ILC2s navigate tissue redistribution during infection using stage-specific S1P receptors [ATAC-seq]
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PROVIDER: PRJNA1126271 | ENA |
REPOSITORIES: ENA
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Project description:Lymphocytes can circulate as well as take residence within tissues. The mechanisms by which circulating populations are recruited to infected tissue sites have been characterized, but the extent and molecular basis of tissue-resident cell recirculation is enigmatic. Here, we show that helminth infection- or IL-25-induced redistribution of intestinal tissue-localized group 2 innate lymphoid cells (ILC2s) requires access to the lymphatic vessel network even though secondary lymphoid structures, which are essential signal hubs for adaptive lymphocyte differentiation and dispatch, are dispensable for tissue ILC2 mobilization. IL-25 signals induce a dramatic change in epigenetic landscape of intestinal ILC2s, enabling the expression of sphingosine-1-phosphate (S1P) receptors. S1PR5 is critical for ILC2 exit from intestinal tissue to lymph, whereas S1PR1 plays a dominant role in ILC2 egress from mesenteric lymph nodes to blood circulation and then to lung, where redistributed ILC2s contribute to tissue repair. The requirement of two S1PRs is largely due to the dynamic expression of the tissue-retention marker CD69, which mediates S1PR1 internalization. This stage-specific requirement of different S1P receptors for ILC2 redistribution during infection illustrates that innate and adaptive lymphocytes share a circulatory network frame but employ specialized navigation cues for their distinct migratory requirements.
2024-06-05 | GSE268826 | GEO
Project description:Lymphocytes can circulate as well as take residence within tissues. The mechanisms by which circulating populations are recruited to infected tissue sites have been characterized, but the extent and molecular basis of tissue-resident cell recirculation is enigmatic. Here, we show that helminth infection- or IL-25-induced redistribution of intestinal tissue-localized group 2 innate lymphoid cells (ILC2s) requires access to the lymphatic vessel network even though secondary lymphoid structures, which are essential signal hubs for adaptive lymphocyte differentiation and dispatch, are dispensable for tissue ILC2 mobilization. IL-25 signals induce a dramatic change in epigenetic landscape of intestinal ILC2s, enabling the expression of sphingosine-1-phosphate (S1P) receptors. S1PR5 is critical for ILC2 exit from intestinal tissue to lymph, whereas S1PR1 plays a dominant role in ILC2 egress from mesenteric lymph nodes to blood circulation and then to lung, where redistributed ILC2s contribute to tissue repair. The requirement of two S1PRs is largely due to the dynamic expression of the tissue-retention marker CD69, which mediates S1PR1 internalization. This stage-specific requirement of different S1P receptors for ILC2 redistribution during infection illustrates that innate and adaptive lymphocytes share a circulatory network frame but employ specialized navigation cues for their distinct migratory requirements.
2024-06-27 | GSE270373 | GEO
Project description:Group 2 innate lymphoid cells (ILC2s) in the lung are stimulated by inhaled allergens. ILC2s do not directly recognize allergens but they are stimulated by cytokines including interleukin (IL)-33 released by damaged epithelium.Lung ILC2s, upon stimulation, produce T helper 2 cell-type cytokines inducing T cell independent allergic lung inflammation. We now report that lung ILC2s, upon activation by an allergen or IL-33, acquire the properties of memory cells. The activated ILC2s initially proliferate and secrete cytokines, followed by a contraction phase as they stop producing cytokines. Nevertheless, some persist long after the resolution of the inflammation and acquire intrinsic capacities to react to unrelated allergens more vigorously than naïve ILC2s, thus mediating a severe allergic lung inflammation. Gene expression profiles of the previously activated ILC2s show a gene signature of memory T cells. These antigen non-specific memory ILC2s may explain why asthma patients are often sensitized to multiple allergens. ILC2s were isolated from mouse lungs from naive and IL-33 injected mice 4 days, 14 days and 4 months after the initial treatment. RNA was extracted from those ILC2 populations and analyzed for gene expression profiles. RNA was also extracted from ILC2s isolated from lung draining mediastinal lymph node (mLN) 4 days and 14 days after IL-33 treatment.
2016-06-30 | E-GEOD-81700 | biostudies-arrayexpress
Project description:Chronic inflammation is associated with disruption of cellular homeostasis, yet the underlying mechanisms remain elusive1. Nucleotide-binding oligomerization domain-containing protein 1/2 (NOD1/2) are intracellular pathogen recognition receptors that activate innate immune responses via sensing bacterial peptidoglycans2-4. We demonstrate that NOD1/2 sense not only microbe-specific molecular patterns but also perturbation of cell homeostasis, and thereby cause inflammation. Host generation of sphingosine-1-phosphate (S1P) via the hydrolysis pathway is essential for NOD1/2 signaling upon such stress. Cytosolic delivery of S1P activates NOD1/2 dependent NF-κB activation and inflammation. Finally, we demonstrate that S1P directly binds to and activates NOD1/2. In sum, we describe a hitherto unknown role of NOD1/2 by revealing that they initiate innate immune responses by surveillance of cellular homeostasis through sensing of cytosolic S1P. Our findings provide a novel link between host cytosolic S1P and NOD1/2 mediated immune activation upon perturbation of cellular homeostasis and thus form the basis for future intervention strategies targeting the S1P-NOD1/2 axis.
