scholarly journals Adenosine metabolized from extracellular ATP promotes type 2 immunity through triggering A2BAR signaling on intestinal epithelial cells

2021 ◽  
Author(s):  
Darine W. El-Naccache ◽  
Fei Chen ◽  
Mark Palma ◽  
Alexander Lemenze ◽  
Wenhui Wu ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Extracellular Atp ◽  
Primary Response ◽  
Intestinal Epithelial ◽  
Intestinal Immunity ◽  
Heligmosomoides Polygyrus ◽  
Intestinal Nematode ◽  
Nematode Parasites ◽  
Type 2 Immunity

AbstractMulticellular intestinal nematode parasites can cross the epithelial barrier potentially causing tissue damage and release of danger associated molecular patterns (DAMPs) that may promote type 2 responses and host protective immunity. We investigated whether adenosine specifically binding the A2B adenosine receptor (A2BAR) on epithelial cells played an important role in driving intestinal immunity. Specific blockade of epithelial cell A2BAR inhibited the host protective memory response to the enteric helminth, Heligmosomoides polygyrus bakeri, including disruption of granuloma development at the host:parasite interface during the transient tissue dwelling larval stage. Memory T cell development was blocked during the primary response and transcriptional analyses revealed profound impairment of A2BAR signaling in epithelial cells and reduced type 2 markers by 24 hours after inoculation. Extracellular ATP was visualized by 24 hours after inoculation and shown in CD39 deficient mice to be critical for the adenosine production mediating initiation of type 2 immunity.

scholarly journals Intestinal epithelial cell secretion of RELM-β protects against gastrointestinal worm infection

2009 ◽  
Vol 206 (13) ◽  
pp. 2947-2957 ◽  
Author(s):  
De'Broski R. Herbert ◽  
Jun-Qi Yang ◽  
Simon P. Hogan ◽  
Kathryn Groschwitz ◽  
Marat Khodoun ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Trichinella Spiralis ◽  
Intestinal Lumen ◽  
Th2 Cells ◽  
Nippostrongylus Brasiliensis ◽  
Intestinal Epithelial ◽  
Cell Secretion ◽  
Heligmosomoides Polygyrus ◽  
Parasitic Helminths

Th2 cells drive protective immunity against most parasitic helminths, but few mechanisms have been demonstrated that facilitate pathogen clearance. We show that IL-4 and IL-13 protect against intestinal lumen-dwelling worms primarily by inducing intestinal epithelial cells (IECs) to differentiate into goblet cells that secrete resistin-like molecule (RELM) β. RELM-β is essential for normal spontaneous expulsion and IL-4–induced expulsion of Nippostrongylus brasiliensis and Heligmosomoides polygyrus, which both live in the intestinal lumen, but it does not contribute to immunity against Trichinella spiralis, which lives within IEC. RELM-β is nontoxic for H. polygyrus in vitro but directly inhibits the ability of worms to feed on host tissues during infection. This decreases H. polygyrus adenosine triphosphate content and fecundity. Importantly, RELM-β–driven immunity does not require T or B cells, alternative macrophage activation, or increased gut permeability. Thus, we demonstrate a novel mechanism for host protection at the mucosal interface that explains how stimulation of epithelial cells by IL-4 and IL-13 contributes to protection against parasitic helminthes that dwell in the intestinal lumen.

scholarly journals Campylobacter jejuni Drives MyD88-Independent Interleukin-6 Secretion via Toll-Like Receptor 2

2009 ◽  
Vol 77 (4) ◽  
pp. 1553-1560 ◽  
Author(s):  
Lorna M. Friis ◽  
Monika Keelan ◽  
Diane E. Taylor
Keyword(s):  
Epithelial Cells ◽  
Campylobacter Jejuni ◽  
Interleukin 6 ◽  
Fluid Transport ◽  
Gastrointestinal Disease ◽  
Primary Response ◽  
Intestinal Epithelial ◽  
Toll Like Receptor ◽  
Independent Manner ◽  
Toll Like Receptor 2

