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1.
Immunity ; 55(2): 237-253.e8, 2022 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-35081371

RESUMEN

The Th17 cell-lineage-defining cytokine IL-17A contributes to host defense and inflammatory disease by coordinating multicellular immune responses. The IL-17 receptor (IL-17RA) is expressed by diverse intestinal cell types, and therapies targeting IL-17A induce adverse intestinal events, suggesting additional tissue-specific functions. Here, we used multiple conditional deletion models to identify a role for IL-17A in secretory epithelial cell differentiation in the gut. Paneth, tuft, goblet, and enteroendocrine cell numbers were dependent on IL-17A-mediated induction of the transcription factor ATOH1 in Lgr5+ intestinal epithelial stem cells. Although dispensable at steady state, IL-17RA signaling in ATOH1+ cells was required to regenerate secretory cells following injury. Finally, IL-17A stimulation of human-derived intestinal organoids that were locked into a cystic immature state induced ATOH1 expression and rescued secretory cell differentiation. Our data suggest that the cross talk between immune cells and stem cells regulates secretory cell lineage commitment and the integrity of the mucosa.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Mucosa Intestinal/citología , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Interleucina-17/metabolismo , Células Madre/metabolismo , Animales , Comunicación Celular , Diferenciación Celular/efectos de los fármacos , Linaje de la Célula/efectos de los fármacos , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/patología , Sulfato de Dextran/efectos adversos , Humanos , Interleucina-17/metabolismo , Interleucina-17/farmacología , Mucosa Intestinal/metabolismo , Intestinos/efectos de los fármacos , Intestinos/metabolismo , Intestinos/patología , Ratones , Ratones Noqueados , FN-kappa B/metabolismo , Receptores de Interleucina-17/deficiencia , Factor de Transcripción SOX9/metabolismo , Transducción de Señal , Células Madre/citología
2.
Cell Physiol Biochem ; 57(1): 1-14, 2023 Jan 25.
Artículo en Inglés | MEDLINE | ID: mdl-36695077

RESUMEN

BACKGROUND/AIMS: The ribosome-inactivating proteins include the biothreat agent, ricin toxin (RT). When inhaled, RT causes near complete destruction of the lung epithelium coincident with a proinflammatory response that includes TNF family cytokines, which are death-inducing ligands. We previously demonstrated that the combination of RT and TNF-related apoptosis inducing ligand (TRAIL) induces caspase-dependent apoptosis, while RT and TNF-α or RT and Fas ligand (FasL) induces cathepsin-dependent cell death in lung epithelial cells. We hypothesize that airway macrophages constitute a major source of cytokines that drive lung epithelial cell death. METHODS: Here, we show that RT-induced apoptosis of the monocytic cell line, U937, leads to the bystander killing of the lung epithelial cell line, A549. U937 cells were treated with ricin. Following this, A549 cells were treated with supernatants from U937 cells and death was measured by WST-1 viability assay. RESULTS: Upon RT-induced U937 cell death, released RT and FasL contributed to A549 cell death. U937 cells also released nuclear protein HMGB1. The release of RT, FasL, and HMGB1 triggered A549 cell necroptosis, rather than cathepsin-dependent killing observed previously with RT and FasL. Reactive oxygen species (ROS) were produced in A549 cells due to HMGB1 ligation of the receptor for advanced glycation end products (RAGE). CONCLUSION: These findings demonstrate the potential for bystander necroptosis of lung epithelial cells during RT toxicosis which may perpetuate or increase the proinflammatory response.


Asunto(s)
Proteína HMGB1 , Ricina , Humanos , Ricina/toxicidad , Células U937 , Necroptosis , Apoptosis , Pulmón/metabolismo , Células Epiteliales/metabolismo , Proteína Ligando Fas , Citocinas/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Catepsinas , Inflamación , Receptor fas
3.
J Immunol ; 207(8): 1959-1963, 2021 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-34544802

RESUMEN

Previous studies indicate that IL-17A plays an important role in mediating the intestinal microbiota and systemic metabolic functions. However, it is not known where IL-17RA signaling occurs to mediate these effects. To investigate this question, we used intestinal epithelial-specific (Il17ra ΔIEC ) and liver-specific (Il17raΔLiver ) IL-17RA knockout mice as well as littermate control mice. Our results indicate that intestinal IL-17RA signaling helps mediate systemic metabolic functions upon exposure to prolonged high-fat diet. Il17ra ΔIEC mice display impaired glucose metabolism, altered hormone and adipokine levels, increased visceral adiposity, and greater hepatic lipid deposition when compared with their littermate controls. We show that IL-17RA-driven changes in microbiota composition are responsible for regulating systemic glucose metabolism. Altogether, our data elucidate the importance of intestinal IL-17RA signaling in regulating high-fat diet-mediated systemic glucose and lipid metabolism.


