Dietary and Microbial Oxazoles Induce Intestinal Inflammation by Modulating Aryl Hydrocarbon Receptor Responses.

Genome-wide association studies have identified risk loci associated with the development of inflammatory bowel disease, while epidemiological studies have emphasized that pathogenesis likely involves host interactions with environmental elements whose source and structure need to be defined. Here, we identify a class of compounds derived from dietary, microbial, and industrial sources that are characterized by the presence of a five-membered oxazole ring and induce CD1d-dependent intestinal inflammation. We observe that minimal oxazole structures modulate natural killer T cell-dependent inflammation by regulating lipid antigen presentation by CD1d on intestinal epithelial cells (IECs). CD1d-restricted production of interleukin 10 by IECs is limited through activity of the aryl hydrocarbon receptor (AhR) pathway in response to oxazole induction of tryptophan metabolites. As such, the depletion of the AhR in the intestinal epithelium abrogates oxazole-induced inflammation. In summary, we identify environmentally derived oxazoles as triggers of CD1d-dependent intestinal inflammatory responses that occur via activation of the AhR in the intestinal epithelium.

Localized microbially induced inflammation influences distant healthy tissues in the human oral cavity.

Variation in human immune response to the same bacterial or viral pathogen is well established in the literature. Variation in immune response to microbial challenge has also been observed within the human oral cavity. Our recent study focused on characterizing observed variations in microbially induced gingival inflammation-resulting in three distinct clinical Inflammatory Responder Types (IRTs): High-IRT, Low-IRT, and Slow-IRT. Here, we applied a high-resolution temporal multiomic analysis during microbially induced inflammation in order to characterize the effects of localized oral inflammation on distant healthy tissues in young healthy adults. Our results highlight a nonlocalized subclinical effect with alterations in proinflammatory host mediators and an ecological shift toward dysbiosis within the subgingival microbiome in an IRT-dependent manner-despite maintained oral hygiene. Our results provide mechanistic insight into how healthy tissues within humans are influenced by distant localized inflammation and may ultimately become susceptible to disease.

Zfp362 potentiates murine colonic inflammation by constraining Treg cell function rather than promoting Th17 cell differentiation.

Mucosal barrier integrity and pathogen clearance is a complex process influenced by both Th17 and Treg cells. Previously, we had described the DNA methylation profile of Th17 cells and identified Zinc finger protein (Zfp)362 to be uniquely demethylated. Here, we generated Zfp362-/- mice to unravel the role of Zfp362 for Th17 cell biology. Zfp362-/- mice appeared clinically normal, showed no phenotypic alterations in the T-cell compartment, and upon colonization with segmented filamentous bacteria, no effect of Zfp362 deficiency on Th17 cell differentiation was observed. By contrast, Zfp362 deletion resulted in increased frequencies of colonic Foxp3+ Treg cells and IL-10+ and RORγt+ Treg cell subsets in mesenteric lymph nodes. Adoptive transfer of naïve CD4+ T cells from Zfp362-/- mice into Rag2-/- mice resulted in a significantly lower weight loss when compared with controls receiving cells from Zfp362+/+ littermates. However, this attenuated weight loss did not correlate with alterations of Th17 cells but instead was associated with an increase of effector Treg cells in mesenteric lymph nodes. Together, these results suggest that Zfp362 plays an important role in promoting colonic inflammation; however, this function is derived from constraining the effector function of Treg cells rather than directly promoting Th17 cell differentiation.

The deposition of lanthanum carbonate may activate macrophages to induce gastrointestinal mucosal injury in patients with chronic kidney disease: an in vitro caco-2/THP-1 macrophage coculture model study.

