RESUMEN

Malassezia, the most abundant fungal commensal on the mammalian skin, has been linked to several inflammatory skin diseases such as atopic dermatitis, seborrheic dermatitis and psoriasis. This study reveals that epicutaneous application with Malassezia globosa (M. globosa) triggers skin inflammation in mice. RNA-sequencing of the resulting mouse lesions indicates activation of Interleukin-17 (IL-17) signaling and T helper 17 (Th17) cells differentiation pathways by M. globosa. Furthermore, our findings demonstrate a significant upregulation of IL-23, IL-23R, IL-17A, and IL-22 expressions, along with an increase in the proportion of Th17 and pathogenic Th17 cells in mouse skin exposed to M. globosa. In vitro experiments illustrate that M. globosa prompts human primary keratinocytes to secrete IL-23 via TLR2/MyD88/NF-κB signaling. This IL-23 secretion by keratinocytes is shown to be adequate for inducing the differentiation of pathogenic Th17 cells in the skin. Overall, these results underscore the significant role of Malassezia in exacerbating skin inflammation by stimulating IL-23 secretion by keratinocytes and promoting the differentiation of pathogenic Th17 cells.

Asunto(s)

Diferenciación Celular , Interleucina-23 , Queratinocitos , Malassezia , Células Th17 , Malassezia/inmunología , Queratinocitos/microbiología , Queratinocitos/inmunología , Queratinocitos/metabolismo , Células Th17/inmunología , Animales , Interleucina-23/metabolismo , Humanos , Ratones , Transducción de Señal , FN-kappa B/metabolismo , Receptor Toll-Like 2/metabolismo , Interleucina-17/metabolismo , Piel/microbiología , Piel/patología , Piel/inmunología , Modelos Animales de Enfermedad , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Células Cultivadas , Ratones Endogámicos C57BL , Interleucina-22

RESUMEN

Introduction: Colitis is an inflammatory bowel disease (IBD) characterized by immune cell dysregulation and alterations in the gut microbiome. In our previous report, we showed a natural product in cruciferous vegetables and ligand of the aryl hydrocarbon receptor (AhR), indole-3-carbinol (I3C), was able to reduce colitis-induced disease severity and microbial dysbiosis in an interleukin-22 (IL-22) dependent manner. Methods: In the current study, we performed single-cell RNA sequencing (scRNAseq) from colonocytes during colitis induction and supplementation with I3C and show how this treatment alters expression of genes involved in IL-22 signaling. To further define the role of IL-22 signaling in I3C-mediated protection during colitis and disease-associated microbial dysbiosis, we generated mice with AhR deficiency in RAR-related orphan receptor c (Rorc)-expressing cells (AhR ΔRorc ) which depletes this receptor in immune cells involved in production of IL-22. Colitis was induced in wildtype (WT), AhR ΔRorc , and littermate (LM) mice with or without I3C treatment. Results: Results showed AhR ΔRorc mice lost the efficacy effects of I3C treatment which correlated with a loss of ability to increase IL-22 by innate lymphoid type 3 (ILC3s), not T helper 22 (Th22) cells. 16S rRNA microbiome profiling studies showed AhR ΔRorc mice were unable to regulate disease-associated increases in Bacteroides, which differed between males and females. Lastly, inoculation with a specific disease-associated Bacteroides species, Bacteroides acidifaciens (B. acidifaciens), was shown to exacerbate colitis in females, but not males. Discussion: Collectively, this report highlights the cell and sex-specific role of AhR in regulating microbes that can impact colitis disease.

Asunto(s)

Bacteroides , Colitis , Interleucina-22 , Interleucinas , Receptores de Hidrocarburo de Aril , Receptores de Hidrocarburo de Aril/metabolismo , Receptores de Hidrocarburo de Aril/genética , Animales , Interleucinas/metabolismo , Colitis/inmunología , Colitis/microbiología , Femenino , Ratones , Masculino , Bacteroides/inmunología , Microbioma Gastrointestinal/inmunología , Disbiosis/inmunología , Ratones Endogámicos C57BL , Indoles/farmacología , Modelos Animales de Enfermedad , Factores Sexuales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Ratones Noqueados

RESUMEN

This single blind placebo-controlled study has as its main objectives to investigate the influence of dark sweet cherries (DSC) consumption on obesity-related dysbiosis, metabolic endotoxemia, and intestinal permeability. Participants (>18 years old, BMI: 30-40 kg m-2) consumed 200 mL of DSC juice with 3 g of DSC powder (n = 19) or a placebo drink (n = 21) twice per day for 30 days. The gut microbiota abundance was investigated using 16S ribosomal RNA sequencing on fecal DNA. Metabolic endotoxemia was evaluated by measuring lipopolysaccharide-binding protein (LBP) in fasting plasma samples. Intestinal permeability was assessed using the lactulose/mannitol (L/M) test and by measuring regeneration islet-derived protein 4 (REG4), and interleukin-22 (IL-22) mRNA levels in stool samples. Results showed that DSC supplementation decreased the abundance of Anaerostipes hadrus (p = 0.02) and Blautia (p = 0.04), whose changes were significant in BMI ≥ 35 participants (p = 0.004 and p = 0.006, respectively). Additionally, DSC prevented the increase of Alistipes shahii (p = 0.005) and Bilophila (p = 0.01) compared to placebo. Notably, DSC intervention favored the abundance of bacteria supporting a healthy gut ecosystem such as Roseburia intestinalis (p = 0.01), Turicibacter (p = 0.01), and Bacteroides vulgatus (p = 0.003) throughout the intervention, along with Clostridium leptum (p = 0.03) compared to placebo. The LBP, L/M ratio, REG-4 and IL-22 mRNA levels remained unchanged in placebo and cherry groups, implying that participants did not experience alterations in intestinal permeability. These findings highlight the potential gut-health benefits of DSC and encourage future research among individuals with BMI ≥ 35 and increased intestinal permeability.