Asunto(s)
Interleucina-17/metabolismo , Mucosa Intestinal/fisiología , Hígado/fisiología , Enfermedades Metabólicas/inmunología , Microbiota/inmunología , Receptores de Interleucina-17/metabolismo , Adipoquinas/metabolismo , Animales , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Glucosa/metabolismo , Hormonas/metabolismo , Humanos , Metabolismo de los Lípidos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal
4.
Cell Rep ; 43(5): 114206, 2024 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-38733584

RESUMEN

The interleukin (IL)-22 cytokine can be protective or inflammatory in the intestine. It is unclear if IL-22 receptor (IL-22Ra1)-mediated protection involves a specific type of intestinal epithelial cell (IEC). By using a range of IEC type-specific Il22Ra1 conditional knockout mice and a dextran sulfate sodium (DSS) colitis model, we demonstrate that IL-22Ra1 signaling in MATH1+ cells (goblet and progenitor cells) is essential for maintaining the mucosal barrier and intestinal tissue regeneration. The IL-22Ra1 signaling in IECs promotes mucin core-2 O-glycan extension and induces beta-1,3-galactosyltransferase 5 (B3GALT5) expression in the colon. Adenovirus-mediated expression of B3galt5 is sufficient to rescue Il22Ra1IEC mice from DSS colitis. Additionally, we observe a reduction in the expression of B3GALT5 and the Tn antigen, which indicates defective mucin O-glycan, in the colon tissue of patients with ulcerative colitis. Lastly, IL-22Ra1 signaling in MATH1+ progenitor cells promotes organoid regeneration after DSS injury. Our findings suggest that IL-22-dependent protective responses involve O-glycan modification, proliferation, and differentiation in MATH1+ progenitor cells.


Asunto(s)
Colitis , Glicosilación , Interleucina-22 , Interleucinas , Receptores de Interleucina , Animales , Humanos , Ratones , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Colitis/metabolismo , Colitis/patología , Colitis/inducido químicamente , Sulfato de Dextran , Galactosiltransferasas/metabolismo , Galactosiltransferasas/genética , Inflamación/patología , Inflamación/metabolismo , Interleucinas/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Mucinas/metabolismo , Receptores de Interleucina/metabolismo , Transducción de Señal , Células Madre/metabolismo
5.
Nat Commun ; 15(1): 1597, 2024 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-38383607

RESUMEN

IL-22 is critical for ameliorating obesity-induced metabolic disorders. However, it is unknown where IL-22 acts to mediate these outcomes. Here we examine the importance of tissue-specific IL-22RA1 signaling in mediating long-term high fat diet (HFD) driven metabolic disorders. To do so, we generated intestinal epithelium-, liver-, and white adipose tissue (WAT)-specific Il22ra1 knockout and littermate control mice. Intestinal epithelium- and liver-specific IL-22RA1 signaling upregulated systemic glucose metabolism. Intestinal IL-22RA1 signaling also mediated liver and WAT metabolism in a microbiota-dependent manner. We identified an association between Oscillibacter and elevated WAT inflammation, likely induced by Mmp12 expressing macrophages. Mechanistically, transcription of intestinal lipid metabolism genes is regulated by IL-22 and potentially IL-22-induced IL-18. Lastly, we show that Paneth cell-specific IL-22RA1 signaling, in part, mediates systemic glucose metabolism after HFD. Overall, these results elucidate a key role of intestinal epithelium-specific IL-22RA1 signaling in regulating intestinal metabolism and alleviating systemic obesity-associated disorders.