The aim of this study was to investigate the effect and possible underlying mechanism of La2(CO3)3 deposition on GI mucosal inflammation. Our results showed that La2(CO3)3 can dissolve in artificial gastric fluids and form lanthanum phosphate (LaPO4) precipitates with an average size of about 1 µm. To mimic the intestinal mucosa and epithelial barrier, we established a Caco-2/THP-1 macrophage coculture model and a Caco-2 monoculture model, respectively. Our findings demonstrated that the medium of THP-1 macrophages stimulated by LaPO4 particles can damage the Caco-2 monolayer integrity in the coculture model, while the particles themselves had no direct impact on the Caco-2 monolayer integrity in the monoculture model. We measured values of trans-epithelial electrical resistance and detected images using a laser scanning confocal microscope. These results indicate that continuous stimulation of LaPO4 particles on macrophages can lead to a disruption of intestinal epithelium integrity. In addition, LaPO4 particles could stimulate THP-1 macrophages to secrete both IL-1ß and IL-8. Although LaPO4 particles can also promote Caco-2 cells to secrete IL-8, the secretion was much lower than that produced by THP-1 macrophages. In summary, the deposition of La2(CO3)3 has been shown to activate macrophages and induce damage to intestinal epithelial cells, which may exacerbate inflammation in patients with chronic kidney disease. Therefore, patients taking lanthanum carbonate, especially those with gastrointestinal mucosal inflammation, should be mindful of the potential for drug deposition in the GI system.

PTK2B regulates immune responses of neutrophils and protects mucosal inflammation in ulcerative colitis.

Neutrophils participate in the pathogenesis of ulcerative colitis (UC) through regulating the intestinal homeostasis. Several inflammatory diseases are reported to be regulated by proline-rich tyrosine kinase 2B (PTK2B). However, the role of PTK2B in regulating the function of neutrophils and the pathogenesis of UC remains unknown. In this study, the mRNA and protein levels of PTK2B in the colonic tissues from UC patients were measured by using quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry. TAE226, a PTK2B inhibitor, was used to inhibit the activity of PTK2B in neutrophils, and then, the pro-inflammatory factors were analyzed by using qRT-PCR and ELISA. To determine the role of PTK2B in intestinal inflammation, a dextran sulfate sodium (DSS)-induced colitis model was established in PTK2B gene knockout (PTK2B KO) and wild-type (WT) mice. We found that compared with healthy donor controls, the expression level of PTK2B was significantly elevated in inflamed mucosa from UC patients. In addition, expression of PTK2B was positively correlated with the severity of disease. Pharmacological inhibition of PTK2B could markedly reduce the generation of reactive oxygen species (ROS), myeloperoxidase (MPO), and antimicrobial peptides (S100a8 and S100a9) in neutrophils. The vitro study showed that tumor necrosis factor (TNF)-α is involved in promoting the expression of PTK2B in neutrophils. As expected, UC patients treated with infliximab, an anti-TNF-α agent, showed significantly reduced level of PTK2B in neutrophils, as well as in the intestinal mucosa. Of note, compared with DSS-treated WT mice, DSS-treated PTK2B KO mice showed more severe colitis symptoms. Mechanistically, PTK2B could enhance neutrophil migration by regulating CXCR2 and GRK2 expression via the p38 MAPK pathway. Additionally, mice treated with TAE226 exhibited the same effects. In conclusion, PTK2B is involved in the pathogenesis of UC by promoting the migration of neutrophils and inhibiting mucosal inflammation, highlighting PTK2B as a new potential therapeutic target to treat UC.

Photobiomodulation in dental implant stability and post-surgical healing and inflammation. A randomised double-blind study.

BACKGROUND: The aim of this randomized clinical trial was to evaluate the effect of diode laser photobiomodulation (PBM) on post-surgical healing, inflammation and implant stability. METHODS: Forty dental implants were inserted into 13 patients. The implants were randomly divided into two groups. The test group (PBM+) underwent two sessions of PBM (combined diode laser of 630 and 808 nm), the first of which after surgery, and the second, 7 days after the surgical procedure. The control group (PBM-) received simulated laser treatment. The implant stability quotient (ISQ) was determined immediately after the surgical procedure, and 7 days, 4 and 8 weeks later. Post-surgical inflammation was assessed following the criteria described by Bloemen and Cols. Healing was calculated using the healing index (HI). RESULTS: No differences were found in terms of the mean values of implant stability between the test and control groups over time. Only two of the implants (18.2%) from the PBM- group were classified with the maximum healing index (HI = 5), whereas in the PBM+ group, nine implants (45%) were classified with the aforementioned index (P < 0.0001). Using the logistic regression, it was determined that the non-application of the laser in the PBM- group caused an OR of 4.333 times of presenting inflammation (IC95% 1.150-16.323; P = 0.030). CONCLUSIONS: The application of 808 nm infra-red laser for bone tissue, and 630 nm for mucosal tissue in two sessions is considered to be an effective way of reducing inflammation and improving early healing. More studies are needed to confirm these results.

