Steroid-resistant human inflammatory ILC2s are marked by CD45RO and elevated in type 2 respiratory disease
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE152130 | GEO | 2021/01/28
REPOSITORIES: GEO
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Project description:Group 2 innate lymphoid cells (ILC2s) orchestrate protective type 2 immunity and tissue homeostatis, but have also been implicated in major human type 2 immunopathologies. However, our understanding of the mechanisms that control human ILC2 activity and phenotypic heterogeneity under inflammatory conditions remains limited. We integrated transcriptome profiling, flowcytometry characterization and functional assays to characterize human ILC2s from non-inflamed and inflamed microenvironments. We show that the transition from a resting to an activated inflammatory state in ILC2s is accompanied by a CD45RA-to-CD45RO isoform switch. CD45RA phosphatase activity suppresses ILC2 activation in resting cells, while exposure to activating cytokines induces IRF4/BATF transcription factors to promote a switch to the enzymatically restrained CD45RO isoform. Importantly, CD45RO+ ILC2 levels are increased in nasal polyps but also in the circulation of patients with chronic rhinosinusitis and asthma, which correlates with disease severity and resistance to steroid therapy. CD45RA-to-CD45RO conversion in ILC2s is sensitive to suppression by glucocorticosteroids, a mainstay therapy for patients with type-2 inflammatory disease. However, once converted, CD45RO+ ILC2s are resistant to steroids, likely via unique intrinsic metabolic reprogramming. In summary, we identify an inflammatory ILC2 subset in humans that is marked by CD45RO and is linked to severe type-2 inflammatory disease and steroid resistance.
2021-01-28 | GSE150846 | GEO
Project description:Steroid-resistant human inflammatory ILC2s are marked by CD45RO and elevated in type 2 respiratory disease
| PRJNA638387 | ENA
Project description:Steroid-resistant human inflammatory ILC2s are marked by CD45RO and elevated in type 2 respiratory diseases
| PRJNA633849 | ENA
Project description:Steroids are the standard treatment for allergic airway inflammation in asthma, but steroid-refractory asthma poses a challenge. Group 2 innate lymphoid cells (ILC2s), such as T helper 2 (TH2) cells, produce key asthma-related type 2 cytokines. Recent insights from mouse and human studies indicate a potential connection between ILC2s and steroid-resistant asthma. Here, we highlight that lung ILC2s, rather than TH2 cells, can develop steroid resistance, allowing them to persist and maintain their disease-driving activity even during steroid treatment. The emergence of multipotent IL-5+IL-13+IL-17A+ ILC2s is associated with steroid-resistant ILC2s. The Janus kinase 3 (JAK3)/signal transducer and activator of transcription (STAT) 3, 5, and 6 pathways contribute to the acquisition of steroid-resistant ILC2s. The JAK3 inhibitor reduces ILC2 survival, proliferation, and cytokine production in vitro and ameliorates ILC2-driven Alternaria-induced asthma. Furthermore, combining a JAK3 inhibitor with steroids results in the inhibition of steroid-resistant asthma. These findings suggest a potential therapeutic approach for addressing this challenging condition in chronic asthma.
| S-EPMC10732531 | biostudies-literature
Project description:To fully characterize the heterogeneity and gene expression profile of mouse lung ILC2s, we generated RORα lineage tracer mice by crossing RoraIRES-Cre (Chou et al., 2013) and R26R-EYFP mice, which have a loxP-flanked stop sequence followed by the gene encoding yellow fluorescent protein (YFP) in the ROSA26 locus. In these RORα-YFP mice, cells expressing Rorα during their development should be irreversibly labeled by YFP. Flow cytometric analyses of lymphocytes in RORα-YFP mice showed that innate lymphoid cells type 2 (ILC2s) were marked by YFP expression. However, both adult and neonatal lung Lin−YFP+ cells were heterogeneous and included not only ILC2s (GATA-3+Thy1+) but also GATA-3−Thy1− and GATA-3lowThy1+ cells. In order to fully assess the lung ILC2 heterogeneity, we analyzed all CD45low/+Linlow cells from adult (6-week-old) and neonatal (12-day-old) RORα-YFP mouse lungs by droplet-based scRNA-seq. Unsupervised clustering of the cells revealed distinct clusters of stromal, B, T, NK cell, DC and ILC2 based on their expression of well-characterized marker genes. We then isolated the ILC2 cluster and performed a second round of unsupervised clustering to examine the existence of possible ILC2 subsets. In both adult and neonatal datasets, ILC2s were divided into subsets with each subset expressing a distinct set of ILC2-associated genes. We validated the existence of distinct ILC2 subsets in adult and neonatal lungs using flow cytometry. We also comprehensively assessed the genes that were specifically and/or differentially expressed by ILC2s compared to other immune and non-immune cell populations in our datasets. This analysis revealed the expression of well-characterized ILC2 genes such as Gata3, Rora, Areg and Il7r as well as other genes with potential immune regulatory functions.