Asunto(s)

Suplementos Dietéticos , Endotoxemia , Heces , Microbioma Gastrointestinal , Obesidad , Permeabilidad , Prunus avium , Humanos , Microbioma Gastrointestinal/efectos de los fármacos , Masculino , Heces/microbiología , Obesidad/microbiología , Obesidad/metabolismo , Obesidad/dietoterapia , Adulto , Femenino , Persona de Mediana Edad , Método Simple Ciego , Interleucina-22 , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Mucosa Intestinal/metabolismo , Adulto Joven , Funcion de la Barrera Intestinal

RESUMEN

Interleukin-22, discovered in the year of 2000, is a pleiotropic Th17 cytokine from the IL-10 family of cytokines. IL-22 signals through the type 2 cytokine receptor complex IL-22R and predominantly activates STAT3. This pathway leads to the transcription of several different types of genes, giving IL-22 context-specific functions ranging from inducing antimicrobial peptide expression to target cell proliferation. In recent years, it has been shown that IL-22 is involved in the pathogenesis of neoplasia in some cancers through its pro-proliferative and anti-apoptotic effects. This review highlights studies with recent discoveries and conclusions drawn on IL-22 and its involvement and function in various cancers. Such a study may be helpful to better understand the role of IL-22 in cancer so that new treatment could be developed targeting IL-22.

Asunto(s)

Interleucina-22 , Interleucinas , Neoplasias , Humanos , Interleucinas/metabolismo , Neoplasias/metabolismo , Neoplasias/inmunología , Neoplasias/patología , Animales , Transducción de Señal , Factor de Transcripción STAT3/metabolismo , Receptores de Interleucina/metabolismo , Receptores de Interleucina/genética

RESUMEN

Introduction: Group 3 innate lymphoid cells (ILC3s) are enriched in the intestinal mucosa and play important roles in host defense against infection and inflammatory diseases. Sirtuin 6 (SIRT6) is a nicotinamide adenine dinucleotide (NAD+)- dependent deacetylase and has been shown to control intestinal epithelial cell differentiation and survival. However, the role of SIRT6 in ILC3s remains unknown. Methods: To investigate the role of SIRT6 in gut ILC3s, we generated SIRT6 conditional knockout mice by crossing Rorccre and Sirt6flox/flox mice. Cell number and cytokine production was examined using flow cytometry. Citrobacter rodentium infection and dextran sodium sulfate-induced colitis models were used to determine the role of SIRT6 in gut defense. RT-qPCR, flow cytometry and immunohistochemistry were used to assess the intestinal inflammatory responses. Results: Here we show that SIRT6 inhibits IL-22 expression in intestinal ILC3s in a cell-intrinsic manner. Deletion of SIRT6 in ILC3s does not affect the cell numbers of total ILC3s and subsets, but results in increased IL-22 production. Furthermore, ablation of SIRT6 in ILC3s protects mice against Citrobacter rodentium infection and dextran sodium sulfate-induced colitis. Our results suggest that SIRT6 may play a role in ILC3 function by regulating gut immune responses against bacterial infection and inflammation. Discussion: Our finding provided insight into the relation of epigenetic regulators with IL-22 production and supplied a new perspective for a potential strategy against inflammatory bowel disease.

Asunto(s)

Citrobacter rodentium , Colitis , Infecciones por Enterobacteriaceae , Inmunidad Innata , Interleucina-22 , Interleucinas , Linfocitos , Ratones Noqueados , Sirtuinas , Animales , Ratones , Linfocitos/inmunología , Linfocitos/metabolismo , Interleucinas/metabolismo , Interleucinas/inmunología , Interleucinas/genética , Sirtuinas/genética , Sirtuinas/metabolismo , Colitis/inmunología , Colitis/inducido químicamente , Citrobacter rodentium/inmunología , Infecciones por Enterobacteriaceae/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Ratones Endogámicos C57BL , Sulfato de Dextran , Modelos Animales de Enfermedad

