Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Homeostatic regulation of Salmonella-induced mucosal inflammation and injury by IL-23.

ABSTRACT: IL-12 and IL-23 regulate innate and adaptive immunity to microbial pathogens through influencing the expression of IFN-?, IL-17, and IL-22. Herein we define the roles of IL-12 and IL-23 in regulating host resistance and intestinal inflammation during acute Salmonella infection. We find that IL-23 alone is dispensable for protection against systemic spread of bacteria, but synergizes with IL-12 for optimal protection. IL-12 promotes the production of IFN-? by NK cells, which is required for resistance against Salmonella and also for induction of intestinal inflammation and epithelial injury. In contrast, IL-23 controls the severity of inflammation by inhibiting IL-12A expression, reducing IFN-? and preventing excessive mucosal injury. Our studies demonstrate that IL-23 is a homeostatic regulator of IL-12-dependent, IFN-?-mediated intestinal inflammation.

SUBMITTER: Awoniyi M

PROVIDER: S-EPMC3356277 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Homeostatic regulation of Salmonella-induced mucosal inflammation and injury by IL-23.

Awoniyi Muyiwa M Miller Samuel I SI Wilson Christopher B CB Hajjar Adeline M AM Smith Kelly D KD

PloS one 20120518 5

IL-12 and IL-23 regulate innate and adaptive immunity to microbial pathogens through influencing the expression of IFN-γ, IL-17, and IL-22. Herein we define the roles of IL-12 and IL-23 in regulating host resistance and intestinal inflammation during acute Salmonella infection. We find that IL-23 alone is dispensable for protection against systemic spread of bacteria, but synergizes with IL-12 for optimal protection. IL-12 promotes the production of IFN-γ by NK cells, which is required for resis ...[more]

PMID: 22624013

Similar Datasets

BATF2 prevents T-cell-mediated intestinal inflammation through regulation of the IL-23/IL-17 pathway.

Project description:Inappropriate activation of the IL-23 signaling pathway causes chronic inflammation through the induction of immunopathological Th17 cells in several tissues including the intestine, whereas adequate Th17 responses are essential for host defense against harmful organisms. In the intestinal lamina propria, IL-23 is primarily produced by innate myeloid cells including dendritic cells (DCs) and macrophages (Mϕs). However, the molecular mechanisms underlying the regulation of IL-23 production by these cells remains poorly understood. In this study, we demonstrated that BATF2 regulates intestinal homeostasis by inhibiting IL-23-driven T-cell responses. Batf2 was highly expressed in intestinal innate myeloid subsets, such as monocytes, CD11b+ CD64+ Mϕs and CD103+ DCs. Batf2-/- mice spontaneously developed colitis and ileitis with altered microbiota composition. In this context, IL-23, but not TNF-α and IL-10, was produced in high quantities by intestinal CD11b+ CD64+ Mϕs from Batf2-/- mice compared with wild-type mice. Moreover, increased numbers of IFN-γ+, IL-17+ and IFN-γ+ IL-17+ CD4+ T cells, but not IL-10+ CD4+ T cells, accumulated in the colons and small intestines of Batf2-/- mice. In addition, RORγt-expressing innate lymphoid cells were increased in Batf2-/- mice. Batf2-/-Rag2-/- mice showed a reduction in intestinal inflammation present in Batf2-/- mice. Furthermore, the high numbers of intestinal IL-17+ and IFN-γ+ IL-17+ CD4+ T cells were markedly reduced in Batf2-/- mice when introducing Il23a deficiency, which was associated with the abrogation of intestinal inflammation. These results indicated that BATF2 in innate myeloid cells is a key molecule for the suppression of IL-23/IL-17 pathway-mediated adaptive intestinal pathology.

| S-EPMC6528702 | biostudies-literature

CCR6 is required for IL-23-induced psoriasis-like inflammation in mice.

