122. FPR1 colocalizes with F-actin and activates Rac1 and Cdc42, which are crucial players in F-actin reorganization in a PI3K-dependent manner10.\nReactive oxygen species (ROS) generation is another mechanism of FPR1-mediated wound healing7. In immune cells such as phagocytes, FPR1 signaling generates ROS in an NADPH oxidase (NOX)2-dependent manner2. On the other hand, ROS generation in epithelial cells via FPR1 activation is mediated by NOX123. AnxA1 promotes wound healing through NOX1-mediated ROS generation in IECs, which inactivates phosphatases such as PTP-PEST and PTEN. These phosphatases have an inhibitory effect on wound healing because they inhibit the activation of FAK and paxillin, which are essential in cell motility and epithelial restitution19. Not only AnxA1 but also fMLP and commensal bacteria maintain FAK and ERK phosphorylation and promote wound healing through the same mechanism used by AnxA1, which inhibits the phosphatase DUSP324,25. In addition to epithelial cells, ROS affect the microbiota composition. Neutrophils activated by FPR1 migrate into inflamed mucosa and rapidly remove microenvironmental oxygen via NOX2-mediated ROS generation. As a result, local enrichment of an anaerobic bacterial consortium occurs. Akkermansia muciniphila, an anaerobic mucosa-associated bacterium, can also activate FPR1 and induce epithelial cell-specific NOX1-dependent redox signaling23 (Fig. 1a)."}

{"project":"2_test","denotations":[{"id":"33082511-27317359-29997544","span":{"begin":753,"end":754},"obj":"27317359"},{"id":"33082511-2542118-29997545","span":{"begin":1171,"end":1172},"obj":"2542118"},{"id":"33082511-25395303-29997545","span":{"begin":1171,"end":1172},"obj":"25395303"},{"id":"33082511-18056353-29997545","span":{"begin":1171,"end":1172},"obj":"18056353"},{"id":"33082511-30930024-29997545","span":{"begin":1171,"end":1172},"obj":"30930024"},{"id":"33082511-2542118-29997546","span":{"begin":1321,"end":1322},"obj":"2542118"},{"id":"33082511-25395303-29997547","span":{"begin":1415,"end":1416},"obj":"25395303"},{"id":"33082511-28857501-29997548","span":{"begin":1836,"end":1838},"obj":"28857501"},{"id":"33082511-22383080-29997549","span":{"begin":2028,"end":2030},"obj":"22383080"},{"id":"33082511-30711419-29997550","span":{"begin":2359,"end":2361},"obj":"30711419"},{"id":"33082511-24034617-29997551","span":{"begin":2823,"end":2825},"obj":"24034617"},{"id":"33082511-4061566-29997552","span":{"begin":4095,"end":4097},"obj":"4061566"},{"id":"33082511-3278869-29997553","span":{"begin":4098,"end":4100},"obj":"3278869"},{"id":"33082511-23281402-29997554","span":{"begin":4363,"end":4365},"obj":"23281402"},{"id":"33082511-19692643-29997554","span":{"begin":4363,"end":4365},"obj":"19692643"},{"id":"33082511-19692643-29997555","span":{"begin":4656,"end":4659},"obj":"19692643"},{"id":"33082511-18056353-29997556","span":{"begin":4799,"end":4801},"obj":"18056353"},{"id":"33082511-28153961-29997557","span":{"begin":4895,"end":4896},"obj":"28153961"},{"id":"33082511-19498085-29997558","span":{"begin":5006,"end":5007},"obj":"19498085"},{"id":"33082511-23281402-29997559","span":{"begin":5421,"end":5423},"obj":"23281402"},{"id":"33082511-21921027-29997560","span":{"begin":5617,"end":5620},"obj":"21921027"},{"id":"33082511-24192910-29997561","span":{"begin":5621,"end":5623},"obj":"24192910"}],"text":"FPRs in the GI tract\nThe GI tract is also referred to as the digestive tract and constitutes the organ system that connects the mouth to the anus. The GI tract contains the mouth, esophagus, stomach, small intestine, large intestine, and anus. Due to the characteristics of the digestive system, many external stimuli, such as food antigens and bacteria, may affect cellular activities in this region. In particular, the gut of human adults contains over ten times more bacterial cells than human cells. These bacteria build their ecosystem in the gut and maintain homeostasis with epithelial cells and immune cells via mutual interaction. Recently, increased interest in the microbiota has revealed that dysbiosis correlates with various human diseases4. In addition, the study of the functional roles of PRRs such as FPRs in the GI tract has attracted interest because many ligands of FPRs, including formylated peptides and lipid metabolites, exist in the GI track.\n\nFPR1 in the GI tract\nFPR1 recognizes formyl peptides with high affinity and is highly expressed in neutrophils. FPR1 is expressed not only in immune cells but also in IECs and intestinal neuronal cells8–11. Several reports show that FPR1 is associated with IBD pathogenesis. Crohn’s disease patients have a high expression level of FPR1 in neutrophils8, and ulcerative colitis (UC) patients exhibit further activation of FPR1 in their intestines9. FPR1 activation in immune cells can induce directional migration of these cells into the inflamed intestinal region. Gliadin, a food antigen that binds to FPR1, decreases intestinal integrity and induces neutrophil migration12.