ABSTRACT Gastrointestinal disease caused by Campylobacter jejuni is characterized by localized inflammation and the destruction of the epithelial cell barrier that forms host innate protection against pathogens. This can lead to an imbalance in fluid transport across the gastrointestinal tract, resulting in severe diarrhea. The mechanisms of host cell receptor recognition of C. jejuni and downstream immune signaling pathways leading to this inflammatory disease, however, remain unclear. The aim of this study was to analyze the mechanisms involved in C. jejuni induction of the acute-phase inflammatory response regulator interleukin-6 (IL-6). Polarized intestinal epithelial Caco-2 monolayers responded to infections with Salmonella enterica serovar Typhimurium and eight isolates of C. jejuni by an increase in levels of expression and secretion of IL-6. No such IL-6 response, however, was produced upon infection with the human commensal organism Lactobacillus rhamnosus GG. The IL-6 signaling pathway was further characterized using short interfering RNA complexes to block gene expression. The inhibition of myeloid differentiation primary response protein 88 (MyD88) expression in this manner did not affect C. jejuni-induced IL-6 secretion, suggesting a MyD88-independent route to IL-6 signal transduction in C. jejuni-infected human epithelial cells. However, a significant reduction in levels of IL-6 was evident in the absence of Toll-like receptor 2 (TLR-2) expression, implying a requirement for TLR-2 in C. jejuni recognition. Caco-2 cells were also treated with heat-inactivated and purified membrane components of C. jejuni to isolate the factor responsible for triggering IL-6 signaling. The results demonstrate that C. jejuni surface polysaccharides induce IL-6 secretion from intestinal epithelial cells via TLR-2 in a MyD88-independent manner.

scholarly journals A mechanism for the induction of type 2 immune responses by a protease allergen in the genital tract

2017 ◽  
Vol 114 (7) ◽  
pp. E1188-E1195 ◽  
Author(s):  
Ji Eun Oh ◽  
Dong Sun Oh ◽  
Hi Eun Jung ◽  
Heung Kyu Lee
Keyword(s):  
Immune Responses ◽  
Genital Tract ◽  
Primary Response ◽  
Lymphoid Cells ◽  
Genital Mucosa ◽  
Type 2 Immunity ◽  
Parasite Infections ◽  
Barrier Surface ◽  
External Stimuli

The genital mucosa is a barrier that is constantly exposed to a variety of pathogens, allergens, and external stimuli. Although both allergen exposure and parasite infections frequently occur in the genital area, the mechanism by which immune responses—particularly type 2 immunity—are induced has rarely been studied in the genital mucosa. Here, we demonstrate the induction of T helper type 2 (Th2) immunity in the genital mucosa in response to a model allergen, the protease papain. Intravaginal papain immunization induced type 2 immunity in a manner that was dependent on protease activity and the estrous phase of the mice. In addition, IL-33 was released from the vaginal epithelia after intravaginal papain immunization, leading to the activation of type 2 innate lymphoid cells (ILC2s). Moreover, the IL-33–MyD88 (myeloid differentiation primary response gene 88) signaling pathway was critical for the induction of type 2 immunity. We also found that Th2 differentiation in response to intravaginal papain treatment requires a specific dendritic cell (DC) subset that is controlled by interferon regulatory factor 4 (IRF4). These findings suggest that type 2 immunity is induced by a unique mechanism in the genital tract, which is an important, but often overlooked, barrier surface.

The Stress signal extracellular ATP modulates antiflagellin immune responses in intestinal epithelial cells

2011 ◽  
Vol 17 (1) ◽  
pp. 319-333 ◽  
Author(s):  
Sabine M. Ivison ◽  
Megan E. Himmel ◽  
Matt Mayer ◽  
Yu Yao ◽  
Arnawaz Kifayet ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Immune Responses ◽  
Intestinal Epithelial Cells ◽  
Extracellular Atp ◽  
Intestinal Epithelial ◽  
Stress Signal

scholarly journals A helminth-derived suppressor of ST2 blocks allergic responses

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Francesco Vacca ◽  
Caroline Chauché ◽  
Abhishek Jamwal ◽  
Elizabeth C Hinchy ◽  
Graham Heieis ◽  
...  
Keyword(s):  
Immune Responses ◽  
Heligmosomoides Polygyrus ◽  
Human Pbmc ◽  
Complement Control Protein ◽  
High Affinity ◽  
Intestinal Nematode ◽  
Control Protein