RESUMEN

Mammalian interleukin-22 (IL-22) attenuates organismal injury by inhibiting reactive oxygen species (ROS) and impeding the NLRP3 inflammasome activation. However, the role of fish IL-22 in this process remains unclear. We characterized MaIL-22, an IL-22 homolog in blunt snout bream (Megalobrama amblycephala). Despite its low sequence identity, it shares conserved structures and close evolutionary relationships with other teleost IL-22s. Furthermore, Aeromonas hydrophila (A. hydrophila) infection leads to tissue injury in M. amblycephala immune organs and concomitantly altered Mail-22 mRNA expression, suggesting that MaIL-22 was involved in the antimicrobial immune response. To explore MaIL-22's biological functions, we produced recombinant MaIL-22 (rMaIL-22) protein and demonstrated it significantly enhanced the survival of M. amblycephala post-A. hydrophila infection. To unravel its protective mechanisms, we explored the ROS/NLRP3 inflammasome axis and its downstream signaling responses. The results showed that rMaIL-22 treatment significantly elevated antioxidant enzyme (T-SOD, CAT and GSH-PX) activities to inhibit MDA activity and scavenge ROS in visceral tissues. Meanwhile, rMaIL-22 impeded the activation of NLRP3 inflammasome by suppressing NLRP3 protein and mRNA expression. This indicated that rMaIL-22 contributed to inhibit A. hydrophila-induced activation of the ROS/NLRP3 inflammasome axis. Consistent with these findings, rMaIL-22 treatment attenuated the expression of proinflammatory cytokines (il-1ß, tnf-α and il-6) and proapoptotic genes (caspase-3 and caspase-8) while promoting antiapoptotic genes (bcl-2b and mcl-1a) expression, ultimately mitigating tissue injury in visceral tissues. In conclusion, our research underscores MaIL-22's key role in microbial immune regulation, offering insights for developing IL-22-targeted therapies and breeding programs.

Asunto(s)

Aeromonas hydrophila , Apoptosis , Enfermedades de los Peces , Infecciones por Bacterias Gramnegativas , Inflamasomas , Inflamación , Interleucina-22 , Interleucinas , Proteína con Dominio Pirina 3 de la Familia NLR , Especies Reactivas de Oxígeno , Animales , Aeromonas hydrophila/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Inflamasomas/metabolismo , Inflamasomas/inmunología , Apoptosis/efectos de los fármacos , Infecciones por Bacterias Gramnegativas/inmunología , Especies Reactivas de Oxígeno/metabolismo , Interleucinas/metabolismo , Interleucinas/inmunología , Enfermedades de los Peces/inmunología , Enfermedades de los Peces/microbiología , Inflamación/inmunología , Proteínas de Peces/metabolismo , Proteínas de Peces/inmunología , Proteínas de Peces/genética , Cyprinidae/inmunología , Cyprinidae/metabolismo , Transducción de Señal

RESUMEN

Atopic dermatitis (AD) is a prevalent and chronic inflammatory skin condition characterized by a multifaceted pathophysiology that gives rise to diverse clinical manifestations. The management of AD remains challenging due to the suboptimal efficacy of existing treatment options. Nonetheless, recent progress in elucidating the underlying mechanisms of the disease has facilitated the identification of new potential therapeutic targets and promising drug candidates. In this review, we summarize the newest data, considering multiple connections between IL-22 and AD. The presence of circulating IL-22 has been found to correlate with the severity of AD and is identified as a critical factor driving the inflammatory response associated with the condition. Elevated levels of IL-22 in patients with AD are correlated with increased proliferation of keratinocytes, alterations in the skin microbiota, and impaired epidermal barrier function. Collectively, these factors contribute to the manifestation of the characteristic symptoms observed in AD.

Asunto(s)

Dermatitis Atópica , Interleucina-22 , Interleucinas , Dermatitis Atópica/patología , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/inmunología , Humanos , Interleucinas/metabolismo , Animales , Queratinocitos/metabolismo , Piel/patología , Piel/metabolismo , Microbiota

RESUMEN

Nucleophosmin 1 (NPM1) is commonly mutated in myelodysplastic syndrome (MDS) and acute myeloid leukemia. Concurrent inflammatory bowel diseases (IBD) and MDS are common, indicating a close relationship between IBD and MDS. Here we examined the function of NPM1 in IBD and colitis-associated colorectal cancer (CAC). NPM1 expression was reduced in patients with IBD. Npm1+/- mice were more susceptible to acute colitis and experimentally induced CAC than littermate controls. Npm1 deficiency impaired the function of interleukin-22 (IL-22)-producing group three innate lymphoid cells (ILC3s). Mice lacking Npm1 in ILC3s exhibited decreased IL-22 production and accelerated development of colitis. NPM1 was important for mitochondrial biogenesis and metabolism by oxidative phosphorylation in ILC3s. Further experiments revealed that NPM1 cooperates with p65 to promote mitochondrial transcription factor A (TFAM) transcription in ILC3s. Overexpression of Npm1 in mice enhanced ILC3 function and reduced the severity of dextran sulfate sodium-induced colitis. Thus, our findings indicate that NPM1 in ILC3s protects against IBD by regulating mitochondrial metabolism through a p65-TFAM axis.