Project description:Psoriasis is a common immune-mediated chronic inflammatory skin disorder, but the mechanisms of pathogenesis are still poorly understood. IL-23 is expressed in psoriatic skin, and IL-23 injection produces IL-22-dependent psoriasiform changes in mouse skin. Th17 cells produce IL-22 and display CCR6, the CCL20 receptor; CCR6+ T cells and CCL20 are abundant in psoriatic skin. We investigated a possible role for CCR6 in recruiting Th17 cells and producing psoriasiform pathology by injecting IL-23 into the skin of WT and Ccr6-/- mice. Unlike for WT mice, IL-23-injected ears of Ccr6-/- mice showed neither substantial epidermal/dermal changes nor increased Il22 mRNA expression. However, injection of IL-22 yielded equivalent psoriasiform changes in WT and Ccr6-/- mice. Surprisingly, IL-23-injected ears of WT and Ccr6-/- mice contained similar numbers of Th cells able to make IL-17A and/or IL-22. Furthermore, in ears of Rag1-/- mice, IL-23 initially induced skin changes and levels of Il22 mRNA that were indistinguishable from WT mice, revealing at least one non-T cell source for IL-22. We conclude that CCR6 is essential in a model of IL-23-induced, IL-22-mediated dermatitis, which develops in sequential T cell-independent and T cell-dependent phases. These findings reveal an expanded role for CCR6 in IL-23-related responses and identify CCR6 as a potential therapeutic target in psoriasis.

| S-EPMC2719919 | biostudies-literature

Prostaglandin mediates IL-23/IL-17-induced neutrophil migration in inflammation by inhibiting IL-12 and IFNgamma production.

Project description:IL-23/IL-17-induced neutrophil recruitment plays a pivotal role in rheumatoid arthritis (RA). However, the mechanism of the neutrophil recruitment is obscure. Here we report that prostaglandin enhances the IL-23/IL-17-induced neutrophil migration in a murine model of RA by inhibiting IL-12 and IFN gamma production. Methylated BSA (mBSA) and IL-23-induced neutrophil migration was inhibited by anti-IL-23 and anti-IL-17 antibodies, COX inhibitors, IL-12, or IFNgamma but was enhanced by prostaglandin E(2) (PGE(2)). IL-23-induced IL-17 production was increased by PGE(2) and suppressed by COX-inhibition or IL-12. Furthermore, COX inhibition failed to reduce IL-23-induced neutrophil migration in IL-12- or IFNgamma-deficient mice. IL-17-induced neutrophil migration was not affected by COX inhibitors, IL-12, or IFNgamma but was inhibited by MK886 (a leukotriene synthesis inhibitor), anti-TNFalpha, anti-CXCL1, and anti-CXCL5 antibodies and by repertaxin (a CXCR1/2 antagonist). These treatments all inhibited mBSA- or IL-23-induced neutrophil migration. IL-17 induced neutrophil chemotaxis through a CXC chemokines-dependent pathway. Our results suggest that prostaglandin plays an important role in IL-23-induced neutrophil migration in arthritis by enhancing IL-17 synthesis and by inhibiting IL-12 and IFNgamma production. We thus provide a mechanism for the pathogenic role of the IL-23/IL-17 axis in RA and also suggest an additional mechanism of action for nonsteroidal anti-inflammatory drugs.

| S-EPMC2667068 | biostudies-literature

Gpr109a Limits Microbiota-Induced IL-23 Production To Constrain ILC3-Mediated Colonic Inflammation.

Project description:A set of coordinated interactions between gut microbiota and the immune cells surveilling the intestine play a key role in shaping local immune responses and intestinal health. Gpr109a is a G protein-coupled receptor expressed at a very high level on innate immune cells and previously shown to play a key role in the induction of colonic regulatory T cells. In this study, we show that Gpr109a-/-Rag1-/- mice exhibit spontaneous rectal prolapse and colonic inflammation, characterized by the presence of an elevated number of IL-17-producing Ror?t+ innate lymphoid cells (ILCs; ILC3). Genetic deletion of Ror?t alleviated the spontaneous colonic inflammation in Gpr109a-/-Rag1-/- mice. Gpr109a-deficient colonic dendritic cells produce higher amounts of IL-23 and thereby promote ILC3. Moreover, the depletion of gut microbiota by antibiotics treatment decreased IL-23 production, ILC3, and colonic inflammation in Gpr109a-/-Rag1-/- mice. The ceca of Gpr109a-/-Rag1-/- mice showed significantly increased colonization by members of Bacteroidaceae, Porphyromonadaceae, Prevotellaceae, Streptococcaceae, Christensenellaceae, and Mogibacteriaceae, as well as IBD-associated microbiota such as Enterobacteriaceae and Mycoplasmataceae, compared with Rag1-/- mice, housed in a facility positive for Helicobacter and murine norovirus. Niacin, a Gpr109a agonist, suppressed both IL-23 production by colonic DCs and ILC3 number in a Gpr109a-dependent manner. Collectively, our data present a model suggesting that targeting Gpr109a will be potentially beneficial in the suppression of IL-23-mediated immunopathologies.

| S-EPMC5893356 | biostudies-literature

Homeostatic IL-23 receptor signaling limits Th17 response through IL-22-mediated containment of commensal microbiota.

