scholarly journals Tumor suppressor p53 regulates intestinal type 2 immunity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chun-Yuan Chang ◽  
Jianming Wang ◽  
Yuhan Zhao ◽  
Juan Liu ◽  
Xue Yang ◽  
...  
Keyword(s):  
Lymphoid Cell ◽  
Critical Role ◽  
Intestinal Type ◽  
Parasitic Infections ◽  
Nippostrongylus Brasiliensis ◽  
Innate Lymphoid Cell ◽  
Type 2 Immunity ◽  
Tuft Cell

AbstractThe role of p53 in tumor suppression has been extensively studied and well-established. However, the role of p53 in parasitic infections and the intestinal type 2 immunity is unclear. Here, we report that p53 is crucial for intestinal type 2 immunity in response to the infection of parasites, such as Tritrichomonas muris and Nippostrongylus brasiliensis. Mechanistically, p53 plays a critical role in the activation of the tuft cell-IL-25-type 2 innate lymphoid cell circuit, partly via transcriptional regulation of Lrmp in tuft cells. Lrmp modulates Ca2+ influx and IL-25 release, which are critical triggers of type 2 innate lymphoid cell response. Our results thus reveal a previously unrecognized function of p53 in regulating intestinal type 2 immunity to protect against parasitic infections, highlighting the role of p53 as a guardian of immune integrity.

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 Detection of succinate by intestinal tuft cells triggers a type 2 innate immune circuit

2018 ◽  
Author(s):  
Marija S. Nadjsombati ◽  
John W. McGinty ◽  
Miranda R. Lyons-Cohen ◽  
Joshua L. Pollack ◽  
G.A. Nagana Gowda ◽  
...  
Keyword(s):  
Small Intestine ◽  
Immune Responses ◽  
Innate Immune ◽  
Nippostrongylus Brasiliensis ◽  
Transduction Pathway ◽  
Type 2 Immunity ◽  
Tuft Cell ◽  
Tuft Cells ◽  
Taste Transduction

SummaryInitiation of immune responses requires innate immune sensing, but immune detection of the helminths, protists, and allergens that stimulate type 2 immunity remains poorly understood. In the small intestine, type 2 immune responses are regulated by a tuft cell-ILC2 signaling circuit. Tuft cells express components of a canonical taste transduction pathway, including the membrane channel TRPM5, but the ligands and receptors that activate tuft cells in the small intestine are unknown. Here we identify succinate as the first ligand that activates intestinal tuft cells to initiate type 2 immune responses. Using mRNA-Seq on tuft cells from different tissues, we show that all tuft cells express the intracellular taste transduction pathway, but expression of upstream receptors is tissue-specific. In the small intestine, tuft cells express the succinate receptor SUCNR1. Remarkably, providing succinate in drinking water is sufficient to induce a multifaceted type 2 immune response in the murine small intestine, involving all known components of the tuft-ILC2 circuit. The helminthNippostrongylus brasiliensissecretes succinate as a metabolite, and sensing of both succinate andN. brasiliensisrequires tuft cells and TRPM5, suggesting a novel paradigm in which type 2 immunity monitors microbial metabolism. Manipulation of succinate sensing may have therapeutic benefit in numerous intestinal diseases.

scholarly journals Group 2 innate lymphoid cell activation in the neonatal lung drives type 2 immunity and allergen sensitization

2017 ◽  
Vol 140 (2) ◽  
pp. 593-595.e3 ◽  
Author(s):  
Catherine A. Steer ◽  
Itziar Martinez-Gonzalez ◽  
Maryam Ghaedi ◽  
Patricia Allinger ◽  
Laura Mathä ◽  
...  
Keyword(s):  
Lymphoid Cell ◽  
Cell Activation ◽  
Innate Lymphoid Cell ◽  
Allergen Sensitization ◽  
Type 2 Immunity ◽  
Neonatal Lung ◽  
Group 2

Role of type 2 innate lymphoid cell and its related cytokines in tumor immunity

2019 ◽  
Vol 235 (4) ◽  
pp. 3249-3257
Author(s):  
Jie Wan ◽  
Wei Cai ◽  
Huixuan Wang ◽  
Jianjun Cheng ◽  
Zhaoliang Su ◽  
...  
Keyword(s):  
Tumor Immunity ◽  
Lymphoid Cell ◽  
Innate Lymphoid Cell

scholarly journals IL-13 deficiency exacerbates lung damage and impairs epithelial-derived type 2 molecules during nematode infection

2020 ◽  
Author(s):  
AL Chenery ◽  
S Rosini ◽  
JE Parkinson ◽  
JA Herrera ◽  
Craig Lawless ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Stress Responses ◽  
Tissue Injury ◽  
Critical Role ◽  
Lung Damage ◽  
Surfactant Protein D ◽  
Nippostrongylus Brasiliensis ◽  
Tissue Remodelling

AbstractIL-13 plays a key role during protective type 2 immune responses at mucosal sites, such as during infection with nematodes. However, dysregulation of IL-13 can also contribute to the pathogenesis of atopic and fibrotic diseases such as allergic asthma. Matrix remodelling is an important component of repair processes in the lung but also a hallmark of chronic conditions involving fibrosis. Hence, understanding the role of IL-13 in tissue remodelling has important clinical implications. Since IL-13 shares receptors and signalling pathways with IL-4, disentangling the relative contributions of these type 2 cytokines has been challenging. Additionally, little is known about the singular role of IL-13 following acute tissue injury. In this study, we used Nippostrongylus brasiliensis infection as a model of acute lung tissue damage comparing responses between WT and IL-13-deficient mice, in which IL-4 signalling is intact. Importantly, we found that IL-13 played a critical role in limiting tissue injury and haemorrhaging in the lung following infection. Through proteomic and transcriptomic profiling, we identified IL-13-dependent changes in matrix and associated regulators. We further showed that IL-13 is required for the induction of epithelial-derived type 2 effector molecules such as RELM-α and surfactant protein D. Pathway analyses predicted that IL-13 was heavily involved in the induction of cellular stress responses and regulation of lung epithelial cell differentiation by suppression of Foxa2 pathways. Thus, we propose that IL-13 has tissue-protective functions during lung injury and regulates epithelial cell responses during type 2 immunity in this acute setting.