The implications of concomitant mucosal inflammation on clinical manifestations and outcomes of sinonasal inverted papilloma.

PURPOSE: This study examines the impact of concomitant mucosal inflammation on clinical manifestations and long-term outcomes of Inverted Papilloma (IP). METHODS: This retrospective cohort study was conducted in five tertiary medical centers. The included patients underwent an attachment-oriented surgical resection for IP with a minimum follow-up of 3 years. RESULTS: Of 185 patients with IP, 65 patients (35.1%) had synchronous mucosal inflammation with polypoid changes. The mean age was 56.7 years, and 69% were males. Most tumors originated from the maxillary sinus. Age, gender, Krouse stage, and tumor attachment site did not differ between the mucosal inflammation and IP-only groups. IP recurrence rate was twofold in the patients with mucosal inflammation (15.4% vs. 7.5%, p = 0.092). However, the difference was not significant, with a similar median time to recurrence between the two groups [15.5 (3-36) months vs. 16(6-96) months, p = 0.712]. In revision cases, IP recurred only in patients with mucosal inflammation (19% vs. 0%, p = 0.07). This group had a significantly worse 5-years recurrence-free survival than revision cases without mucosal inflammation (80.6% vs. 100%, p = 0.04). CONCLUSIONS: IP in the setting of mucosal inflammation might be associated with a higher recurrence rate, predominantly after revision surgery. Otolaryngologists should consider this during these patients' diagnosis, surgical planning, and follow-up.

Radiopathologic predictors of 1- and 2-year frontal sinusotomy outcomes in a southeast Asian chronic rhinosinusitis population.

BACKGROUND: The frontal sinus and its drainage pathway are difficult spaces to navigate surgically. The complexity of the frontal recess anatomy as well as inflammatory factors may influence outcomes of endoscopic frontal sinusotomy. It is not clear which factors are more important in determining post-operative frontal ostium patency. OBJECTIVE: The objective is to investigate whether the distribution of fronto-ethmoidal cells, frontal recess dimensions and sinonasal inflammation predict frontal ostium patency at 1- and 2-years after endoscopic frontal sinusotomy. METHODS: A retrospective review of 94 chronic rhinosinusitis patients (185 sides) who had undergone endoscopic frontal sinusotomies between 2015 and 2019 was conducted. Computed tomography was used to evaluate the type of fronto-ethmoidal cells present and determine the dimensions of the frontal recess. The International Classification of the Radiological Complexity of frontal recess and frontal sinus was used to grade the complexity of frontal recess anatomy. Mucosal inflammation was graded according to a structured histopathology report. Frontal ostium patency at 1- and 2-years post-operatively was recorded. RESULTS: The frontal ostium patency rates were 80.9% and 73.4% at 1- and 2-years respectively. Eosinophilic predominance (adjusted OR 3.5, 95% CI 1.6-8.0, p = 0.003) and mucosal ulceration on histology (adjusted OR 4.5, 95% CI 1.1-17.9, p = 0.033) predicted ostial stenosis at 1 year. Smoking (adjusted OR 7.6, 95% CI 2.4-24.7, p = 0.001), aspirin exacerbated respiratory disease (AERD) (adjusted OR 7.6, 95% CI 1.9-30.1, p = 0.004) and histological findings of severe inflammation (adjusted OR 8.9, 95% CI 1.9-41.2, p = 0.005) were independent predictors of ostial stenosis at 2 years. Frontal cell patterns, frontal recess dimensions and frontal recess complexity did not predict frontal ostium stenosis at both 1- and 2-years post-operatively. CONCLUSION: Post-operative control of sinonasal inflammation is important in maintaining frontal ostium patency, regardless of frontal cell patterns or frontal recess dimensions.