Asunto(s)
Hígado , Enfermedades Metabólicas , Animales , Ratones , Hígado/metabolismo , Inflamación/metabolismo , Obesidad/metabolismo , Metabolismo de los Lípidos , Glucosa/metabolismo , Enfermedades Metabólicas/metabolismo , Lípidos , Dieta Alta en Grasa/efectos adversos , Ratones Endogámicos C57BL
6.
Mucosal Immunol ; 14(2): 389-401, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33060802

RESUMEN

Interleukin-22 (IL-22) signaling in the intestines is critical for promoting tissue-protective functions. However, since a diverse array of cell types (absorptive and secretory epithelium as well as stem cells) express IL-22Ra1, a receptor for IL-22, it has been difficult to determine what cell type(s) specifically respond to IL-22 to mediate intestinal mucosal host defense. Here, we report that IL-22 signaling in the small intestine is positively correlated with Paneth cell differentiation programs. Our Il22Ra1fl/fl;Lgr5-EGFP-creERT2-specific knockout mice and, independently, our lineage-tracing findings rule out the involvement of Lgr5+ intestinal stem cell (ISC)-dependent IL-22Ra1 signaling in regulating the lineage commitment of epithelial cells, including Paneth cells. Using novel Paneth cell-specific IL-22Ra1 knockout mice (Il22Ra1fl/fl;Defa6-cre), we show that IL-22 signaling in Paneth cells is required for small intestinal host defense. We show that Paneth cell maturation, antimicrobial effector function, expression of specific WNTs, and organoid morphogenesis are dependent on cell-intrinsic IL-22Ra1 signaling. Furthermore, IL-22 signaling in Paneth cells regulates the intestinal commensal bacteria and microbiota-dependent IL-17A immune responses. Finally, we show ISC and, independently, Paneth cell-specific IL-22Ra1 signaling are critical for providing immunity against Salmonella enterica serovar Typhimurium. Collectively, our findings illustrate a previously unknown role of IL-22 in Paneth cell-mediated small intestinal host defense.


Asunto(s)
Interleucinas/metabolismo , Microbiota/fisiología , Células de Paneth/metabolismo , Receptores de Interleucina/metabolismo , Salmonella typhi/fisiología , Células Th17/inmunología , Fiebre Tifoidea/inmunología , Animales , Diferenciación Celular , Inmunidad Mucosa , Interleucinas/genética , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células de Paneth/patología , Receptores de Interleucina/genética , Transducción de Señal , Interleucina-22
7.
Toxins (Basel) ; 11(8)2019 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-31374990

RESUMEN

Ricin is a member of the ribosome-inactivating protein (RIP) family of toxins and is classified as a biothreat agent by the Centers for Disease Control and Prevention (CDC). Inhalation, the most potent route of toxicity, triggers an acute respiratory distress-like syndrome that coincides with near complete destruction of the lung epithelium. We previously demonstrated that the TNF-related apoptosis-inducing ligand (TRAIL; CD253) sensitizes human lung epithelial cells to ricin-induced death. Here, we report that ricin/TRAIL-mediated cell death occurs via apoptosis and involves caspases -3, -7, -8, and -9, but not caspase-6. In addition, we show that two other TNF family members, TNF-α and Fas ligand (FasL), also sensitize human lung epithelial cells to ricin-induced death. While ricin/TNF-α- and ricin/FasL-mediated killing of A549 cells was inhibited by the pan-caspase inhibitor, zVAD-fmk, evidence suggests that these pathways were not caspase-dependent apoptosis. We also ruled out necroptosis and pyroptosis. Rather, the combination of ricin plus TNF-α or FasL induced cathepsin-dependent cell death, as evidenced by the use of several pharmacologic inhibitors. We postulate that the effects of zVAD-fmk were due to the molecule's known off-target effects on cathepsin activity. This work demonstrates that ricin-induced lung epithelial cell killing occurs by distinct cell death pathways dependent on the presence of different sensitizing cytokines, TRAIL, TNF-α, or FasL.


Asunto(s)
Proteína Ligando Fas/toxicidad , Ricina/toxicidad , Ligando Inductor de Apoptosis Relacionado con TNF/toxicidad , Factor de Necrosis Tumoral alfa/toxicidad , Células A549 , Clorometilcetonas de Aminoácidos/farmacología , Inhibidores de Caspasas/farmacología , Muerte Celular/efectos de los fármacos , Humanos , Pulmón/citología , Células U937
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