The IL-33-ST2 pathway is an important initiator of type 2 immune responses. We previously characterised the HpARI protein secreted by the model intestinal nematode Heligmosomoides polygyrus, which binds and blocks IL-33. Here, we identify H. polygyrus Binds Alarmin Receptor and Inhibits (HpBARI) and HpBARI_Hom2, both of which consist of complement control protein (CCP) domains, similarly to the immunomodulatory HpARI and Hp-TGM proteins. HpBARI binds murine ST2, inhibiting cell surface detection of ST2, preventing IL-33-ST2 interactions, and inhibiting IL-33 responses in vitro and in an in vivo mouse model of asthma. In H. polygyrus infection, ST2 detection is abrogated in the peritoneal cavity and lung, consistent with systemic effects of HpBARI. HpBARI_Hom2 also binds human ST2 with high affinity, and effectively blocks human PBMC responses to IL-33. Thus, we show that H. polygyrus blocks the IL-33 pathway via both HpARI which blocks the cytokine, and also HpBARI which blocks the receptor.

scholarly journals Migratory CD103+ dendritic cells suppress helminth-driven type 2 immunity through constitutive expression of IL-12

2015 ◽  
Vol 213 (1) ◽  
pp. 35-51 ◽  
Author(s):  
Bart Everts ◽  
Roxane Tussiwand ◽  
Leentje Dreesen ◽  
Keke C. Fairfax ◽  
Stanley Ching-Cheng Huang ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Constitutive Expression ◽  
Helminth Parasites ◽  
Th2 Response ◽  
Heligmosomoides Polygyrus ◽  
Th2 Cell ◽  
Type 2 Immunity ◽  
Necessary And Sufficient

CD8α+ and CD103+ dendritic cells (DCs) play a central role in the development of type 1 immune responses. However, their role in type 2 immunity remains unclear. We examined this issue using Batf3−/− mice, in which both of these DC subsets are missing. We found that Th2 cell responses, and related events such as eosinophilia, alternative macrophage activation, and immunoglobulin class switching to IgG1, were enhanced in Batf3−/− mice responding to helminth parasites. This had beneficial or detrimental consequences depending on the context. For example, Batf3 deficiency converted a normally chronic intestinal infection with Heligmosomoides polygyrus into an infection that was rapidly controlled. However, liver fibrosis, an IL-13–mediated pathological consequence of wound healing in chronic schistosomiasis, was exacerbated in Batf3−/− mice infected with Schistosoma mansoni. Mechanistically, steady-state production of IL-12 by migratory CD103+ DCs, independent of signals from commensals or TLR-initiated events, was necessary and sufficient to exert the suppressive effects on Th2 response development. These findings identify a previously unrecognized role for migratory CD103+ DCs in antagonizing type 2 immune responses.

scholarly journals Exosomes secreted by nematode parasites transfer small RNAs to mammalian cells and modulate innate immunity

2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Amy H. Buck ◽  
Gillian Coakley ◽  
Fabio Simbari ◽  
Henry J. McSorley ◽  
Juan F. Quintana ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Gastrointestinal Nematode ◽  
Parasitic Nematodes ◽  
Heligmosomoides Polygyrus ◽  
Nematode Parasites ◽  
Intestinal Origin ◽  
Mouse Cells ◽  
Host Tissues

Abstract In mammalian systems RNA can move between cells via vesicles. Here we demonstrate that the gastrointestinal nematode Heligmosomoides polygyrus, which infects mice, secretes vesicles containing microRNAs (miRNAs) and Y RNAs as well as a nematode Argonaute protein. These vesicles are of intestinal origin and are enriched for homologues of mammalian exosome proteins. Administration of the nematode exosomes to mice suppresses Type 2 innate responses and eosinophilia induced by the allergen Alternaria. Microarray analysis of mouse cells incubated with nematode exosomes in vitro identifies Il33r and Dusp1 as suppressed genes, and Dusp1 can be repressed by nematode miRNAs based on a reporter assay. We further identify miRNAs from the filarial nematode Litomosoides sigmodontis in the serum of infected mice, suggesting that miRNA secretion into host tissues is conserved among parasitic nematodes. These results reveal exosomes as another mechanism by which helminths manipulate their hosts and provide a mechanistic framework for RNA transfer between animal species.

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