Evolution of Embryo Implantation Was Enabled by the Origin of Decidual Stromal Cells in Eutherian Mammals.

Mammalian pregnancy evolved in the therian stem lineage, that is, before the common ancestor of marsupials and eutherian (placental) mammals. Ancestral therian pregnancy likely involved a brief phase of attachment between the fetal and maternal tissues followed by parturition-similar to the situation in most marsupials including the opossum. In all eutherians, however, embryo attachment is followed by implantation, allowing for a stable fetal-maternal interface and an extended gestation. Embryo attachment induces an attachment reaction in the uterus that is homologous to an inflammatory response. Here, we elucidate the evolutionary mechanism by which the ancestral inflammatory response was transformed into embryo implantation in the eutherian lineage. We performed a comparative uterine transcriptomic and immunohistochemical study of three eutherians, armadillo (Dasypus novemcinctus), hyrax (Procavia capensis), and rabbit (Oryctolagus cuniculus); and one marsupial, opossum (Monodelphis domestica). Our results suggest that in the eutherian lineage, the ancestral inflammatory response was domesticated by suppressing one of its modules detrimental to pregnancy, namely, neutrophil recruitment by cytokine IL17A. Further, we propose that this suppression was mediated by decidual stromal cells, a novel cell type in eutherian mammals. We tested a prediction of this model in vitro and showed that decidual stromal cells can suppress the production of IL17A from helper T cells. Together, these results provide a mechanistic understanding of early stages in the evolution of eutherian pregnancy.

Inflammatory Bowel Diseases (IBD) and the Microbiome-Searching the Crime Scene for Clues.

Inflammatory bowel diseases (IBD) develop via convergence of environmental, microbial, immunological, and genetic factors. Alterations in the gut microbiota have been associated with development and progression of IBD, but it is not clear which populations of microbes are involved or how they might contribute to IBD. We review the genetic and environmental factors affecting the gut microbiota, the roles of gut microbes and their bioproducts in the development and clinical course of IBD, and strategies by which microbiome-based therapies can be used to prevent, manage, and eventually cure IBD. We discuss research findings that help bridge the gap between the basic sciences and clinical application.

Administration of probiotics to healthy volunteers: effects on reactivity of intestinal mucosa and systemic leukocytes.

BACKGROUND: Oral administration of health-promoting bacteria is increasingly used in clinical practise. These bacteria have anti-inflammatory characteristics and modulate the immune system without major reported side effects. The mechanisms of action are not yet fully defined. Our aim was to study systemic effects of probiotics by measurements of leukocytes as well as local effects on rectal mucosal biopsies after adding a standardized inflammatory stimulus in vitro. METHODS: Fourteen healthy subjects were randomized to receive 1010 colony forming units/day orally of the probiotic strain Lactiplantibacillus plantarum 299 (Lp299), n = 7, or Bifidobacterium infantis CURE21 (CURE21), n = 7, for six weeks. Rectal biopsies were taken before and after ingestion of either probiotic strain product, for stimulation in vitro with tumour necrosis factor alpha (TNF-α) at 10 and 100 ng/ml respectively up to 8 h. Blood tests were sampled before and after treatment. Lactate dehydrogenase (LDH) confirmed viable tissue. RESULTS: Composition of the intestinal microbiota was not changed. Systemic leukocytes decreased after administration of CURE21 (P<0.05) and Lp299 (P<0.01). Levels of the pro-inflammatory cytokine IL-6 in rectal mucosa after stimulation with TNF-α were attenuated after ingestion of Lp299. No effect was seen with CURE21. CONCLUSIONS: Administration of these probiotic strains to healthy humans show both a systemic and local reduction of inflammatory response by lowering leukocyte counts, and for Lp299 IL-6 levels in rectal mucosa. Probiotics may play an important role in the reduction of inflammatory responses expected after trauma during surgery or after pelvic irradiation. Trial registration Clinical Trials, registration number NCT01534572, retrospectively registered ( http://www.clinicaltrials.gov ).