Asunto(s)

Colitis , Inmunidad Mucosa , Ratones Noqueados , Mitocondrias , Proteínas Nucleares , Nucleofosmina , Fosforilación Oxidativa , Animales , Mitocondrias/metabolismo , Ratones , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Humanos , Colitis/inmunología , Colitis/metabolismo , Linfocitos/inmunología , Linfocitos/metabolismo , Ratones Endogámicos C57BL , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/metabolismo , Interleucina-22 , Inmunidad Innata , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/metabolismo , Sulfato de Dextran , Masculino , Interleucinas/metabolismo , Interleucinas/genética , Interleucinas/inmunología , Femenino

RESUMEN

Circular RNAs (circRNAs) are demonstrated to be involved in psoriasis progression. CircRNAs can act as RNA-binding protein (RBP) sponges. Here, we investigated the action of circAKR1B10 in psoriasis, and explored the potential proteins interacted with circAKR1B10. Levels of genes and proteins were assayed by qRT-PCR and western blotting analyses. Keratinocytes in functional groups were treated with interleukin (IL)-22. Functional analysis were conducted using MTT, 5-ethynyl-2'-deoxyuridine (EdU), and transwell assays, respectively. Interaction analysis among circAKR1B10, Eukaryotic initiation factor 4 A-III (EIF4A3) and Aurora Kinase A (AURKA) was conducted using bioinformatics analysis, RNA pull-down assay, and RNA immunoprecipitation (RIP) assay. CircAKR1B10 was highly expressed in psoriasis patients and IL-22-induced keratinocytes. Functionally, knockdown of circAKR1B10 abolished IL-22-induced proliferation, migration and invasion in keratinocytes. AURKA expression was also higher in psoriasis patients and IL-22-induced keratinocytes, and was negatively correlated with circAKR1B10 expression. Moreover, AURKA silencing reduced the proliferative, migratory and invasive abilities of IL-22-induced keratinocytes. Mechanistically, circAKR1B10 interacted with EIF4A3 protein to stabilize and regulate AURKA expression. CircAKR1B10 contributes to IL-22-induced proliferation, migration and invasion in keratinocytes via up-regulating AURKA expression through interacting with EIF4A3 protein.

Asunto(s)

Aurora Quinasa A , Movimiento Celular , Proliferación Celular , Factor 4A Eucariótico de Iniciación , Interleucina-22 , Interleucinas , Queratinocitos , Psoriasis , ARN Circular , Humanos , Aurora Quinasa A/metabolismo , Aurora Quinasa A/genética , ARN Circular/genética , ARN Circular/metabolismo , Queratinocitos/metabolismo , Proliferación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Psoriasis/patología , Psoriasis/metabolismo , Psoriasis/genética , Factor 4A Eucariótico de Iniciación/metabolismo , Factor 4A Eucariótico de Iniciación/genética , Interleucinas/metabolismo , Interleucinas/genética , ARN Helicasas DEAD-box

RESUMEN

Metabolic dysfunction-associated steatotic liver disease (MASLD) comprises a spectrum of liver diseases that span simple steatosis, metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis and may progress to cirrhosis and cancer. The pathogenesis of MASLD is multifactorial and is driven by environmental, genetic, metabolic and immune factors. This review will focus on the role of the type 3 cytokines IL-17 and IL-22 in MASLD pathogenesis and progression. IL-17 and IL-22 are produced by similar adaptive and innate immune cells such as Th17 and innate lymphoid cells, respectively. IL-17-related signaling is upregulated during MASLD resulting in increased chemokines and proinflammatory cytokines in the liver microenvironment, enhanced recruitment of myeloid cells and T cells leading to exacerbation of inflammation and liver disease progression. IL-17 may also act directly by activating hepatic stellate cells resulting in increased fibrosis. In contrast, IL-22 is a pleiotropic cytokine with a dominantly protective signature in MASLD and is currently being tested as a therapeutic strategy. IL-22 also exhibits beneficial metabolic effects and abrogates MASH-related inflammation and fibrosis development via inducing the production of anti-oxidants and anti-apoptotic factors. A sex-dependent effect has been attributed to both cytokines, most importantly to IL-22 in MASLD or related conditions. Altogether, IL-17 and IL-22 are key effectors in MASLD pathogenesis and progression. We will review the role of these two cytokines and cells that produce them in the development of MASLD, their interaction with host factors driving MASLD including sexual dimorphism, and their potential therapeutic benefits.

Asunto(s)

Interleucina-17 , Interleucina-22 , Interleucinas , Humanos , Interleucina-17/metabolismo , Interleucina-17/inmunología , Interleucinas/metabolismo , Interleucinas/inmunología , Animales , Hígado Graso/inmunología , Hígado Graso/metabolismo , Hígado Graso/patología , Enfermedades Metabólicas/metabolismo , Enfermedades Metabólicas/inmunología , Hígado/patología , Hígado/metabolismo , Hígado/inmunología

RESUMEN

How group 3 innate lymphoid cells (ILC3s) regulate mucosal protection in the presence of T cells remains poorly understood. Here, we examined ILC3 function in intestinal immunity using ILC3-deficient mice that maintain endogenous T cells, T helper 17 (TH17) cells, and secondary lymphoid organs. ILC3s were dispensable for generation of TH17 and TH22 cell responses to commensal and pathogenic bacteria, and absence of ILC3s did not affect IL-22 production by CD4 T cells before or during infection. However, despite the presence of IL-22-producing T cells, ILC3s and ILC3-derived IL-22 were required for maintaining homeostatic functions of the intestinal epithelium. T cell-sufficient, ILC3-deficient mice were capable of pathogen clearance and survived infection with a low dose of Citrobacter rodentium. However, ILC3s promoted pathogen tolerance at early time points of infection by activating tissue-protective immune pathways. Consequently, ILC3s were indispensable for survival after high-dose infection. Our results demonstrate a context-dependent role for ILC3s in immune-sufficient animals and provide a blueprint for uncoupling of ILC3 and TH17 cell functions.