scholarly journals A critical role for c‐Myc in group 2 innate lymphoid cell activation

Allergy ◽  
2020 ◽  
Vol 75 (4) ◽  
pp. 841-852 ◽  
Author(s):  
Longyun Ye ◽  
Jiexue Pan ◽  
Mingwei Liang ◽  
Muhammad Asghar Pasha ◽  
Xiaofei Shen ◽  
...  
Keyword(s):  
Lymphoid Cell ◽  
Cell Activation ◽  
Critical Role ◽  
Innate Lymphoid Cell ◽  
Group 2

scholarly journals T-bet controls intestinal mucosa immune responses via repression of type 2 innate lymphoid cell function

2018 ◽  
Vol 12 (1) ◽  
pp. 51-63 ◽  
Author(s):  
N. Garrido-Mesa ◽  
J-H. Schroeder ◽  
E. Stolarczyk ◽  
A. L. Gallagher ◽  
J. W. Lo ◽  
...  
Keyword(s):  
Immune Responses ◽  
Intestinal Mucosa ◽  
Lymphoid Cell ◽  
Cell Function ◽  
Innate Lymphoid Cell

Abstract P288: Systemic Administration of an Angiotensin Type-2 Receptor Agonist Decreases Renal Regulatory T Cells

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Ellen E Gillis ◽  
Jennifer C Sullivan
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Critical Role ◽  
High Dose ◽  
Ang Ii ◽  
Osmotic Minipump ◽  
Angiotensin Type 2 Receptor ◽  
Angiotensin Type

There is increasing evidence supporting a critical role of the immune system in the development of hypertension. Our lab has previously reported sex differences in the renal T cell profile in both Spontaneously Hypertensive Rats (SHR) and Angiotensin II (Ang II) models of hypertension, with females having more anti-inflammatory regulatory T cells (Tregs) than males. Ang II has a well-defined role in the activation of pro-inflammatory T cells in hypertension via the angiotensin type-1 receptor (AT1R). Less is known about the role of the angiotensin type-2 receptor (AT2R) in the regulation of immune cells, although the AT2R has been shown to be cardioprotective and AT2R expression is greater in females than males. Based on the potential anti-hypertensive role of AT2Rs, we hypothesized that administration of an AT2R agonist, Compound 21 (C21), would increase renal Tregs, and this increase would be greater in females due to greater AT2R expression. Male and female SHR (10 weeks of age, n=3-4) were implanted with telemetry units for continuous monitoring of mean arterial pressure (MAP). Following 10 days of recovery, baseline MAP was recorded for 5 days. Rats were then divided into the following treatment groups: surgical controls, low dose C21 (150 ng/kg/min, sc by osmotic minipump), high dose C21 (300 ng/kg/min, sc by osmotic minipump). Kidneys were harvested after 2 weeks of treatment and flow cytometry was performed on whole kidney homogenates. MAP was not altered by C21 treatment in males (137±4 vs 134±4 vs 134±4 mmHg; n.s.) or females (128±2 vs 136±5 vs 134±4 mmHg; n.s.). Interestingly, despite having no effect on MAP, there was a significant decrease in renal CD3 + CD4 + FoxP3 + Tregs in females following both low and high doses of C21 (data expressed as % CD3 + CD4 + cells: 6±0.6 vs 3±0.6 vs 3.5±1.3 %, respectively; p=0.02). Tregs decrease in males following the high dose of C21 only (data expressed as % CD3 + CD4 + cells: 3.3±0.3 vs 3.3±0.5 vs 1.7±0.7 %, respectively; p=0.05). Total CD3 + T cells, CD3 + CD4 + T cells, and Th17 cells were not altered by C21 treatment. In conclusion, AT2R activation suppresses renal Tregs, and females are more sensitive than males. These data suggest a novel role for AT2R regulation in the kidney in hypertension.

Targeting mTOR Signaling in Type 2 Diabetes Mellitus and Diabetes Complications

2022 ◽  
Vol 23 ◽  
Author(s):  
Lin Yang ◽  
Zhixin Zhang ◽  
Doudou Wang ◽  
Yu Jiang ◽  
Ying Liu
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Protein Complexes ◽  
Cell Metabolism ◽  
Critical Role ◽  
Mtor Inhibitors ◽  
Mtor Signaling

Abstract: The mechanistic target of rapamycin (mTOR) is a pivotal regulator of cell metabolism and growth. In the form of two different multi-protein complexes, mTORC1 and mTORC2, mTOR integrates cellular energy, nutrient and hormonal signals to regulate cellular metabolic homeostasis. In type 2 diabetes mellitus (T2DM) aberrant mTOR signaling underlies its pathological conditions and end-organ complications. Substantial evidence suggests that two mTOR-mediated signaling schemes, mTORC1-p70S6 kinase 1 (S6K1) and mTORC2-protein kinase B (AKT), play a critical role in insulin sensitivity and that their dysfunction contributes to development of T2DM. This review summaries our current understanding of the role of mTOR signaling in T2DM and its associated complications, as well as the potential use of mTOR inhibitors in treatment of T2DM.

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