Targeting gut barrier dysfunction with phytotherapies: Effective strategy against chronic diseases.

The intestinal epithelial layer serves as a physical and functional barrier between the microbe-rich lumen and immunologically active submucosa; it prevents systemic translocation of microbial pyrogenic products (e.g. endotoxin) that elicits immune activation upon translocation to the systemic circulation. Loss of barrier function has been associated with chronic 'low-grade' systemic inflammation which underlies pathogenesis of numerous no-communicable chronic inflammatory disease. Thus, targeting gut barrier dysfunction is an effective strategy for the prevention and/or treatment of chronic disease. This review intends to emphasize on the beneficial effects of herbal formulations, phytochemicals and traditional phytomedicines in attenuating intestinal barrier dysfunction. It also aims to provide a comprehensive understanding of intestinal-level events leading to a 'leaky-gut' and systemic complications mediated by endotoxemia. Additionally, a variety of detectable markers and diagnostic criteria utilized to evaluate barrier improving capacities of experimental therapeutics has been discussed. Collectively, this review provides rationale for targeting gut barrier dysfunction by phytotherapies for treating chronic diseases that are associated with endotoxemia-induced systemic inflammation.

Increased IgA anti-citrullinated protein antibodies in the periodontal inflammatory exudate of healthy individuals compared to rheumatoid arthritis patients.

AIM: To assess rheumatoid arthritis (RA)-associated autoantibodies in the gingivocrevicular fluid (GCF) of RA patients and healthy controls with or without periodontal disease, as chronic mucosal inflammation in periodontal disease is hypothesized to contribute to the formation of these autoantibodies. MATERIALS AND METHODS: Anti-citrullinated protein antibodies (ACPA), rheumatoid factor (RF), and their IgA isotypes were assessed in the serum and GCF of RA patients (n = 72) and healthy controls (HC, n = 151). The presence and levels of these antibodies were studied in relation to interleukin (IL)-8 and periodontal disease. RESULTS: In contrast to the HC, the levels of ACPA and RF in the serum and GCF of the RA patients were strongly correlated (p < .0001). The HC with high levels of IgA-ACPA (n = 27) also had significantly higher levels of total IgG, total IgA, and IL-8 in the GCF than the HC with low levels of IgA-ACPA in the GCF (n = 124). Periodontal inflammation and smoking were seen more frequently in the group with high levels of IgA-ACPA compared to the group with low IgA-ACPA. CONCLUSION: The IgA-ACPA in the GCF of HC may be associated with periodontal inflammation and smoking, and could be involved in the progression to RA.

Unravelling of nitric oxide signalling: A potential biomarker with multifaceted complex mechanism associated with canine inflammatory bowel disease (IBD).

Inflammatory bowel disease (IBD) is an important chronic condition associated with the infection affecting the gastrointestinal tract (G.I.) in dogs. Several factors' viz. gastrointestinal tract lymphoid tissue (GALT), permeability defects, genetic, ischemic, biochemical, psychosomatic disorders, infectious and parasitic agents, dietary allergies, and adverse drug reactions are associated with inflammatory bowel disease. The most noticeable clinical signs are vomiting, diarrhea, changes in appetite, weight loss, anorexia, ascites and peripheral edema. Nitric oxide (NO), a pleiotropic free radical messenger molecule plays an immense role in playing mucosal inflammation in the intestine through activation of NO synthase enzyme (iNOS). The complex mechanism associated with inflammation in the G.I. tract is also correlated with the expression of iNOS, enzymatic activity, and NO production. NO exerts a beneficial role in maintaining epithelial permeability as well as the immune response in acute colitis. But the excessive production of NO causes adverse effects. In the review, the author suggests that a complex phenomenon is associated with competing biochemical pathways triggered by NO through the regulation of mucosal inflammation in inflammatory bowel disease. This review is a unique compilation about the role of NO in the pathogenesis of inflammatory bowel disease of the dogs.

