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 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 IL-17A both initiates (via IFNγ suppression) and limits the pulmonary type-2 immune response to nematode infection

2019 ◽  
Author(s):  
Jesuthas Ajendra ◽  
Alistair L. Chenery ◽  
James E. Parkinson ◽  
Brian H. K. Chan ◽  
Stella Pearson ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Protein Production ◽  
Transcriptional Profiling ◽  
Nippostrongylus Brasiliensis ◽  
Trichuris Muris ◽  
Type 2 Immunity ◽  
Type 2 Immune Response ◽  
Neutrophil Depletion

ABSTRACTNippostrongylus brasiliensis is a well-defined model of type-2 immunity but the early lung-migrating phase is dominated by innate IL-17A production and neutrophilia. Using N. brasiliensis infection we confirm previous observations that Il17a-KO mice exhibit an impaired type-2 immune response. Neutrophil depletion and reconstitution studies demonstrated that neutrophils contribute to the subsequent eosinophilia but are not responsible for the ability of IL-17A to promote type-2 cytokine responses. Transcriptional profiling of the lung on day 2 of N. brasiliensis infection revealed an increased Ifnγ signature in the Il17a-KO mice confirmed by enhanced IFNγ protein production. Depletion of early IFNγ rescued type-2 immune responses in the Il17a-KO mice demonstrating that IL-17A-mediated suppression of IFNγ promotes type-2 immunity. Notably, when IL-17A was blocked later in infection, the type-2 response increased. IL-17A regulation of type-2 immunity was lung-specific and infection with Trichuris muris, revealed that IL-17A promotes a type-2 immune response in the lung even when a parasite lifecycle is restricted to the intestine. Together our data reveal IL-17A as a major regulator of pulmonary type-2 immunity which supports the development of a protective type-2 immune response but subsequently limits the magnitude of that response.

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 Tuft cell-produced cysteinyl leukotrienes and IL-25 synergistically drive lung type 2 inflammation

2021 ◽  
Author(s):  
Saltanat Ualiyeva ◽  
Evan R Lemire ◽  
Amelia Boyd ◽  
Caitlin Wong ◽  
Juying Lai ◽  
...  
Keyword(s):  
Immune Response ◽  
Epithelial Cells ◽  
Airway Epithelial Cells ◽  
Innate Immune ◽  
Cysteinyl Leukotrienes ◽  
Tuft Cell ◽  
Tuft Cells ◽  
Lung Eosinophilia ◽  
Type 2 Inflammation

Aeroallergen sensing by airway epithelial cells can trigger pathogenic immune responses leading to chronic type 2 inflammation, the hallmark of airway diseases such as asthma. Airway tuft cells are specialized chemosensory epithelial cells and the dominant source of the epithelial cytokine IL-25 in the trachea and of cysteinyl leukotrienes (CysLTs) in the naive murine nasal mucosa. The interaction of IL-25 and CysLTs and the contribution of tuft cell-derived CysLTs to the development of allergen-triggered inflammation in the airways has not been clarified. Here we show that inhalation of LTC4 in combination with a subthreshold dose of IL25 leads to dramatic synergistic induction of type 2 inflammation throughout the lungs, causing rapid eosinophilia, dendritic cell (DC) and inflammatory type 2 innate lymphoid cell (ILC2) expansion, and goblet cell metaplasia. While lung eosinophilia is dominantly mediated through the classical CysLT receptor CysLT1R, type 2 cytokines and activation of innate immune cells require signaling through both CysLT1R and CysLT2R. Tuft cell-specific deletion of the terminal enzyme requisite for CysLT production, Ltc4s, was sufficient to reduce both the innate immune response in the lung: eosinophilia, ILC2 activation and DC recruitment, and the systemic immune response in the draining lymph nodes after inhalation of the mold aeroallergen Alternaria. Our findings identify surprisingly potent synergy of CysLTs and IL-25 downstream of aeroallergen-trigged activation of airway tuft cells leading to a highly polarized type 2 immune response and further implicate airway tuft cells as powerful modulators of type 2 immunity in the lungs.

scholarly journals Mitochondrial transcription factor A in RORγt+ lymphocytes regulate small intestine homeostasis and metabolism

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zheng Fu ◽  
Joseph W. Dean ◽  
Lifeng Xiong ◽  
Michael W. Dougherty ◽  
Kristen N. Oliff ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Small Intestine ◽  
Th17 Cells ◽  
Tissue Remodeling ◽  
Mitochondrial Transcription ◽  
Mitochondrial Transcription Factor ◽  
Tuft Cell ◽  
Mitochondrial Transcription Factor A

