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A c-type lectin triggers immune surveillance by innate lymphoid cells for eradication of attaching-and-effacing bacteria.

ABSTRACT: Although gut protection to infection is ensured by innate lymphoid cells (ILCs), how ILCs are regulated remains poorly understood. Here, we show that secretion of the c-type lectin Reg3b downstream of Ripk2 signaling pathway was crucial for immune surveillance by ILCs against Citrobacter rodentium that mimics human infection with attaching-and-effacing bacteria. Unexpectedly, phosphorylation of signal transducer and activator of transcription 3 (STAT3) and secretion of both tumor necrosis factor alpha (Tnf-a) and interleukin-17A (IL-17A) were blunted in mutant mice contributing to their susceptibility to a primary infection. We further determined that influx of neutrophils was triggered by Reg3b through an intact IL-17A signaling. Loss of either Reg3b or Ripk2 weakened Tnf-a secretion by intestinal phagocytes lowering their propensity to promote IL17A secretion by ILCs early in infection. These results provide a previously unrecognized mechanism by which intestinal epithelial cells reciprocally regulate early production of IL-17A by ILCs preventing from overcolonization by opportunistic enteropathogenic bacterium.

ORGANISM(S): Mus musculus

PROVIDER: GSE95653 | GEO | 2019/03/31

REPOSITORIES: GEO

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IL-22 plays an indispensable role in early host defense against attaching and effacing (A/E) bacterial pathogens

Project description:Infection by attaching and effacing (A/E) pathogens poses a serious threat to public health, as was highlighted by the recent outbreak of E. coli O157:H7 infection in the United States. Here, by using a murine A/E pathogen, Citrobacter rodentium, we demonstrate that C. rodentium infection is lethal to IL-22-/- mice within two weeks. IL-22, in the early phase of infection, is indispensable for preventing the invasion of bacteria through the intestinal epithelium, and thereby preventing systemic spread and mortality. We also show that IL-23 is required for the early induction of IL-22 during C. rodentium infection. Finally, our data suggest that IL-22 exerts its function by boosting the innate immune responses of colonic epithelial cells, especially though the induction of anti-microbial proteins, RegIIIβ and RegIIIγ. Keywords: treatment comparison

2008-02-11 | GSE10010 | GEO

Deconstructing a type III secretion system effector network unravels the inherent robustness and plasticity in pathogenesis and immunity

Project description:Many Gram-negative pathogens use type III secretion systems to inject networks of effectors that subvert host cell processes. We modelled the robustness of such network using the mouse pathogen Citrobacter rodentium (encoding 31 effectors) through sequential deletions of effector genes, generating 100 distinct mutant combinations, which were tested in vivo. Counterintuitively, mutants lacking 19 unrelated effectors (CR14) or 10 immune-modulating effectors (CRi9) colonised and induced conserved molecular signatures of infection in intestinal epithelial cells. Specifically, CRi9 triggered heightened colonic secretion of TNF, IL-22, IL-17A and IFN-γ, while CR14 induced high-level secretion of IL-6 and GM-CSF with lower recruitment of myeloid cells. Yet, both CR14 and CRi9 induced sterile immunity. A machine learning model, trained on the mutant phenotypes and effector function, predicted an unprecedented combination of colonisation-failure effector mutations, which was validated experimentally. These results reveal the robustness and combinatorial plasticity of both the effector network and host immunity.

2022-04-06 | PXD018740 | Pride

IL-17A plays a central role in the expression of psoriasis signature genes through induction of IkappaB-zeta in keratinocytes