Project description:Mammalian hosts are colonized with commensal microbes in various mucosal and epithelial tissues, including the intestinal tract. In mice, the presence of segmented filamentous bacteria (SFB) promotes Th17 differentiation and the development of autoimmune disease. Here, we demonstrate that the IL-23 pathway dynamically regulates the abundance of SFB as well as mucosal barrier function in the adult animal. Genetic or pharmacological inactivation of the pathway selectively perturbs the abundance of a small group of commensals, including SFB, and results in an impaired mucosal barrier. Defective barrier function leads to systemic dissemination of microbial products, provoking induction of the IL-23 pathway with dual consequences: IL-23 drives IL-22 production to reinforce mucosal barrier function and elicit antimicrobial activities, and it also drives the differentiation of Th17 cells in an attempt to combat escaped microbes in the lamina propria and in distal tissues. Thus, barrier defects generate a systemic environment that facilitates Th17 development.

| S-EPMC4183330 | biostudies-literature

Epithelial-derived IL-23 promotes oral mucosal immunopathology

Project description:At mucosal surfaces, epithelial cells provide a structural barrier and an immune defense system. However, dysregulated epithelial responses can contribute to disease states. Here, we demonstrate that epithelial intrinsic production of IL-23 triggers an inflammatory loop in the prevalent oral disease, periodontitis. Epithelial IL-23 expression localized to areas proximal to the disease-associated microbiome, is evident both in experimental models and in patients with common and genetic forms of disease. Mechanistically, flagellated microbial species of the periodontitis microbiome, trigger epithelial IL-23 induction in a TLR5-dependent manner. Intriguingly, unlike other Th17-driven diseases, here non-hematopoietic cell-derived IL-23 serves as an initiator of pathogenic inflammation. Beyond periodontitis, analysis of publicly available datasets reveals expression of epithelial IL-23 in settings of infection, malignancy, and autoimmunity, suggesting a broader role for epithelial-intrinsic IL-23 in human disease. Collectively, this work highlights an unappreciated role for the barrier epithelium in the induction of IL-23-mediated inflammation.

2024-05-08 | GSE243173 | GEO

An NK Cell Perforin Response Elicited via IL-18 Controls Mucosal Inflammation Kinetics during Salmonella Gut Infection.

Project description:Salmonella Typhimurium (S.Tm) is a common cause of self-limiting diarrhea. The mucosal inflammation is thought to arise from a standoff between the pathogen's virulence factors and the host's mucosal innate immune defenses, particularly the mucosal NAIP/NLRC4 inflammasome. However, it had remained unclear how this switches the gut from homeostasis to inflammation. This was studied using the streptomycin mouse model. S.Tm infections in knockout mice, cytokine inhibition and -injection experiments revealed that caspase-1 (not -11) dependent IL-18 is pivotal for inducing acute inflammation. IL-18 boosted NK cell chemoattractants and enhanced the NK cells' migratory capacity, thus promoting mucosal accumulation of mature, activated NK cells. NK cell depletion and Prf-/- ablation (but not granulocyte-depletion or T-cell deficiency) delayed tissue inflammation. Our data suggest an NK cell perforin response as one limiting factor in mounting gut mucosal inflammation. Thus, IL-18-elicited NK cell perforin responses seem to be critical for coordinating mucosal inflammation during early infection, when S.Tm strongly relies on virulence factors detectable by the inflammasome. This may have broad relevance for mucosal defense against microbial pathogens.

| S-EPMC4920399 | biostudies-literature

Engineered Lactococcus lactis Secreting IL-23 Receptor-Targeted REX Protein Blockers for Modulation of IL-23/Th17-Mediated Inflammation.