Pathobiology of neutrophil-epithelial interactions.

Polymorphonuclear neutrophils (PMNs) are innate immune system cells that play an essential role in eradicating invading pathogens. PMN migration to sites of infection/inflammation requires exiting the microcirculation and subsequent crossing of epithelial barriers in mucosa-lined organs such as the lungs and intestines. Although these processes usually occur without significant damage to surrounding host tissues, dysregulated/excessive PMN transmigration and resultant bystander-tissue damage are characteristic of numerous mucosal inflammatory disorders. Mechanisms controlling PMN extravasation have been well characterized, but the molecular details regarding regulation of PMN migration across mucosal epithelia are poorly understood. Given that PMN migration across mucosal epithelia is strongly correlated with disease symptoms in many inflammatory mucosal disorders, enhanced understanding of the mechanisms regulating PMN transepithelial migration should provide insights into clinically relevant tissue-targeted therapies aimed at ameliorating PMN-mediated bystander-tissue damage. This review will highlight current understanding of the molecular interactions between PMNs and mucosal epithelia and the associated functional consequences.

Comparative proteomics analysis indicates that palmatine contributes to transepithelial migration by regulating cellular adhesion.

CONTEXT: Palmatine, a biologically active isoquinoline alkaloid, possesses multiple pharmaceutical activities against mucosal infection and inflammation. OBJECTIVE: There are no reports about the influence of palmatine on uterine mucosal epithelial cells. MATERIALS AND METHODS: We used proteomics to analyse differentially expressed proteins (DEPs) in goat endometrial epithelial cells (EECs) stimulated by lipopolysaccharide (LPS, 5 µg/mL, the dosage can induce inflammatory response, according to our previous study) for 12 h and then treated with palmatine (80 µg/mL) for 8 h; the dosage was selected based on MTT assay. The EECs without any treatment were used as controls. Every group was treated in triplicate. RESULTS: A total of 428 DEPs in LPS-stimulated group and 486 DEPs in the palmatine-treated group were identified. Functional annotation analysis showed that palmatine mainly regulated the protein expression of structural molecules involved in the response to stimuli. Pathway analysis showed that cell adhesion molecule (CaM) pathways were most significant enriched due to palmatine treatment. Junction adhesion molecule 1 (JAM1), nectin 1 (NECT1) and cadherin 5 (CDH5), which play important roles in the transepithelial migration (TEpM) of leukocytes, were significantly downregulated by palmatine. Meanwhile, other proteins essential to the maintenance of cell adhesion and those that facilitate leukocyte migration were upregulated after palmatine treatment. Discussion and conclusions: The results suggested that palmatine regulates the expression of CaMs to affect TEpM during uterine mucosal inflammation and provides novel insight to understanding and developing palmatine pharmacology. Palmatine is a promising drug for treatment of mucosal inflammation.

[Expression of pro- and anti-apoptotic molecules in the mucous membrane of the nasal cavity with polypous rhinosinusitis]. / Ekspressiya pro- i antiapoptoticheskikh molekul v slizistoi obolochke polosti nosa pri polipoznom rinosinusite.

OBJECTIVE: To study the expression of proapoptotic (p53, p21) and antiapoptotic (MDM2) factors, as well as the distribution of proliferating PCNA-immunoreactive cells in the nasal mucosa in various types of polyposis rhinosinusitis (PRS). MATERIAL AND METHODS: We studied the immunolocalization of proapoptotic (p53, p21) and antiapoptotic (MDM2) factors, as well as the distribution of proliferating PCNA immunoreactive cells in the mucous membrane of the nasal cavity for various types of polypous rhinosinusitis. RESULTS AND DISCUSSION: Comparing with the control group, increased expression of all factors is detected. The main portion of marked cells is located in the loose connective tissue of the lamina propria of mucous membrane, a relatively small number of cells are detected in the epithelial layer. The edematous, eosinophilic (allergic) type of PRS is characterized by the expression of p53 and PCNA and by the reduction of MDM2 immunoreactive cells, while the expression of p53 and p21 is reduced in fibroinflammatory (neutrophilic) type. CONCLUSION: PRS is accompanied by epithelial metaplasia, by formation of inflammatory cell infiltrates, fibrosis and edema. The results are discussed in connection with the data on the regulatory role of apoptosis in the pathomorphism of chronic productive inflammation.

