ILC2 promote type 2 immunity in colonic epithelial cells during N. brasiliensis infection.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE213424 | GEO | 2022/10/28
REPOSITORIES: GEO
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Project description:ILC2 contribute to tissue immunity by secreting large amounts of cytokines upon activation. However, their role in steady state tissue homeostasis remains incompletely explored. We tested the impact of ILC2 on tissue immunity in steady state the lungs by scRNA sequencing of myeloid and epithelial cells from mice specifically lacking ILC2 (Nmur1-Cre Id2 fl/fl). Transcripts typically associated with type 2 immunity were reduced in ILC2-deficient mice, indicating a non-redundant role of ILC2 for type 2 tissue immunity that cannot be compensated by other cell types. These findings highlight the importance of ILC2 for balancing tissue homeostasis in the healthy murine lung.
2022-11-07 | GSE212940 | GEO
Project description:The type 2 cytokines interleukin (IL)-4, IL-5, IL-9 and IL-13 play critical roles in stimulating innate and adaptive immune responses required for resistance to helminth infection and promotion of allergic inflammation, metabolic homeostasis and tissue repair. Group 2 innate lymphoid cells (ILC2s) are a potent source of type 2 cytokines and while significant advances have been made in understanding the cytokine milieu that promotes ILC2 responses, there are fundamental gaps in knowledge regarding how ILC2 responses are regulated by other stimuli. In this report, we demonstrate that ILC2s in the gastrointestinal tract co-localize with cholinergic neurons that express the neuropeptide neuromedin U (NMU). In contrast to other hematopoietic cells, ILC2s selectively express the NMU receptor 1 (NMUR1). In vitro stimulation of ILC2s with NMU induced rapid cell activation, proliferation and secretion of type 2 cytokines IL-5, IL-9 and IL-13 that was dependent on cell-intrinsic expression of NMUR1 and Gaq protein. In vivo administration of NMU triggered potent type 2 cytokine responses characterized by ILC2 activation, proliferation and eosinophil recruitment that was associated with accelerated expulsion of the gastrointestinal nematode Nippostrongylus brasiliensis or induction of lung inflammation. Conversely, worm burden was higher in Nmur1-/- mice compared to control mice. Further, use of gene-deficient mice and adoptive cell transfer experiments revealed that ILC2s were necessary and sufficient to mount NMU-elicited type 2 cytokine responses. Together, these data indicate that the NMU-NMUR1 neuronal signaling circuit provides a selective and previously unrecognized mechanism through which the enteric nervous system and innate immune system integrate to promote rapid type 2 cytokine responses that can induce anti-microbial, inflammatory and tissue-protective type 2 responses at mucosal sites.
2017-08-18 | GSE101624 | GEO
Project description:The type 2 cytokines interleukin (IL)-4, IL-5, IL-9 and IL-13 play critical roles in stimulating innate and adaptive immune responses required for resistance to helminth infection and promotion of allergic inflammation, metabolic homeostasis and tissue repair. Group 2 innate lymphoid cells (ILC2s) are a potent source of type 2 cytokines and while significant advances have been made in understanding the cytokine milieu that promotes ILC2 responses, there are fundamental gaps in knowledge regarding how ILC2 responses are regulated by other stimuli. In this report, we demonstrate that ILC2s in the gastrointestinal tract co-localize with cholinergic neurons that express the neuropeptide neuromedin U (NMU). In contrast to other hematopoietic cells, ILC2s selectively express the NMU receptor 1 (NMUR1). In vitro stimulation of ILC2s with NMU induced rapid cell activation, proliferation and secretion of type 2 cytokines IL-5, IL-9 and IL-13 that was dependent on cell-intrinsic expression of NMUR1 and Gaq protein. In vivo administration of NMU triggered potent type 2 cytokine responses characterized by ILC2 activation, proliferation and eosinophil recruitment that was associated with accelerated expulsion of the gastrointestinal nematode Nippostrongylus brasiliensis or induction of lung inflammation. Conversely, worm burden was higher in Nmur1-/- mice compared to control mice. Further, use of gene-deficient mice and adoptive cell transfer experiments revealed that ILC2s were necessary and sufficient to mount NMU-elicited type 2 cytokine responses. Together, these data indicate that the NMU-NMUR1 neuronal signaling circuit provides a selective and previously unrecognized mechanism through which the enteric nervous system and innate immune system integrate to promote rapid type 2 cytokine responses that can induce anti-microbial, inflammatory and tissue-protective type 2 responses at mucosal sites.
2017-08-18 | GSE101623 | GEO
Project description:Here, we report the generation of a new mouse model based on the Nmur1 promoter as a driver for simultaneous expression of Cre recombinase and green fluorescent protein (GFP), which allows gene targeting in ILC2 without affecting other innate and adaptive immune cells. By removing Id2 and Gata-3 using Cre-mediated gene deletion in Nmur1-expressing cells, we have generated mice with selective and specific deficiency in ILC2. ILC2-deficient mice have decreased eosinophil counts in steady state and are unable to recruit eosinophils in the airways in models of allergic asthma. Further, ILC2-deficient mice fail to mount an appropriate immune and epithelial type 2 response resulting in a profound defect in worm control and a non-protective type 3 immune response. In total, our data establish non-redundant functions for ILC2s in the presence of adaptive immune cells at steady state and during diseases and argue for a multilayered organization of the immune system based on a spatiotemporal division of labor.
