scholarly journals Up-regulation of gasdermin C in mouse small intestine is associated with lytic cell death in enterocytes in worm-induced type 2 immunity

2021 ◽  
Vol 118 (30) ◽  
pp. e2026307118
Author(s):  
Ranhui Xi ◽  
Julia Montague ◽  
Xiaoli Lin ◽  
Chanyi Lu ◽  
Weiwei Lei ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Expansion ◽  
Lymphoid Cells ◽  
Hek293 Cells ◽  
Classical Type ◽  
Wild Type ◽  
Villus Atrophy ◽  
Type 2 Immunity ◽  
Tuft Cell

“Taste-like” tuft cells in the intestine trigger type 2 immunity in response to worm infection. The secretion of interleukin-13 (IL-13) from type 2 innate lymphoid cells (ILC2) represents a key step in the tuft cell–ILC2 cell–intestinal epithelial cell circuit that drives the clearance of worms from the gut via type 2 immune responses. Hallmark features of type 2 responses include tissue remodeling, such as tuft and goblet cell expansion, and villus atrophy, yet it remains unclear if additional molecular changes in the gut epithelium facilitate the clearance of worms from the gut. Using gut organoids, we demonstrated that IL-4 and IL-13, two type 2 cytokines with similar functions, not only induced the classical type 2 responses (e.g., tuft cell expansion) but also drastically up-regulated the expression of gasdermin C genes (Gsdmcs). Using an in vivo worm-induced type 2 immunity model, we confirmed the up-regulation of Gsdmcs in Nippostrongylus brasiliensis–infected wild-type C57BL/6 mice. Consistent with gasdermin family members being principal effectors of pyroptosis, overexpression of Gsdmc2 in human embryonic kidney 293 (HEK293) cells triggered pyroptosis and lytic cell death. Moreover, in intestinal organoids treated with IL-4 or IL-13, or in wild-type mice infected with N. brasiliensis, lytic cell death increased, which may account for villus atrophy observed in worm-infected mice. Thus, we propose that the up-regulated Gsdmc family may be major effectors for type 2 responses in the gut and that Gsdmc-mediated pyroptosis may provide a conduit for the release of antiparasitic factors from enterocytes to facilitate the clearance of worms.

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.

scholarly journals Concerted IL-25R and IL-4Rα signaling drive innate type 2 effector immunity for optimal helminth expulsion

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Katherine A Smith ◽  
Stephan Löser ◽  
Fumi Varyani ◽  
Yvonne Harcus ◽  
Henry J McSorley ◽  
...  
Keyword(s):  
Chronic Infection ◽  
Lymphoid Cells ◽  
Helminth Parasites ◽  
Wild Type ◽  
Heligmosomoides Polygyrus ◽  
Innate Effector ◽  
Interleukin 25 ◽  
Deficient Mice

Interleukin 25 (IL-25) is a major 'alarmin' cytokine, capable of initiating and amplifying the type immune response to helminth parasites. However, its role in the later effector phase of clearing chronic infection remains unclear. The helminth Heligmosomoides polygyrus establishes long-term infections in susceptible C57BL/6 mice, but is slowly expelled in BALB/c mice from day 14 onwards. We noted that IL-25R (Il17rb)-deficient BALB/c mice were unable to expel parasites despite type 2 immune activation comparable to the wild-type. We then established that in C57BL/6 mice, IL-25 adminstered late in infection (days 14–17) drove immunity. Moreover, when IL-25 and IL-4 were delivered to Rag1-deficient mice, the combination resulted in near complete expulsion of the parasite, even following administration of an anti-CD90 antibody to deplete innate lymphoid cells (ILCs). Hence, effective anti-helminth immunity during chronic infection requires an innate effector cell population that is synergistically activated by the combination of IL-4Rα and IL-25R signaling.

scholarly journals Development of Recombinant Cell Line Co-expressing Mutated Nav1.5, Kir2.1, and hERG for the Safety Assay of Drug Candidates

2012 ◽  
Vol 17 (6) ◽  
pp. 773-784 ◽  
Author(s):  
Masato Fujii ◽  
Susumu Ohya ◽  
Hisao Yamamura ◽  
Yuji Imaizumi
Keyword(s):  
Cell Death ◽  
Cell Line ◽  
Gene Transfection ◽  
Screening Method ◽  
Hek293 Cells ◽  
Wild Type ◽  
Single Action ◽  
Channel Inhibition ◽  
Recombinant Cell Line ◽  
Recombinant Cell