\nNeutrophils are the first immune cells that migrate into inflamed tissues, and the most dominant pathological characteristic of IBD is the migration of neutrophils into the intestinal mucosa13. Despite the lack of a major chemotactic receptor, neutrophils with Fpr1 knockout can still migrate into inflamed intestinal mucosa in the dextran sulfate sodium (DSS)-induced colitis model14. In DSS-induced colitis, neutrophil migration is induced by other chemokines, such as CXCL2, and FPR1 affects the resolution and recovery of the intestinal barrier. Another report showed that Fpr1 deletion elicits decreased leukocyte migration into the inflamed intestine in a trinitrobenzene sulfonic acid-induced colitis model15. Blocking bacterial dissemination in the intestinal epithelium is a critical factor in regulating the resolution of inflammation. During Toxoplasma gondii infection, neutrophils form a ‘cast’ in the gut lumen to separate bacteria from the epithelium and to regulate the bacterial population (Fig. 1a). Neutrophils with Fpr1 knockout are able to migrate into the lamina propria but cannot migrate into the gut lumen, where they can regulate bacterial containment16.\nFig. 1 Functional roles of FPRs in the regulation of immune responses in the GI tract.\na Neutrophils migrate into the inflamed GI tract toward various chemoattractants. In the case of Toxoplasma gondii and bacterial infection, neutrophils migrate to the gut lumen in an FPR1-dependent manner to regulate bacterial containment and to separate luminal contents from the epithelium. Neutrophils activated by FPR1 remove microenvironmental oxygen by NOX2-mediated ROS generation, resulting in local enrichment of an anaerobic bacterial consortium. In particular, Akkermansia muciniphila facilitates epithelial wound healing through an epithelial NOX1-dependent mechanism. Monocytes, which facilitate epithelial remodeling during wound closure, migrate into the inflamed site via the CCL20-CCR6 axis. FPR2 expression is related to the expression of CCR6 in monocytes. b M cells and DCs in Peyer’s patches recognize LL-37 via FPR2, promoting DC activation with increased phagocytosis, expression of CD40, and production of IL-6 and IL-12. Follicular DCs express CXCL13 and B cell-activating factor, supporting germinal center B cell activation in Peyer’s patches via FPR2 signaling.\nThere are some reports demonstrating that introduction of fMLP into the gut induces colitis17,18. However, the dose used in these models was extremely high compared to physiological concentrations. Other studies have shown that not only fMLP but also various ligands of FPR1, such as AnxA1, and commensal bacteria, elicit epithelial barrier-protective effects19–22. IECs express Hsp27 via FPR1 stimulation, which has an epithelial-protective effect21. fMLP decreases TNF-α-induced NF-κB signaling and proinflammatory cytokine production and induces IEC migration. Moreover, fMLP can promote gastric epithelial cell proliferation by interacting with FPR122. FPR1 colocalizes with F-actin and activates Rac1 and Cdc42, which are crucial players in F-actin reorganization in a PI3K-dependent manner10.\nReactive oxygen species (ROS) generation is another mechanism of FPR1-mediated wound healing7. In immune cells such as phagocytes, FPR1 signaling generates ROS in an NADPH oxidase (NOX)2-dependent manner2. On the other hand, ROS generation in epithelial cells via FPR1 activation is mediated by NOX123. AnxA1 promotes wound healing through NOX1-mediated ROS generation in IECs, which inactivates phosphatases such as PTP-PEST and PTEN. These phosphatases have an inhibitory effect on wound healing because they inhibit the activation of FAK and paxillin, which are essential in cell motility and epithelial restitution19. Not only AnxA1 but also fMLP and commensal bacteria maintain FAK and ERK phosphorylation and promote wound healing through the same mechanism used by AnxA1, which inhibits the phosphatase DUSP324,25. In addition to epithelial cells, ROS affect the microbiota composition. Neutrophils activated by FPR1 migrate into inflamed mucosa and rapidly remove microenvironmental oxygen via NOX2-mediated ROS generation. As a result, local enrichment of an anaerobic bacterial consortium occurs. Akkermansia muciniphila, an anaerobic mucosa-associated bacterium, can also activate FPR1 and induce epithelial cell-specific NOX1-dependent redox signaling23 (Fig. 1a)."}