Project description:In psoriasis lesions, a diverse mixture of cytokines is upregulated which influence each other generating a complex inflammatory situation. Although this is the case, the inhibition of Interleukin-17A (IL-17A) alone showed unprecedented clinical results in patients, indicating that IL-17A is a critical inducer of psoriasis pathogenesis. To elucidate IL-17A-driven keratinocyte-intrinsic signaling pathways, we treated monolayers of normal human epidermal keratinocytes in vitro with a mixture of 6 cytokines (IL-17A, TNF-a, IL-17C, IL-22, IL-36g and IFN-g) involved in psoriasis, to mimic the inflammatory milieu in psoriasis lesions. Microarray and gene set enrichment analysis revealed that this cytokine mixture induced similar gene expression changes with the previous transcriptome studies using psoriasis lesions. Importantly, we identified a set of IL-17A-regulated genes in keratinocytes, which recapitulate typical psoriasis genes exemplified by DEFB4A, S100A7, IL19 and CSF3, based on differences in the expression profiles of cells stimulated with 6 cytokines versus cells stimulated with only 5 cytokines lacking IL-17A. Furthermore a specific IL-17A-induced gene, NFKBIZ, which encodes IkappaB-zeta, a transcriptional regulator for NF-kappaB, was demonstrated to have a significant role for IL-17A-induced gene expression. Thus, we present novel in vitro data from normal human keratinocytes that would help elucidating the IL-17A-driven keratinocyte activation in psoriasis. Cytokine mixture-induced gene expression in primary normal human epidermal keratinocytes (NHEKs) was measured at 24 hours after exposure. NHEKs were exposed to the combination of selected six cytokines (IL-17A: 100 ng/ml, TNF-a: 10 ng/ml, IFN-g: 10 ng/ml, IL-17C: 100 ng/ml, IL-22: 100 ng/ml, IL-36g: 500 ng/ml) , or to the different combinations of five of the six cytokines (in total, 7 different treatments and one untreated control). No replicate experiments were conducted.

2016-03-08 | E-GEOD-77719 | biostudies-arrayexpress

Type Three Secretion System in Attaching and Effacing Pathogens.

Project description:Enteropathogenic Escherichia coli and enterohemorrhagic E. coli are diarrheagenic bacterial human pathogens that cause severe gastroenteritis. These enteric pathotypes, together with the mouse pathogen Citrobacter rodentium, belong to the family of attaching and effacing pathogens that form a distinctive histological lesion in the intestinal epithelium. The virulence of these bacteria depends on a type III secretion system (T3SS), which mediates the translocation of effector proteins from the bacterial cytosol into the infected cells. The core architecture of the T3SS consists of a multi-ring basal body embedded in the bacterial membranes, a periplasmic inner rod, a transmembrane export apparatus in the inner membrane, and cytosolic components including an ATPase complex and the C-ring. In addition, two distinct hollow appendages are assembled on the extracellular face of the basal body creating a channel for protein secretion: an approximately 23 nm needle, and a filament that extends up to 600 nm. This filamentous structure allows these pathogens to get through the host cells mucus barrier. Upon contact with the target cell, a translocation pore is assembled in the host membrane through which the effector proteins are injected. Assembly of the T3SS is strictly regulated to ensure proper timing of substrate secretion. The different type III substrates coexist in the bacterial cytoplasm, and their hierarchical secretion is determined by specialized chaperones in coordination with two molecular switches and the so-called sorting platform. In this review, we present recent advances in the understanding of the T3SS in attaching and effacing pathogens.

| S-EPMC5073101 | biostudies-literature

IL-17A Promotes HIV-1 Dissemination/Replication and abrogates the Interferon-Mediated Antiviral Immunity in Intestinal Epithelial Cells

Project description:The crosstalk between intestinal epithelial cells (IEC) and Th17-polarized CD4+ T-cells is critical for mucosal homeostasis, with HIV-1 causing major alterations in people living with HIV (PLWH) despite antiretroviral therapy (ART). Here, we used a model of IEC:T-cell co-culture to investigate the effects of IL-17A and TNF, two cytokines produced by Th17-cells, in regulating IEC ability to promote de novo infection and viral outgrowth from reservoir cells. Our results demonstrated that IL-17A in the presence/absence of TNF acts on IEC to increase HIV capture and trans infection of CD3/CD28-activated T-cells from uninfected individuals. Also, IL-17A-exposed IEC significantly increased HIV replication and outgrowth in CD3/CD28-activated T-cells infected with HIV in vitro and isolated from ART-treated PLWH, respectively. Exposure of IEC to IL-17A resulted in decreased type I IFN levels, as measured using the 293T-KEK cell based assay. Illumina RNA sequencing performed on cytokine-activated IEC before/after co-culture with T-cells of ART-treated PLWH revealed a molecular signature associated with IL-17A-mediated proviral effects. This signature includes decreased expression of transcripts linked to type I IFN production/response (DDX60, IRF7, STAT1) and HIV restriction (IFITM1, TRIM5, IF2AK2, MX1, MX2, IFIT1,3,5, PARP12, HERC6, ISG15, viperin, BST2, OAS2/3), and increased expression of Th17-attracting chemokines (CCL20).