To provide a high-throughput screening method for human ether-a-go-go-gene–related gene (hERG) K+ channel inhibition, a new recombinant cell line, in which single action potential (AP)–induced cell death was produced by gene transfection. Mutated human cardiac Na+ channel Nav1.5 (IFM/Q3), which shows extremely slow inactivation, and wild-type inward rectifier K+ channel, Kir2.1, were stably co-expressed in HEK293 cells (IFM/Q3+Kir2.1). In IFM/Q3+Kir2.1, application of single electrical stimulation (ES) elicited a long AP lasting more than 30 s and led cells to die by more than 70%, whereas HEK293 co-transfected with wild-type Nav1.5 and Kir2.1 fully survived. The additional expression of hERG K+ channels in IFM/Q3+Kir2.1 shortened the duration of evoked AP and thereby markedly reduced the cell death. The treatment of the cells with hERG channel inhibitors such as nifekalant, E-4031, cisapride, terfenadine, and verapamil, recovered the prolonged AP and dose-dependently facilitated cell death upon ES. The EC50 values to induce the cell death were 3 µM, 19 nM, 17 nM, 74 nM, and 3 µM, respectively, whereas 10 µM nifedipine did not induce cell death. Results indicate the high utility of this cell system for hERG K+ channel safety assay.

scholarly journals Activation of intestinal tuft cell-expressed Sucnr1 triggers type 2 immunity in the mouse small intestine

2018 ◽  
Vol 115 (21) ◽  
pp. 5552-5557 ◽  
Author(s):  
Weiwei Lei ◽  
Wenwen Ren ◽  
Makoto Ohmoto ◽  
Joseph F. Urban ◽  
Ichiro Matsumoto ◽  
...  
Keyword(s):  
Goblet Cell ◽  
Mucosal Immunity ◽  
Cell Activation ◽  
Nippostrongylus Brasiliensis ◽  
Infectious Agents ◽  
Cell Hyperplasia ◽  
Type 2 Immunity ◽  
Tuft Cell ◽  
Tuft Cells

The hallmark features of type 2 mucosal immunity include intestinal tuft and goblet cell expansion initiated by tuft cell activation. How infectious agents that induce type 2 mucosal immunity are detected by tuft cells is unknown. Published microarray analysis suggested that succinate receptor 1 (Sucnr1) is specifically expressed in tuft cells. Thus, we hypothesized that the succinate–Sucnr1 axis may be utilized by tuft cells to detect certain infectious agents. Here we confirmed that Sucnr1 is specifically expressed in intestinal tuft cells but not in other types of intestinal epithelial cells, and demonstrated that dietary succinate induces tuft and goblet cell hyperplasia via Sucnr1 and the tuft cell-expressed chemosensory signaling elements gustducin and Trpm5. Conventional mice with a genetic Sucnr1 deficiency (Sucnr1−/−) showed diminished immune responses to treatment with polyethylene glycol and streptomycin, which are known to enhance microbiota-derived succinate, but responded normally to inoculation with the parasitic worm Nippostrongylus brasiliensis that also produces succinate. Thus, Sucnr1 is required for microbiota-induced but not for a generalized worm-induced type 2 immunity.

scholarly journals Cytoplasmic Death Signal Triggered by Src-Mediated Phosphorylation of the Adenovirus E4orf4 Protein

2002 ◽  
Vol 22 (1) ◽  
pp. 41-56 ◽  
Author(s):  
Marie-Claude Gingras ◽  
Claudia Champagne ◽  
Mélanie Roy ◽  
Josée N. Lavoie
Keyword(s):  
Cell Death ◽  
Adenovirus Type ◽  
Wild Type ◽  
Membrane Blebbing ◽  
Signaling Complex ◽  
Phosphorylated Proteins ◽  
Apoptotic Signal

ABSTRACT In transformed cells, the adenovirus E4orf4 death factor works in part by inducing a Src-mediated cytoplasmic apoptotic signal leading to caspase-independent membrane blebbing and cell death. Here we show that Src-family kinases modulate E4orf4 phosphorylation on tyrosine residues. Mutation of tyrosines 26, 42, and 59 to phenylalanines inhibited Src-induced phosphorylation of E4orf4 in vivo and in vitro but had no effect on the molecular association of E4orf4 with Src. However, in contrast to wild-type E4orf4, the nonphosphorylatable E4orf4 mutant was unable to modulate Src-dependent phosphorylation and was deficient in recruiting a subset of tyrosine-phosphorylated proteins. Indeed, the Src substrates cortactin and p62dok were found to associate with wild-type E4orf4 but not with the nonphosphorylatable E4orf4. Importantly, the nonphosphorylatable mutant E4orf4 was preferentially distributed in the cell nucleus, was unable to induce membrane blebbing, and had a highly impaired killing activity. Conversely, an activated form of E4orf4 was obtained by mutation of tyrosine 42 to glutamic acid. This pseudophosphorylated mutant E4orf4 was enriched in the cytoplasm and plasma membrane, showed increased binding to phosphotyrosine-containing proteins, and induced a dramatic blebbing phenotype associated with increased cell death. Altogether, our findings strongly suggest that Src-mediated phosphorylation of adenovirus type 2 E4orf4 is critical to promoting its cytoplasmic and membrane localization and is required for the transduction of E4orf4-Src-dependent induction of membrane blebbing. We propose that E4orf4 acts in part by uncoupling Src-dependent signals to drive the formation of a signaling complex that triggers a cytoplasmic death signal.