Asunto(s)

Citrobacter rodentium , Infecciones por Enterobacteriaceae , Inmunidad Innata , Mucosa Intestinal , Linfocitos , Ratones Endogámicos C57BL , Animales , Inmunidad Innata/inmunología , Ratones , Linfocitos/inmunología , Citrobacter rodentium/inmunología , Infecciones por Enterobacteriaceae/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Ratones Noqueados , Interleucina-22 , Inmunidad Mucosa/inmunología , Células Th17/inmunología

RESUMEN

The intestinal tract generates significant reactive oxygen species (ROS), but the role of T cell antioxidant mechanisms in maintaining intestinal homeostasis is poorly understood. We used T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), which impaired glutathione (GSH) production, crucially reducing IL-22 production by Th17 cells in the lamina propria, which is critical for gut protection. Under steady-state conditions, Gclc deficiency did not alter cytokine secretion; however, C. rodentium infection induced increased ROS and disrupted mitochondrial function and TFAM-driven mitochondrial gene expression, resulting in decreased cellular ATP. These changes impaired the PI3K/AKT/mTOR pathway, reducing phosphorylation of 4E-BP1 and consequently limiting IL-22 translation. The resultant low IL-22 levels led to poor bacterial clearance, severe intestinal damage, and high mortality. Our findings highlight a previously unrecognized, essential role of Th17 cell-intrinsic GSH in promoting mitochondrial function and cellular signaling for IL-22 protein synthesis, which is critical for intestinal integrity and defense against gastrointestinal infections.

Asunto(s)

Glutatión , Interleucina-22 , Interleucinas , Mitocondrias , Células Th17 , Animales , Interleucinas/metabolismo , Mitocondrias/metabolismo , Glutatión/metabolismo , Células Th17/metabolismo , Células Th17/inmunología , Ratones , Transducción de Señal , Especies Reactivas de Oxígeno/metabolismo , Ratones Endogámicos C57BL , Citrobacter rodentium , Intestinos/patología , Intestinos/inmunología , Inflamación/metabolismo , Inflamación/patología , Infecciones por Enterobacteriaceae/inmunología , Infecciones por Enterobacteriaceae/metabolismo , Infecciones por Enterobacteriaceae/patología , Ratones Noqueados , Serina-Treonina Quinasas TOR/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología

RESUMEN

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a complex gastrointestinal condition influenced by genetic, microbial, and environmental factors, among which the gut microbiota plays a crucial role and has emerged as a potential therapeutic target. Ganoderic acid A (GAA), which is a lanostane triterpenoid compound derived from edible mushroom Ganoderma lucidum, has demonstrated the ability to modulate gut dysbiosis. Thus, we investigated the impact of GAA on IBD using a dextran sodium sulfate (DSS)-induced colitis mouse model. GAA effectively prevented colitis, preserved epithelial and mucus layer integrity, and modulated the gut microbiota. In addition, GAA promoted tryptophan metabolism, especially 3-IAld generation, activated the aryl hydrocarbon receptor (AhR), and induced IL-22 production. Fecal microbiota transplantation validated the mediating role of the gut microbiota in the IBD protection conferred by GAA. Our study suggests that GAA holds potential as a nutritional intervention for ameliorating IBD by influencing the gut microbiota, thereby regulating tryptophan metabolism, enhancing AhR activity, and ultimately improving gut barrier function.

Asunto(s)

Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Lanosterol , Receptores de Hidrocarburo de Aril , Triptófano , Animales , Humanos , Masculino , Ratones , Bacterias/clasificación , Bacterias/metabolismo , Bacterias/genética , Bacterias/aislamiento & purificación , Bacterias/efectos de los fármacos , Modelos Animales de Enfermedad , Microbioma Gastrointestinal/efectos de los fármacos , Ácidos Heptanoicos , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/microbiología , Interleucina-22 , Lanosterol/análogos & derivados , Lanosterol/farmacología , Ratones Endogámicos C57BL , Receptores de Hidrocarburo de Aril/metabolismo , Receptores de Hidrocarburo de Aril/genética , Triptófano/metabolismo

