Neuropeptide CGRP limits ILC2 responses and constrains type 2 inflammation
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE131996 | GEO | 2019/06/25
REPOSITORIES: GEO
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Project description:Neuroimmune interactions have emerged as critical modulators of allergic inflammation, and type 2 innate lymphoid cells (ILC2s) are an important cell type for mediating these interactions. Here, we show that ILC2s expressed both the neuropeptide CGRP (Calcitonin Gene-Related Peptide) and its receptor. CGRP potently inhibited alarmin-driven type 2 cytokine production and proliferation by lung ILC2s both in vitro and in vivo. CGRP induced marked changes in ILC2 expression programs in vivo and in vitro, attenuating alarmin-driven proliferative and effector responses. A distinct subset of ILCs scored highly for a CGRP-specific gene signature after in vivo alarmin stimulation, suggesting CGRP regulated this response. Finally, we observed increased ILC2 proliferation and type 2 cytokine production and exaggerated responses to alarmins in mice lacking the CGRP receptor. Together, these data indicate that endogenous CGRP is a critical negative regulator of ILC2 responses in vivo.
2019-10-08 | GSE136154 | 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: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:Allergic conjunctivitis is a chronic inflammatory disease that is characterized by severe itch in the conjunctiva; but how neuro-immune interactions shape the pathogenesis of severe itch remains unclear. We identified a subset of memory-type pathogenic Th2 cells that preferentially expressed Il1rl1-encoding ST2 and Calca-encoding calcitonin gene-related peptide (CGRP) in the inflammatory conjunctiva using a single-cell analysis. The IL-33-ST2 axis in memory Th2 cells controlled the axonal elongation of the peripheral sensory C-fiber and the induction of severe itch. Pharmacological blockade and genetic deletion of CGRP signaling in vivo attenuated scratching behavior. The analysis of giant papillae from patients with severe allergic conjunctivitis revealed ectopic lymphoid structure formation with the accumulation of IL-33-producing epithelial cells and CGRP-producing pathogenic CD4+ T cells accompanied by peripheral nerve elongation. Thus, the IL-33-ST2-CGRP axis directs severe itch with neuro-reconstruction in the inflammatory conjunctiva and is a potential therapeutic target for severe itch in allergic conjunctivitis.
2022-05-20 | GSE203217 | GEO
Project description:A distinct population of Foxp3+CD4+ regulatory T (Treg) cells promotes repair of acutely or chronically injured skeletal muscle. The accumulation of these cells depends critically on interleukin (IL)-33 produced by local mesenchymal stromal cells (mSCs). An intriguing physical association between muscle nerves, IL-33+ mSCs and Tregs has been reported, and begs a deeper exploration of this cell triumvirate. Here we evidence a striking proximity between IL-33+ muscle mSCs and both large-fiber nerve bundles and small-fiber sensory neurons; report that muscle mSCs transcribe an array of genes encoding neuropeptides, neuropeptide receptors and other nerve-related proteins; define muscle mSC subtypes that express both IL-33 and the receptor for the calcitonin-gene-related peptide (CGRP); and demonstrate that up- or down- tuning of CGRP signals augments or diminishes, respectively, IL-33 production by muscle mSCs and later accumulation of muscle Tregs. Indeed, a single injection of CGRP induced much of the genetic program elicited in mSCs early after acute skeletal muscle injury. These findings highlight neural/stromal/immune-cell cross-talk in tissue repair, suggesting future therapeutic approaches.
2020-02-10 | GSE143426 | GEO
Project description:A distinct population of Foxp3+CD4+ regulatory T (Treg) cells promotes repair of acutely or chronically injured skeletal muscle. The accumulation of these cells depends critically on interleukin (IL)-33 produced by local mesenchymal stromal cells (mSCs). An intriguing physical association between muscle nerves, IL-33+ mSCs and Tregs has been reported, and begs a deeper exploration of this cell triumvirate. Here we evidence a striking proximity between IL-33+ muscle mSCs and both large-fiber nerve bundles and small-fiber sensory neurons; report that muscle mSCs transcribe an array of genes encoding neuropeptides, neuropeptide receptors and other nerve-related proteins; define muscle mSC subtypes that express both IL-33 and the receptor for the calcitonin-gene-related peptide (CGRP); and demonstrate that up- or down- tuning of CGRP signals augments or diminishes, respectively, IL-33 production by muscle mSCs and later accumulation of muscle Tregs. Indeed, a single injection of CGRP induced much of the genetic program elicited in mSCs early after acute skeletal muscle injury. These findings highlight neural/stromal/immune-cell cross-talk in tissue repair, suggesting future therapeutic approaches.