2020-01-01 | GSE124828 | GEO
Project description:We analyzed the total proteome of group 2 innate lymphoid cells (ILC2s) after different stimulation with interleukin-33 (IL-33), a cytokine playing a critical role in human asthma, and TL1A, a TNF-family cytokine also known to activate ILC2s. Upon combined stimulation with IL-33 plus TL1A, we show that lung ILC2s produce high amounts of IL-9 and acquire a transient ‘ILC9’ phenotype. This phenotype is characterized by simultaneous production of large amounts of type 2 cytokines (IL-5, IL-13 and IL-9), induction of the IL-2 receptor CD25 (Il2ra), and of the transcription factors IRF4, JunB and BATF, that form immune-specific complexes known to induce IL-9 expression.
2024-03-05 | PXD041987 | Pride
Project description:The cleavage of sphingoid base phosphates by sphingosine-1-phosphate (S1P) lyase to produce phosphoethanolamine and a fatty aldehyde is the final degradative step in the sphingolipid metabolic pathway. We have studied mice with an inactive S1P lyase gene and have found that, in addition to the expected increase of sphingoid base phosphates, other sphingolipids (including sphingosine, ceramide, and sphingomyelin) were substantially elevated in the serum and /or liver of these mice. This latter increase is consistent with a reutilization of the sphingosine backbone for sphingolipid synthesis due to its inability to exit the sphingolipid metabolic pathway. Furthermore, the S1P lyase deficiency resulted in changes in the levels of serum and liver lipids not directly within the sphingolipid pathway, including phospholipids, triacyglycerol, diacylglycerol, and cholesterol. Even though lipids in serum and lipid storage were elevated in liver, adiposity was reduced in the S1P lyase-deficient mice. Microarray analysis of lipid metabolism genes in liver showed that the S1P lyase deficiency caused widespread changes in their expression pattern. These results demonstrate that S1P lyase is a key regulator of the levels of multiple sphingolipid substrates and reveal functional links between the sphingolipid metabolic pathway and other lipid metabolic pathways that may be mediated by shared lipid substrates and changes in gene expression programs. The disturbance of lipid homeostasis by altered sphingolipid levels may be relevant to metabolic diseases. Experiment Overall Design: RNA samples from liver for three sphingosine-1-phosphate lyase knock-out and three WT mice.
2010-02-05 | E-GEOD-18745 | biostudies-arrayexpress
Project description:Sphingosine 1-phosphate (S1P), a lipid chemoattractant, guides immune cells from the low-S1P environment of tissues into the high-S1P environment of circulatory fluids. Most notably, S1P directs T cell exit from lymph nodes (LN), where T cells are initially activated to fight pathogens, into lymph, from which T cells flow into blood and ultimately reach inflamed tissues. T cells follow these gradients primarily using S1P receptor 1 (S1PR1). The drugs Gilenya and Siponimod, both FDA-approved for the autoimmune disease multiple sclerosis, target S1PR1. They blind self-reactive T cells to S1P gradients, block them from exiting LN, and thus prevent them from infiltrating the central nervous system. While recent work has revealed key aspects of how S1P gradients are established at steady-state, very little is known about S1P distribution in disease, and in turn how changing S1P gradients may affect the immune response. Here, we find that LN S1P increases during an immune response, which prolongs the time T cells spend in the LN before exiting into lymph. Inflammatory monocytes, which had not previously been implicated in shaping S1P gradients, are an important source of this S1P. Inflammatory monocytes must express the early activation marker CD69 to supply S1P to T cells; CD69 represses transcription of S1P receptor 5 (S1pr5), enabling monocytes to infiltrate the LN T zone and efficiently release S1P. Here we compared RNA sequencing of inflammatory monocytes WT or CD69-KO infiltrating the draining lymph node.$
2020-12-23 | GSE139006 | GEO
Project description:Innate lymphoid cells (ILCs) are considered to be the innate counterparts of adaptive T lymphocytes and play important roles in host defense, tissue repair, metabolic homeostasis, and inflammatory diseases. ILCs are generally thought of as tissue-resident cells, but whether ILCs strictly behave in a tissue-resident manner or can move between sites during infection is unclear. We show here that IL-25- or helminthic infection-induced inflammatory ILC2s are not tissue-resident but circulating cells, which arise from resting ILC2s residing in intestinal lamina propria and then migrate to mesenteric lymph nodes, spleen, lung, and liver. IL-25 induces rapid proliferation of the intestinal ILC2s and a change in their sensitivity to S1P-mediated chemotaxis, leading to lymphatic entry, blood circulation, and accumulation in periphery sites, including the lung where they contribute to anti-helminth defense and tissue repair. Our finding of cytokine-driven expansion and migration of innate lymphocytes, a behavioral parallel to the antigen-driven priming, expansion, and migration of adaptive lymphocytes to effector sites in distant tissues, provides a significant advance in our overall understanding of ILCs and indicates that ILCs complement adaptive immunity by providing both local and distant site effector protection during infection.
2018-01-08 | GSE104708 | GEO