2021-03-01 | GSE147045 | GEO

IL-1beta activates IL-17 via calcium

Project description:IL-17A production via NLRP3 inflammasome-dependent IL-1β secretion aginst Pneumococcal inflammation in mice

2018-12-25 | GSE118195 | GEO

Vγ6+ γδ T cells play a critical role in protection against infection by Escherichia coli

Project description:γδ T cells producing interleukin 17A (IL-17A), which are mainly Vγ4 and Vγ6 subsets, are involved in protection against infection by extracellular bacteria. Using a new Vγ6-specific monoclonal antibody (mAb) (1C10-1F7) which we recently developed, we found that IL-17A+ Vγ6+ γδ T cells increased predominantly in the peritoneal cavity compared with IL-17A+ Vγ4+ γδ T cells during intraperitoneal Escherichia coli infection. The number of IL-17A+ Vγ6+ γδ T cells, which rapidly became CD69+ from CD69-, peaked at 12 h after infection. In vivo treatment with 1C10-1F7 mAb significantly inhibited the accumulation of neutrophils and hampered the resolution of E. coli infection. These results suggest that rapid activation of IL-17A+ Vγ6+ γδ T cells contributed to host defence against E. coli infection.

2020-02-28 | GSE144617 | GEO

Gene expression of Listeria monocytogenes-infected HepG2 hepatocellular carcinoma in the presense of IL-17Aand IL-22

Project description:IL-17A and IL-22 induced several inflammation-induced genes and anti-microbial molecules including Pla2g2a and Lcn2 on HepG2 cells when the cells were treated with the cytokines before Listeria monocytogenes infection. HepG2 cells were treated with 50 ng/ml IL-17A and 10 ng/ml IL-22 before L. monocytogenes in vitro infection at MOI 10. Reference cells were not treated with the cytokines before the infection. Two independent experiments were carried out.

2015-12-17 | E-GEOD-71248 | biostudies-arrayexpress

Effects of siRNA gene silencing on transcriptional responses of human synovial fibroblasts to TNF and IL-17A (RNA-seq Data 2)

Project description:TNF and IL-17A synergistic effects on gene expression after silencing CUX1, LIFR, STAT3, STAT4, ELF3

2019-06-01 | GSE129487 | GEO

Systemic human ILC precursors provide a substrate for tissue ILC differentiation

Project description:Innate lymphoid cells (ILCs) represent innate versions of T helper and cytotoxic T cells that differentiate from committed ILC precursors (ILCP). Still, how ILCP relate to mature tissue-resident ILCs remains unclear. We identify ILCP that are present in the blood and all tested lymphoid and non-lymphoid human tissues. Human ILCP fail to express the signature transcription factors (TF) and cytokine outputs of mature NK cells and ILCs but are epigenetically poised to do so. Human ILCP robustly generate all ILC subsets in vitro and in vivo. While human ILCP express RAR related orphan receptor C (RORC), circulating ILCP can be found in RORC-deficient patients that retain potential for EOMES+ NK cells, T-BET+ ILC1, GATA-3+ ILC2 and for IL-22+ but not for IL-17A+ ILC3. We propose a model of tissue ILC differentiation (‘ILC-poiesis’) whereby diverse ILC subsets are generated in situ from ILCP in response to environmental stressors, inflammation and infection.

2017-03-19 | GSE90640 | GEO

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