RESUMEN

BACKGROUND: Intestinal barrier dysfunction is a significant contributor to the recurrence and refractory of ulcerative colitis (UC). Promoting the interaction between group 3 innate lymphoid cells (ILC3s) and gut flora is a valuable strategy for mucosal repair. Paeoniae decoction (PD) is a compound commonly used in clinical treatment of UC, but its exact mechanism remains unclear. PURPOSE: We aimed to investigate the protective effect of PD on intestinal mucosal injury induced by dextran sulfate sodium (DSS) in chronic colitis, as well as to elucidate its potential mechanism. METHODS: C57BL/6 mice were induced with chronic colitis by 2 % DSS and divided into four groups: control group, model group, PD low dose (4 g/kg), and high dose (8 g/kg) group. The effectiveness of PD in treating chronic colitis mice was evaluated based on changes in body weight, colon length, colon pathological tissue scores, and the mRNA levels of inflammatory factors IL-6 and IL-1ß. The expressions of intestinal epithelial tight junction proteins (ZO-1 and Occludin), IL-22, and MUC2 were observed using immunofluorescence and RT-PCR. Additionally, the proportion of ILC3 and natural cytotoxicity receptor (NCR)+ ILC3 in the colon were detected using flow cytometry. Furthermore, UHPLC-QE-MS was utilized to identify chemical components of PD and network pharmacology was employed to predict potential pathways for PD intervention in UC. Subsequently, MNK-3 cells (ILC3 in vitro cell line) and NCM460 cells were used to verify the network pharmacology results. Finally, the effects of PD on UC gut flora have been explored using in vitro fermentation and 16S rDNA techniques. RESULTS: The results showed that PD significantly restored body weight and colon length in mice with chronic colitis, while also reducing colon inflammatory cell infiltration and the expression of IL-6 and IL-1ß. Additionally, PD notably promoted the expression of MUC2, ZO-1, Occludin, and IL-22, as well as increasing the ratio of ILC3 and NCR+ILC3. UHPLC-QE-MS analysis identified 443 components of PD, and network pharmacology suggested that PD could target the aryl hydrocarbon receptor (AHR) signaling pathway, which was confirmed by MNK-3 cells and in vitro fermentation experiments. Furthermore, MNK-3-conditioned medium (CM) increased the expression of ZO-1 and Occludin in NCM460 cells. In addition, 16S rDNA results indicated that PD promoted the abundance of Lactobacillales, thus contributing to mucosal damage repair by activating the AHR signal in ILC3s. CONCLUSION: In summary, our study demonstrates that PD repairs intestinal mucosal damage in chronic colitis by regulating the interaction of gut flora with ILC3, and the specific mechanism is related to the activation of AHR signaling pathway.

Asunto(s)

Sulfato de Dextran , Microbioma Gastrointestinal , Interleucina-22 , Mucosa Intestinal , Ratones Endogámicos C57BL , Paeonia , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Ratones , Masculino , Paeonia/química , Linfocitos/efectos de los fármacos , Proteína de la Zonula Occludens-1/metabolismo , Interleucinas/metabolismo , Modelos Animales de Enfermedad , Interleucina-1beta/metabolismo , Ocludina/metabolismo , Interleucina-6/metabolismo , Colon/efectos de los fármacos , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inducido químicamente , Medicamentos Herbarios Chinos/farmacología , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Mucina 2

RESUMEN

In maintaining organismal homeostasis, gut immunity plays a crucial role. The coordination between the microbiota and the immune system through bidirectional interactions regulates the impact of microorganisms on the host. Our research focused on understanding the relationships between substantial changes in jejunal intestinal flora and metabolites and intestinal immunity during porcine epidemic diarrhea virus (PEDV) infection in piglets. We discovered that Lactobacillus rhamnosus GG (LGG) could effectively prevent PEDV infection in piglets. Further investigation revealed that LGG metabolites interact with type 3 innate lymphoid cells (ILC3s) in the jejunum of piglets through the aryl hydrocarbon receptor (AhR). This interaction promotes the activation of ILC3s and the production of interleukin-22 (IL-22). Subsequently, IL-22 facilitates the proliferation of IPEC-J2 cells and activates the STAT3 signaling pathway, thereby preventing PEDV infection. Moreover, the AhR receptor influences various cell types within organoids, including intestinal stem cells (ISCs), Paneth cells, and enterocytes, to promote their growth and development, suggesting that AhR has a broad impact on intestinal health. In conclusion, our study demonstrated the ability of LGG to modulate intestinal immunity and effectively prevent PEDV infection in piglets. These findings highlight the potential application of LGG as a preventive measure against viral infections in livestock.IMPORTANCEWe observed high expression of the AhR receptor on pig and human ILC3s, although its expression was negligible in mouse ILC3s. ILC3s are closely related to the gut microbiota, particularly the secretion of IL-22 stimulated by microbial signals, which plays a crucial regulatory role in intestinal immunity. In our study, we found that metabolites produced by beneficial gut bacteria interact with ILC3s through AhR, thereby maintaining intestinal immune homeostasis in pigs. Moreover, LGG feeding can enhance the activation of ILC3s and promote IL-22 secretion in the intestines of piglets, ultimately preventing PEDV infection.

Asunto(s)

Infecciones por Coronavirus , Inmunidad Innata , Interleucina-22 , Interleucinas , Linfocitos , Virus de la Diarrea Epidémica Porcina , Receptores de Hidrocarburo de Aril , Animales , Receptores de Hidrocarburo de Aril/metabolismo , Porcinos , Interleucinas/metabolismo , Virus de la Diarrea Epidémica Porcina/inmunología , Linfocitos/inmunología , Linfocitos/metabolismo , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/prevención & control , Infecciones por Coronavirus/veterinaria , Infecciones por Coronavirus/virología , Infecciones por Coronavirus/metabolismo , Microbioma Gastrointestinal/inmunología , Enfermedades de los Porcinos/inmunología , Enfermedades de los Porcinos/virología , Enfermedades de los Porcinos/prevención & control , Enfermedades de los Porcinos/microbiología , Yeyuno/inmunología , Yeyuno/metabolismo , Transducción de Señal , Ligandos , Intestinos/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo

RESUMEN

Group 3 innate lymphoid cells (ILC3s) play key roles in intestinal inflammation. Olfactomedin 4 (OLFM4) is highly expressed in the colon and has a potential role in dextran sodium sulfate-induced colitis. However, the detailed mechanisms underlying the effects of OLFM4 on ILC3-mediated colitis remain unclear. In this study, we identify OLFM4 as a positive regulator of IL-22+ILC3. OLFM4 expression in colonic ILC3s increases substantially during intestinal inflammation in humans and mice. Compared to littermate controls, OLFM4-deficient (OLFM4-/-) mice are more susceptible to bacterial infection and display greater resistance to anti-CD40 induced innate colitis, together with impaired IL-22 production by ILC3, and ILC3s from OLFM4-/-mice are defective in pathogen resistance. Besides, mice with OLFM4 deficiency in the RORγt compartment exhibit the same trend as in OLFM4-/-mice, including colonic inflammation and IL-22 production. Mechanistically, the decrease in IL-22+ILC3 caused by OLFM4 deficiency involves the apoptosis signal-regulating kinase 1 (ASK1)- p38 MAPK signaling-dependent downregulation of RAR-related orphan receptor gamma (RORγt) protein. The OLFM4-metadherin (MTDH) complex upregulates p38/RORγt signaling, which is necessary for IL-22+ILC3 activation. The findings indicate that OLFM4 is a novel regulator of IL-22+ILC3 and essential for modulating intestinal inflammation and tissue homeostasis.

Asunto(s)

Colitis , Interleucina-22 , Interleucinas , Ratones Noqueados , Animales , Ratones , Interleucinas/metabolismo , Interleucinas/genética , Colitis/genética , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/inmunología , Colitis/patología , Humanos , Linfocitos/inmunología , Linfocitos/metabolismo , Ratones Endogámicos C57BL , Factor Estimulante de Colonias de Granulocitos/metabolismo , Factor Estimulante de Colonias de Granulocitos/genética , Inmunidad Innata , Inflamación/metabolismo , Inflamación/genética , Masculino , Glicoproteínas

RESUMEN

Objective: To investigate the roles of histone H3K27me3 methylation and its regulatory enzymes JMJD3 and EZH2 in the differentiation of Th17 cells in ankylosing spondylitis (AS), to unveil their potential involvement in the pathogenesis of AS, and to provide new strategies and targets for the clinical treatment of AS by analyzing the methylation state of H3K27me3 and its interactions with Th17-related factors. Methods: A total of 84 AS patients (42 active AS patiens and 42 patients in the stable phase of AS) were enrolled for the study, while 84 healthy volunteers were enrolled as the controls. Blood samples were collected. Peripheral blood mononuclear cells were isolated. ELISA assay was performed to examine Th17 cells and the relevant cytokines IL-21, IL-22, and IL-17. The mRNA expressions of RORc, JAK2, and STAT3 were analyzed by RT-PCR, the protein expressions of RORc, JAK2/STAT3 pathway protein, H3K27me3 and the relevant protease (EZH2 and JMJD3) were determined by Western blot. Correlation between H3K27me3, EZH2 and JMJD3 and the key signaling pathway molecules of Th cell differentiation was analyzed by Pearson correlation analysis. Results: The mRNA expressions of RORc, JAK2, and STAT3 were significantly higher in the active phase group than those in the stable phase group ( P<0.05). The relative grayscale values of H3K27me3 and EZH2 in the active phase group were lower than those of the stable phase group, which were lower than those of the control group, with the differences being statistically significant ( P<0.05). The relative grayscale values of JMJD3, RORc, JAK2, pJAK2, STAT3, and pSTAT3 proteins were significantly higher in the active phase group than those in the stable phase group, which were higher than those in the control group (all P<0.05). The proportion of Th17 and the expression level of inflammatory factors in the active period group were higher than those in the other two groups (P<0.05). H3K27me3 was negatively correlated with RORc, JAK2, STAT3, and IL-17, JMJD3 was positvely correlated with JAK2, STAT3, and IL-17, and EZH2 was negatively correlated with JAK2, STAT3, and IL-17 (all P<0.05). Conclusion: The low expression of H3K27me3 in AS is influenced by the gene loci JMJD3 and EZH2, which can regulate the differentiation of Th17 cells and thus play a role in the pathogenesis and progression of AS.

Asunto(s)

Diferenciación Celular , Proteína Potenciadora del Homólogo Zeste 2 , Epigénesis Genética , Histonas , Interleucina-17 , Histona Demetilasas con Dominio de Jumonji , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares , Factor de Transcripción STAT3 , Espondilitis Anquilosante , Células Th17 , Humanos , Espondilitis Anquilosante/genética , Espondilitis Anquilosante/metabolismo , Células Th17/metabolismo , Células Th17/citología , Células Th17/inmunología , Histona Demetilasas con Dominio de Jumonji/metabolismo , Histona Demetilasas con Dominio de Jumonji/genética , Histonas/metabolismo , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Interleucina-17/metabolismo , Interleucina-17/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Janus Quinasa 2/metabolismo , Janus Quinasa 2/genética , Metilación , Interleucinas/metabolismo , Interleucinas/genética , Interleucina-22 , Masculino , Femenino , Adulto

RESUMEN

Germline activating mutations in STAT3 cause a multi-systemic autoimmune and autoinflammatory condition. By studying a mouse model, Toth et al. (https://doi.org/10.1084/jem.20232091) propose a role for dysregulated IL-22 production by Th17 cells in causing some aspects of immune-mediated skin inflammation in human STAT3 GOF syndrome.