2020-02-10 | GSE143425 | GEO
Project description:A distinct population of Foxp3+CD4+ regulatory T (Treg) cells promotes repair of acutely or chronically injured skeletal muscle. The accumulation of these cells depends critically on interleukin (IL)-33 produced by local mesenchymal stromal cells (mSCs). An intriguing physical association between muscle nerves, IL-33+ mSCs and Tregs has been reported, and begs a deeper exploration of this cell triumvirate. Here we evidence a striking proximity between IL-33+ muscle mSCs and both large-fiber nerve bundles and small-fiber sensory neurons; report that muscle mSCs transcribe an array of genes encoding neuropeptides, neuropeptide receptors and other nerve-related proteins; define muscle mSC subtypes that express both IL-33 and the receptor for the calcitonin-gene-related peptide (CGRP); and demonstrate that up- or down- tuning of CGRP signals augments or diminishes, respectively, IL-33 production by muscle mSCs and later accumulation of muscle Tregs. Indeed, a single injection of CGRP induced much of the genetic program elicited in mSCs early after acute skeletal muscle injury. These findings highlight neural/stromal/immune-cell cross-talk in tissue repair, suggesting future therapeutic approaches.
2020-02-10 | GSE143424 | GEO
Project description:ILC2 cells are a newly described cell type whose biology and contribution to disease are poorly understood. ILC2 cells are activated by allergens, viral infection, and/or epithelial damage via IL-33 and IL-25. ILC2 cells require IL-2, IL-7, IL-25 and IL-33 for their survival and expansion. In mice, ILC2s produce multiple mediators primarily associated with type 2 inflammation (IL-13, IL-5, IL-4, IL-6, IL-9, IL-10, GM-CSF, amphiregulin). ILC2 cells may contribute to the pathology of asthma through multiple mediators that include IL-13-independent pathways. Our goal is to compare transcriptional profiles of IL-33- or IL-25-activated ILC2 cells from blood to characterize these cells and to identify marker(s) that can be utilized to detect them in human tissue. ILC2 cells (Lineage negative, CRTH2+, CD161+, CD127+) were purified from human blood of 5 different donors by flow cytometry. The ILC2 yield ranged from 20,000 to 165,000 cells per donor (0.001-0.008% WBC). Purified ILC2s were expanded in vitro in the presence of IL-2, IL-7, IL-33 and IL-25 (each at 50 ng/ml) for 7-10 days. Expanded cells maintained the ILC2 phenotype (Lineage negative, CRTH2+, CD161+, CD127+). The cells were rested for 2 days in the presence of 1 ng/ml IL-2 and IL-7 and then treated in the presence of 1 ng/ml IL-2 and IL-7 with either media control, IL-25 (50 ng/ml), IL-33 (50 ng/ml), and/or TSLP (50 ng/ml) in combination, for 6 or 24 hours. Whole RNA was isolated via the RNeasy kit (Qiagen). Stratagene Universal Human Reference RNA was used as the reference.
2013-12-31 | E-GEOD-45458 | biostudies-arrayexpress
Project description:Group 2 innate lymphoid cells (ILC2s) in mouse lungs are activated by the epithelium-derived alarmin IL-33. Activated ILC2s proliferate and produce IL-5 and IL-13 that drive allergic responses. In neonatal lungs, IL-33 is spontaneously released resulting in activation of lung ILC2s. Here we report that neonatal lung ILC2 activation has significant effects on ILC2 functions in adulthood. Most neonatal lung ILC2s incorporated bromodeoxyuridine (BrdU) and persisted into adulthood. BrdU+ ILC2s in adult lungs responded more intensely to IL-33 treatment than BrdU- ILC2s. In IL-33 deficient (KO) mice, lung ILC2s develop normally but they are not activated in the neonatal period. Lung ILC2s in KO mice responded less intensely to IL-33 in adulthood compared to wild type (WT) ILC2s. While there was no difference in the number of lung ILC2s, there were fewer IL-13+ ILC2s in IL-33KO than IL-33WT mice. The impaired responsiveness of ILC2s in KO mice was reversed by intranasal injections of IL-33 in the neonatal period. These results suggest that activation of lung ILC2s by endogenous IL-33 in the neonatal period may “train” ILC2s seeding the lung after birth to become long-lasting resident cells that respond more efficiently to challenges later in life.
2020-04-14 | GSE148545 | GEO