Project description:Lactococcus lactis, a probiotic bacterium of food origin, has recently been demonstrated as a suitable strain for the production and in vivo delivery of therapeutically important proteins into the gut. We aimed to engineer recombinant L. lactis cells producing/secreting REX binding proteins that have been described as IL-23 receptor (IL-23R) blockers and IL-23R antagonists suppressing the secretion of cytokine IL-17A, a pivotal step in the T-helper Th17-mediated pro-inflammatory cascade, as well as in the development of autoimmune diseases, including inflammatory bowel disease (IBD). To reach this goal, we introduced cDNA sequences coding for REX009, REX115, and REX125 proteins into plasmid vectors carrying a Usp45 secretion signal, a FLAG tag sequence consensus, and a LysM-containing cA surface anchor (AcmA), thus allowing cell-surface peptidoglycan anchoring. These plasmids, or their non-FLAG/non-AcmA versions, were introduced into L. lactis host cells, thus generating unique recombinant L. lactis-REX strains. We demonstrate that all three REX proteins are expressed in L. lactis cells and are efficiently displayed on the bacterial surface, as tested by flow cytometry using an anti-FLAG antibody conjugate. Upon 10-fold concentration of the conditioned media, a REX125 secretory variant can be detected by Western blotting. To confirm that the FLAG/non-FLAG REX proteins displayed by L. lactis retain their binding specificity, cell-surface interactions of REX proteins with an IL-23R-IgG chimera were demonstrated by flow cytometry. In addition, statistically significant binding of secreted REX009 and REX115 proteins to bacterially produced, soluble human IL-23R was confirmed by ELISA. We conclude that REX-secreting L. lactis strains were engineered that might serve as IL-23/IL-23R blockers in an experimentally induced mouse model of colitis.

| S-EPMC6560508 | biostudies-literature

Lacrimal gland-derived IL-22 regulates IL-17-mediated ocular mucosal inflammation.

Project description:Inflammatory damage of mucosal surface of the eye is a hallmark of dry eye disease (DED) and, in severe cases, can lead to significant discomfort, visual impairment, and blindness. DED is a multifactorial autoimmune disorder with a largely unknown pathogenesis. Using a cross-sectional patient study and a well-characterized murine model of DED, herein we investigated the immunoregulatory function of interleukin-22 (IL-22) in the pathogenesis of DED. We found that IL-22 levels were elevated in lacrimal fluids of DED patients and inversely correlated with severity of disease. Acinar cells of the lacrimal glands (LGs), not inflammatory immune cells, are the primary source of IL-22, which suppresses inflammation in ocular surface epithelial cells upon desiccating stress. Moreover, loss of function analyses using IL-22 knockout mice demonstrated that IL-22 is essential for suppression of ocular surface infiltration of Th17 cells and inhibition of DED induction. Our novel findings elucidate immunoregulatory function of LG-derived IL-22 in inhibiting IL-17-mediated ocular surface epitheliopathy in DED thus making IL-22 a new relevant therapeutic target.

| S-EPMC5496813 | biostudies-literature

Critical Role of LTB4/BLT1 in IL-23-Induced Synovial Inflammation and Osteoclastogenesis via NF-?B.

Project description:IL-23 activates the synthesis and production of leukotriene B4 (LTB4) in myeloid cells, which modulate inflammatory arthritis. In this study we investigated the role of LTB4 and its receptor LTB4R1 (BLT1) in synovial inflammation and osteoclast differentiation. Specifically, we used IL-23 in vivo gene transfer to induce arthritis in mice and showed that elevated serum LTB4 and synovial expression of 5-lipoxygenase correlated with increased disease severity by histological evaluation and paw swelling compared with GFP gene transfer controls. To further investigate the effect of the LTB4 pathway in bone loss, we performed osteoclast differentiation assays by stimulating with M-CSF and receptor activator of NF-?B ligand bone marrow cells derived from BLT1+/+ and/or BLT1-/- mice and used quantitative PCR for gene expression analysis in terminally differentiated osteoclasts. Deficiency in BLT1 resulted in the upregulation of osteoclast-related genes and an increase in the formation of giant, multinucleated TRAP+ cells capable of F-actin ring formation. Additionally, BLT1 deficiency showed an increase of phosphorylated NF-?B and phosphorylated I?B levels in osteoclasts. We also performed real-time calcium imaging to study the effect of BLT1 deficiency in receptor activator of NF-?-B ligand-induced activation of intracellular calcium flux in vitro. Our data show that LTB4 and its receptor BLT1 exacerbate synovial inflammation in vivo and bone resorption in vitro, suggesting that LTB4 and BLT1 could be effectively targeted for the treatment of musculoskeletal diseases.

| S-EPMC5173389 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data