Renin-angiotensin system promotes colonic inflammation by inducing TH17 activation via JAK2/STAT pathway.

Previous studies suggest that the renin-angiotensin system (RAS) is a pathogenic factor for colitis. The goal of this study was to elucidate the molecular mechanism whereby angiotensin II (ANG II) promotes colonic inflammation. We found that renin was highly induced in colonic biopsies from patients with ulcerative colitis or Crohn's disease, and colonic renin and ANG II levels were markedly increased in a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model, indicating that the colonic RAS is activated in colitis. Renin transgenic (RenTg) mice exhibited increased phosphorylation in Janus kinase-2 (JAK2) and signal transducer and activator of transcription1/3 (STAT1/3) within colonic mucosa at baseline and following TNBS induction, suggesting that ANG II promotes colonic inflammation via the JAK2/STAT1/3 pathway. Treatment with pan-JAK inhibitor tofacitinib blocked JAK2 and STAT1/3 phosphorylation, attenuated T helper (TH)1 and TH17 responses, alleviated colitis, and prevented death of RenTg mice in TNBS model. ANG II stimulated JAK2/STAT1/3 phosphorylation in both Jurkat T lymphocytes and HCT116 epithelial cells. In vitro polarization assays demonstrated that ANG II directly promoted TH17 polarization, but not TH1 polarization, via JAK2/STAT1/3. ANG II stimulation of transforming growth factor-ß1 (TGFß1), IL-6, myosin light chain kinase, and p53 upregulated modulator of apoptosis in HCT116 cells was also mediated by JAK2/STAT1/3. These observations suggest that ANG II promotes TH17 polarization directly as well as indirectly by inducing production of TH17-polarizing cytokines (e.g., TGFß1 and IL-6) from colonic epithelial cells, both via the JAK2/STAT pathway. Therefore, colonic RAS promotes colonic inflammation, at least in part, by stimulating TH17 activation. NEW & NOTEWORTHY This study demonstrates that the local renin-angiotensin system in the colon is activated in colitis development, which promotes mucosal T helper cell activation through the JAK2/STAT pathway. These observations provide molecular evidence that the renin-angiotensin system is a pathogenic factor for the development of inflammatory bowel diseases.

Central Role of the NF-κB Pathway in the Scgb1a1-Expressing Epithelium in Mediating Respiratory Syncytial Virus-Induced Airway Inflammation.