AbstractRORγt+ lymphocytes, including interleukin 17 (IL-17)-producing gamma delta T (γδT17) cells, T helper 17 (Th17) cells, and group 3 innate lymphoid cells (ILC3s), are important immune regulators. Compared to Th17 cells and ILC3s, γδT17 cell metabolism and its role in tissue homeostasis remains poorly understood. Here, we report that the tissue milieu shapes splenic and intestinal γδT17 cell gene signatures. Conditional deletion of mitochondrial transcription factor A (Tfam) in RORγt+ lymphocytes significantly affects systemic γδT17 cell maintenance and reduces ILC3s without affecting Th17 cells in the gut. In vivo deletion of Tfam in RORγt+ lymphocytes, especially in γδT17 cells, results in small intestine tissue remodeling and increases small intestine length by enhancing the type 2 immune responses in mice. Moreover, these mice show dysregulation of the small intestine transcriptome and metabolism with less body weight but enhanced anti-helminth immunity. IL-22, a cytokine produced by RORγt+ lymphocytes inhibits IL-13-induced tuft cell differentiation in vitro, and suppresses the tuft cell-type 2 immune circuit and small intestine lengthening in vivo, highlighting its key role in gut tissue remodeling.

New perspectives on IL-33 and IL-1 family cytokines as innate environmental sensors

2018 ◽  
Vol 46 (5) ◽  
pp. 1345-1353 ◽  
Author(s):  
Ian C. Scott ◽  
D. Gareth Rees ◽  
E. Suzanne Cohen
Keyword(s):  
Immune Responses ◽  
Allergic Inflammation ◽  
Proteolytic Processing ◽  
Innate Immune ◽  
Environmental Sensors ◽  
Biological Functions ◽  
Soluble Receptors ◽  
Direct Sensing ◽  
Proteolytic Activities

Interleukin (IL)-1 family cytokines are important initiators of innate immunity and host defence; however, their uncontrolled activities can cause tissue-damaging inflammation. Consequently, IL-1 family cytokines have sophisticated regulatory mechanisms to control their activities including proteolytic processing for their activation and the deployment of soluble receptors and receptor antagonists to limit their activities. IL-33 is a promoter of type 2 immunity and allergic inflammation through its alarmin activity that can rapidly initiate local immune responses by stimulating innate immune cells following exposure to environmental insults, pathogens, or sterile injury. Recent publications have provided new insights into how the range and duration of IL-33 activity is regulated by direct sensing of host-derived and exogenous proteolytic activities as well as oxidative changes during tissue damage. Here, we discuss how this impacts our understanding of the roles of IL-33 in initiating immune responses and the evidence that these sensing mechanisms might regulate the activities of other IL-1 family cytokines and their biological functions. Finally, we discuss translational challenges these discoveries pose for the accurate detection of different forms of these cytokines.

scholarly journals ncRNAs in Type-2 Immunity

2020 ◽  
Vol 6 (1) ◽  
pp. 10 ◽  
Author(s):  
Riccardo Guidi ◽  
Christopher J. Wedeles ◽  
Mark S. Wilson
Keyword(s):  
Immune Responses ◽  
Immune Cell ◽  
Allergic Diseases ◽  
Parasitic Helminths ◽  
Medical Needs ◽  
Type 2 Immunity ◽  
Non Coding Rna ◽  
Immune Mediated ◽  
Immunological Diseases

Immunological diseases, including asthma, autoimmunity and immunodeficiencies, affect a growing percentage of the population with significant unmet medical needs. As we slowly untangle and better appreciate these complex genetic and environment-influenced diseases, new therapeutically targetable pathways are emerging. Non-coding RNA species, which regulate epigenetic, transcriptional and translational responses are critical regulators of immune cell development, differentiation and effector function, and may represent one such new class of therapeutic targets. In this review we focus on type-2 immune responses, orchestrated by TH2 cell-derived cytokines, IL-4, IL-5 and IL-13, which stimulate a variety of immune and tissue responses- commonly referred to as type-2 immunity. Evolved to protect us from parasitic helminths, type-2 immune responses are observed in individuals with allergic diseases, including Asthma, atopic dermatitis and food allergy. A growing number of studies have identified the involvement of various RNA species, including microRNAs (miRNA) and long non-coding (lncRNA), in type-2 immune responses and in both clinical and pre-clinical disease settings. We highlight these recent findings, identify gaps in our understanding and provide a perspective on how our current understanding can be harnessed for novel treat opportunities to treat type-2 immune-mediated diseases.

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