scholarly journals IL-33–Responsive Lineage−CD25+CD44hi Lymphoid Cells Mediate Innate Type 2 Immunity and Allergic Inflammation in the Lungs

2011 ◽  
Vol 188 (3) ◽  
pp. 1503-1513 ◽  
Author(s):  
Kathleen R. Bartemes ◽  
Koji Iijima ◽  
Takao Kobayashi ◽  
Gail M. Kephart ◽  
Andrew N. McKenzie ◽  
...  
Keyword(s):  
Allergic Inflammation ◽  
Lymphoid Cells ◽  
Type 2 Immunity

scholarly journals DOCK8 deficiency causes a skewing to type 2 immunity in the gut with expansion of group 2 innate lymphoid cells

2021 ◽  
Vol 559 ◽  
pp. 135-140
Author(s):  
Keisuke Matsubara ◽  
Kazufumi Kunimura ◽  
Nana Yamane ◽  
Ryosuke Aihara ◽  
Tetsuya Sakurai ◽  
...  
Keyword(s):  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Type 2 Immunity ◽  
Dock8 Deficiency ◽  
Group 2

scholarly journals Interleukin (IL)-33 is dispensable for Schistosoma mansoni worm maturation and the maintenance of egg-induced pathology in intestines of infected mice

2020 ◽  
Author(s):  
Jean Pierre Kambala Mukendi ◽  
Risa Nakamura ◽  
Satoshi Uematsu ◽  
Shinjiro Hamano
Keyword(s):  
Lymph Nodes ◽  
Wild Type ◽  
Mesenteric Lymph Nodes ◽  
Schistosome Infection ◽  
Mesenteric Lymph ◽  
Type 2 Immunity ◽  
Transient Impairment ◽  
Inflammatory Infiltrates

Abstract Background: Schistosomes are trematode worms that dwell in their definitive host’s blood vessels, where females lay eggs that need to be discharged into the environment with host excreta to maintain their life cycle. Both worms and eggs require type 2 immunity for their maturation and excretion, respectively. However, immune molecules that orchestrate such immunity remain unclear. IL-33 is one of the epithelium-derived cytokines that induce type 2 immunity in tissues. This study aimed at determining its role in the maturation, reproduction, and excretion of S. mansoni eggs, and in the maintenance of egg-induced pathology in the intestines of mice.Methods: Using S. mansoni-infected IL-33-deficient (IL-33-/-) and wild-type (WT) mice, the morphology of worms and the number of eggs in intestinal tissues were studied at different time points of infection. IL-5 and IL-13 production in spleens and mesenteric lymph nodes were measured. Tissue histology was performed on the terminal ilea of infected and non-infected mice.Results: Morphology-wise, worms from IL-33-/- and WT mice at the fourth and sixth weeks of infection did not differ. The number of eggs in intestinal tissues did not differ much between IL-33-/- and WT mice. In the sixth week of infection, IL-33-/- mice presented impaired type 2 immunity in intestines, characterized by decreased production of IL-5 and IL-13 in mesenteric lymph nodes and fewer inflammatory infiltrates with fewer eosinophils in the ilea. Otherwise there was no difference between IL-33-/- and WT mice in the levels of IL-25 and thymic stromal lymphopoietin (TSLP) in intestinal tissues.Conclusions: Despite its ability to initiate type 2 immunity in tissues, IL-33 alone seems dispensable for S. mansoni maturation and its absence may not affect much the accumulation of eggs in intestinal tissues. The transient impairment of type 2 immunity observed in the intestines, but not spleens, highlights the importance of IL-33 over IL-25 and TSLP in initiating, but not maintaining, locally-induced type 2 immunity in intestinal tissues during schistosome infection. Further studies are needed to decipher the role of each of them in schistosomiasis and clarify the possible interactions that might exist between them.

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