Lower respiratory tract infection with respiratory syncytial virus (RSV) produces profound inflammation. Despite an understanding of the role of adaptive immunity in RSV infection, the identity of the major sentinel cells initially triggering inflammation is controversial. Here we evaluate the role of nonciliated secretoglobin (Scgb1a1)-expressing bronchiolar epithelial cells in RSV infection. Mice expressing a tamoxifen (TMX)-inducible Cre recombinase-estrogen receptor fusion protein (CreERTM) knocked into the Scgb1a1 locus were crossed with mice that harbor a RelA conditional allele (RelAfl ), with loxP sites flanking exons 5 to 8 of the Rel homology domain. The Scgb1a1CreERTM/+ × RelAfl/fl mouse is a RelA conditional knockout (RelACKO) of a nonciliated epithelial cell population enriched in the small bronchioles. TMX-treated RelACKO mice have reduced pulmonary neutrophilic infiltration and impaired expression and secretion of NF-κB-dependent cytokines in response to RSV. In addition, RelACKO mice had reduced expression levels of interferon (IFN) regulatory factor 1/7 (IRF1/7) and retinoic acid-inducible gene I (RIG-I), components of the mucosal IFN positive-feedback loop. We demonstrate that RSV replication induces RelA to complex with bromodomain-containing protein 4 (BRD4), a cofactor required for RNA polymerase II (Pol II) phosphorylation, activating the atypical histone acetyltransferase (HAT) activity of BRD4 required for phospho-Ser2 Pol II formation, histone H3K122 acetylation, and cytokine secretion in vitro and in vivo TMX-treated RelACKO mice have less weight loss and reduced airway obstruction/hyperreactivity yet similar levels of IFN-γ production despite higher levels of virus production. These data indicate that the nonciliated Scgb1a1-expressing epithelium is a major innate sensor for restricting RSV infection by mediating neutrophilic inflammation and chemokine and mucosal IFN production via the RelA-BRD4 pathway.IMPORTANCE RSV infection is the most common cause of infant hospitalizations in the United States, resulting in 2.1 million children annually requiring medical attention. RSV primarily infects nasal epithelial cells, spreading distally to produce severe lower respiratory tract infections. Our study examines the role of a nonciliated respiratory epithelial cell population in RSV infection. We genetically engineered a mouse that can be selectively depleted of the NF-κB/RelA transcription factor in this subset of epithelial cells. These mice show an impaired activation of the bromodomain-containing protein 4 (BRD4) coactivator, resulting in reduced cytokine expression and neutrophilic inflammation. During the course of RSV infection, epithelial RelA-depleted mice have reduced disease scores and airway hyperreactivity yet increased levels of virus replication. We conclude that RelA-BRD4 signaling in nonciliated bronchiolar epithelial cells mediates neutrophilic airway inflammation and disease severity. This complex is an attractive target to reduce the severity of infection.

Tripartite motif-containing (TRIM) 21 negatively regulates intestinal mucosal inflammation through inhibiting TH1/TH17 cell differentiation in patients with inflammatory bowel diseases.

BACKGROUND: Tripartite motif-containing (TRIM) 21 has been implicated in the pathogenesis of several types of autoimmune diseases. OBJECTIVE: We sought to elucidate TRIM21 expression in patients with inflammatory bowel diseases (IBDs) and its role in regulating intestinal mucosal inflammation. METHODS: TRIM21 expression was analyzed in the inflamed mucosa of patients with IBDs by means of quantitative RT-PCR and immunohistochemistry. Peripheral blood CD4+ T cells were transfected with lentivirus-expressing TRIM21 (LV-TRIM21) or LV-sh-TRIM21, and cytokine expression was determined by using quantitative RT-PCR and ELISA. TRIM21-/- mice were generated, and trinitrobenzene sulfonic acid- and CD45RBhighCD4+ T cell-induced colitis models were established to determine its role in induction of intestinal inflammation. RESULTS: TRIM21 was expressed predominantly in CD4+ T cells and decreased markedly in the inflamed mucosa of patients with IBDs compared with healthy control subjects. Ectopic expression of TRIM21 inhibited IBD CD4+ T cells to differentiate into TH1 and TH17 cells, whereas downregulation of TRIM21 had the opposite effects. TRIM21-/- mice had more severe colitis after administration of trinitrobenzene sulfonic acid compared with wild-type mice, which was characterized by increased expression of IFN-γ, TNF-α, and IL-17A in the colon. TRIM21-/-CD45RBhighCD4+ T cells reconstituted into recombination-activating gene (Rag1)-/- mice induced more severe colitis than in wild-type control mice. Mechanistically, interferon regulatory factor 3 was identified as a functional downstream target of TRIM21 in that silencing of interferon regulatory factor 3 suppressed TRIM21-/-CD4+ T-cell differentiation into TH1 and TH17 cells. CONCLUSIONS: TRIM21 plays a protective role in mucosal inflammation through inhibiting TH1 and TH17 cell differentiation. Thus TRIM21 might serve as a potential therapeutic target for the treatment of IBDs.