2022-10-28 | GSE212011 | GEO
Project description:Type 2 innate lymphoid cells (ILC2s) promote mucosal homeostasis, yet also contribute to pathologic type 2 inflammation in allergic asthma. Alarmin cytokines produced by damaged and stressed epithelial cells, such as IL-25, activate ILC2s, but it remains unclear if these cytokines are unique in switching homeostatic ILC2s into pro-inflammatory cells that drive tissue inflammation. To identify molecular cues that modulate ILC responses to alarmins, we collected single-cell RNA-seq profiles of lung-resident ILCs at steady state and after in vivo stimulation. Computational and functional analysis identified that ILC2s express the neuropeptide receptor Nmur1. Neuromedin U (NMU), the ligand of Nmur1, activates ILCs in vitro, and when co-administered with IL-25 in vivo, NMU dramatically amplifies allergic inflammation and induces ILC2 expansion. Finally, loss of NMU/Nmur1-signaling reduces ILC2 frequency and effector function following allergen challenge in vivo. Our results demonstrate that Nmur1 signaling modifies alarmin-mediated ILC2 responses to promote pro-inflammatory ILCs, and highlights the importance of neuro-immune crosstalk in allergic inflammatory responses at mucosal surfaces.
2017-09-17 | GSE102299 | GEO
Project description:In this work we show that neuromedin U receptor 1 (NMUR1)-mediated signaling programs SI eosinophils to support epithelial cell differentiation and barrier immunity. The global transcriptional profiling of eosinophils from different tissues of mice revealed that Nmur1 was expressed in a subset of eosinophils specifically in the SI. Fate mapping analyses showed that NMUR1 expression in SI eosinophils was imprinted by local microenvironment and further enhanced by the inflammation. Genetic deletion of NMUR1 decreased the numbers of eosinophils, degranulation activity, and goblet cell differentiation in the SI. Chemogenetic manipulation of NMU-expressing cells significantly altered the goblet cell differentiation and mucus secretion. Eosinophil-organoid co-culture experiments demonstrated that NMU-mediated eosinophil activation directly promoted the growth of intestinal organoids and formation of budding domains and complex crypt–villus structures. Finally, the deficiency of NMUR1 compromised anti-parasite immunity. Thus, NMU regulates epithelial cell differentiation and function through stimulating NMUR1-expressing eosinophils in the SI, highlighting the importance of neuro-immune-epithelium crosstalk in maintaining tissue homeostasis.
2023-09-01 | GSE211112 | GEO
Project description:Adaptation of immune cells to tissue-specific microenvironments is a crucial process in homeostasis and inflammation. Here, we show that murine effector type 2 innate lymphoid cells (ILC2s) from various organs are equally effective in repopulating ILC2 niches in other anatomical locations where they adapt tissue-specific phenotypes of target organs. Single-cell transcriptomics of ILC2 populations revealed upregulation of retinoic acid (RA) signaling in ILC2s during adaptation to the small intestinal microenvironment, and RA signaling mediated reprogramming of kidney effector ILC2s towards the small intestinal phenotype in vitro and in vivo. Inhibition of intestinal ILC2 adaptation by blocking RA signaling impaired worm expulsion during Strongyloides ratti infection, indicating functional importance of ILC2 tissue imprinting. In conclusion, this study highlights that effector ILC2s retain the ability to adapt to changing tissue-specific microenvironments, enabling them to exert tissue-specific functions, such as promoting control of intestinal helminth infections.
2023-09-15 | GSE242569 | GEO
Project description:Adaptation of immune cells to tissue-specific microenvironments is a crucial process in homeostasis and inflammation. Here, we show that murine effector type 2 innate lymphoid cells (ILC2s) from various organs are equally effective in repopulating ILC2 niches in other anatomical locations where they adapt tissue-specific phenotypes of target organs. Single-cell transcriptomics of ILC2 populations revealed upregulation of retinoic acid (RA) signaling in ILC2s during adaptation to the small intestinal microenvironment, and RA signaling mediated reprogramming of kidney effector ILC2s towards the small intestinal phenotype in vitro and in vivo. Inhibition of intestinal ILC2 adaptation by blocking RA signaling impaired worm expulsion during Strongyloides ratti infection, indicating functional importance of ILC2 tissue imprinting. In conclusion, this study highlights that effector ILC2s retain the ability to adapt to changing tissue-specific microenvironments, enabling them to exert tissue-specific functions, such as promoting control of intestinal helminth infections.
2023-09-15 | GSE242562 | GEO
Project description:Males and females exhibit profound differences in immune responses and disease susceptibility. However, the factors responsible for sex differences in tissue immunity remain poorly understood. Here, we uncover a dominant role for type 2 innate lymphoid cells (ILC2) in shaping sexual immune dimorphism within the skin. Mechanistically, negative regulation of ILC2 by androgens leads to a reduction in dendritic cell (DC) accumulation and activation in males, and reduced tissue immunity. Collectively, this work uncovers an androgen-ILC2-DC axis in controlling sexual immune dimorphism. Moreover, this work proposes that tissue immune set-points are defined by the dual action of sex hormones and the microbiota, with sex hormones controlling the strength of local immunity and microbiota calibrating its tone.
2024-04-09 | GSE253294 | GEO
Project description:Males and females exhibit profound differences in immune responses and disease susceptibility. However, the factors responsible for sex differences in tissue immunity remain poorly understood. Here, we uncover a dominant role for type 2 innate lymphoid cells (ILC2) in shaping sexual immune dimorphism within the skin. Mechanistically, negative regulation of ILC2 by androgens leads to a reduction in dendritic cell (DC) accumulation and activation in males, and reduced tissue immunity. Collectively, this work uncovers an androgen-ILC2-DC axis in controlling sexual immune dimorphism. Moreover, this work proposes that tissue immune set-points are defined by the dual action of sex hormones and the microbiota, with sex hormones controlling the strength of local immunity and microbiota calibrating its tone.
2024-04-09 | GSE253293 | GEO