Asunto(s)

Interleucina-22 , Factor de Transcripción STAT3 , Piel , Células Th17 , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Animales , Humanos , Células Th17/inmunología , Células Th17/metabolismo , Piel/metabolismo , Piel/patología , Interleucinas/genética , Interleucinas/metabolismo , Mutación con Ganancia de Función , Ratones , Inflamación/metabolismo

RESUMEN

Oral administration of harmless antigens can induce suppression of reactive immune responses, a process that capitalises on the ability of the gastrointestinal tract to tolerate exposure to food and commensal microbiome without triggering inflammatory responses. Repeating exposure to type II collagen induces oral tolerance and inhibits induction of arthritis, a chronic inflammatory joint condition. Although some mechanisms underlying oral tolerance are described, how dysregulation of gut immune networks impacts on inflammation of distant tissues like the joints is unclear. We used undenatured type II collagen in a prophylactic regime -7.33 mg/kg three times/week- to describe the mechanisms associated with protective oral immune-therapy (OIT) in gut and joint during experimental Collagen-Induced Arthritis (CIA). OIT reduced disease incidence to 50%, with reduced expression of IL-17 and IL-22 in the joints of asymptomatic mice. Moreover, whilst the gut tissue of arthritic mice shows substantial damage and activation of tissue-specific immune networks, oral administration of undenatured type II collagen protects against gut pathology in all mice, symptomatic and asymptomatic, rewiring IL-17/IL-22 networks. Furthermore, gut fucosylation and microbiome composition were also modulated. These results corroborate the relevance of the gut-joint axis in arthritis, showing novel regulatory mechanisms linked to therapeutic OIT in joint disease.

Asunto(s)

Artritis Experimental , Colágeno Tipo II , Microbioma Gastrointestinal , Homeostasis , Animales , Artritis Experimental/inmunología , Artritis Experimental/prevención & control , Colágeno Tipo II/inmunología , Ratones , Microbioma Gastrointestinal/efectos de los fármacos , Masculino , Articulaciones/inmunología , Articulaciones/efectos de los fármacos , Articulaciones/patología , Ratones Endogámicos DBA , Interleucina-17/metabolismo , Interleucina-22 , Administración Oral

RESUMEN

SjÓ§gren's syndrome is a systemic autoimmune disease primarily targeting the salivary and lacrimal glands. Our previous investigations have shown that administration of interleukin-22 (IL-22), an IL-10 family cytokine known for its complex and context-dependent effects on tissues, either protective- or detrimental, to salivary glands leads to hypofunction and pathological changes of salivary glands in C57BL/6 mice and in non-obese diabetic (NOD) mice, the latter being a commonly used model of SjÓ§gren's syndrome. This study aims to delineate the pathophysiological roles of endogenously produced IL-22 in the development of salivary gland pathologies and dysfunction associated with SjÓ§gren's disease in the NOD mouse model. Our results reveal that neutralizing IL-22 offered a protective effect on salivary gland function without significantly affecting the immune cell infiltration of salivary glands or the autoantibody production. Blockade of IL-22 reduced the levels of phosphorylated STAT3 in salivary gland tissues of NOD mice, while its administration to salivary glands had the opposite effect. Correspondingly, the detrimental impact of exogenously applied IL-22 on salivary glands was almost completely abrogated by a specific STAT3 inhibitor. Moreover, IL-22 blockade led to a downregulation of protein amounts of Ten-Eleven-Translocation 2, a methylcytosine dioxygenase critical for mediating interferon-induced responses, in salivary gland epithelial cells. IL-22 neutralization also exerted a protective effect on the salivary gland epithelial cells that express high levels of surface EpCAM and bear the stem cell potential, and IL-22 treatment in vitro hampered the survival/expansion of these salivary gland stem cells, indicating a direct negative impact of IL-22 on these cells. In summary, this study has uncovered a critical pathogenic role of the endogenous IL-22 in the pathogenesis of Sjögren's disease-characteristic salivary gland dysfunction and provided initial evidence that this effect is dependent on STAT3 activation and potentially achieved through fostering Tet2-mediated interferon responses in salivary gland epithelial cells and negatively affecting the EpCAMhigh salivary gland stem cells.

Asunto(s)

Interleucina-22 , Glándulas Salivales , Síndrome de Sjögren , Animales , Femenino , Humanos , Ratones , Modelos Animales de Enfermedad , Interleucinas/inmunología , Interleucinas/metabolismo , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Glándulas Salivales/patología , Glándulas Salivales/inmunología , Glándulas Salivales/metabolismo , Síndrome de Sjögren/inmunología , Factor de Transcripción STAT3/metabolismo