2020-10-27 | GSE123994 | GEO
Project description:Mechanosensitive ion channels sense force and pressure in immune cells to drive the inflammatory response in highly mechanical organs. Here we report that Piezo1 channels repress group 2 innate lymphoid cells (ILC2s)-driven type 2 inflammation in the lungs. Piezo1 is induced on lung ILC2s upon activation, as genetic ablation of Piezo1 in ILC2s increases their function and exacerbates the development of airway hyperreactivity (AHR). Conversely, Piezo1 agonist Yoda1 reduces ILC2-driven lung inflammation. Mechanistically, Yoda1 inhibits ILC2 cytokine secretion and proliferation in a KLF2-dependent manner, as we further found that Piezo1 engagement reduces ILC2 oxidative metabolism. Consequently, in vivo Yoda1 treatment notably reduces the development of AHR in experimental models of ILC2-driven allergic asthma. Human circulating ILC2s express and induce Piezo1 upon activation, as Yoda1 treatment of humanized mice reduces human ILC2-driven AHR. Our studies define Piezo1 as a critical regulator of ILC2s and we propose the potential of Piezo1 activation as a novel therapeutic approach for the treatment of ILC2-driven allergic asthma.
2024-02-20 | GSE255882 | GEO
Project description:Mechanosensitive ion channels sense force and pressure in immune cells to drive the inflammatory response in highly mechanical organs. Here we report that Piezo1 channels repress group 2 innate lymphoid cells (ILC2s)-driven type 2 inflammation in the lungs. Piezo1 is induced on lung ILC2s upon activation, as genetic ablation of Piezo1 in ILC2s increases their function and exacerbates the development of airway hyperreactivity (AHR). Conversely, Piezo1 agonist Yoda1 reduces ILC2-driven lung inflammation. Mechanistically, Yoda1 inhibits ILC2 cytokine secretion and proliferation in a KLF2-dependent manner, as we further found that Piezo1 engagement reduces ILC2 oxidative metabolism. Consequently, in vivo Yoda1 treatment notably reduces the development of AHR in experimental models of ILC2-driven allergic asthma. Human circulating ILC2s express and induce Piezo1 upon activation, as Yoda1 treatment of humanized mice reduces human ILC2-driven AHR. Our studies define Piezo1 as a critical regulator of ILC2s and we propose the potential of Piezo1 activation as a novel therapeutic approach for the treatment of ILC2-driven allergic asthma.
2024-02-20 | GSE255881 | GEO
Project description:Group 2 innate lymphoid cell (ILC2), an innate counterpart of T helper 2 cell, plays a critical role in type 2 immune responses. However, the molecular regulation mechanism of ILC2 is still unclear. Here, we find that STAT3 signaling is essential for ILC2 effector function and could drive both acute and chronic allergic inflammation in the lung. Mechanistically, allergic alarmin IL-33 induces a non-canonical STAT3 phosphorylation at serine 727 in ILC2, which leads to its mitochondrial translocation. Mitochondrial STAT3 further promotes the methionine cycle through ATP synthesis and fuel the generation of S-adenosylmethionine (SAM), which supports the epigenetic reprogramming of type 2 cytokines in ILC2. STAT3 deficiency dampens the mitochondrial function and methionine metabolism, thus results in impairment of the ILC2 cytokines expression. Interestingly, inhibition the mitochondrial translocation of STAT3 could remarkably ameliorate the allergic lung inflammation. Together, our findings establish mitochondrial STAT3 as a key regulator shaping ILC2 effector function through metabolic and epigenetic regulation
2022-01-25 | GSE166081 | GEO
Project description:Group 2 innate lymphoid cells (ILC2s) reside in multiple tissues including lymphoid organs and barrier surfaces, and secrete type 2 cytokines including interleukin (IL)-5, IL-9 and IL-13. These cells participate in multiple physiological processes including allergic inflammation, tissue repair, metabolic homeostasis and host defense against helminth infections. Recent studies indicate that neuropeptides can play an important role in regulating ILC2 responses, however, the mechanisms that underlie these processes in vivo remain incompletely defined. Here, we identify that activated ILC2s upregulate choline acetyltransferase (ChAT)—the enzyme responsible for the biosynthesis of acetylcholine (ACh)—following infection with the helminth parasite Nippostrongylus brasiliensis or treatment with alarmins or cytokines including IL-25, IL-33 and thymic stromal lymphopoietin (TSLP). ILC2s also express acetylcholine receptors (AChRs), and ACh administration promotes ILC2 cytokine production and elicits expulsion of helminth infection. In accordance with this, ChAT deficiency in ILC2s leads to defective ILC2 responses and impaired immunity against helminth infection. Together, these results reveal a previously unrecognized role of the ChAT-ACh pathway in promoting type 2 innate immunity to helminth infection.
2021-03-05 | GSE164705 | GEO
Project description:We have identified CD25high and CD25low ILC2 subsets in various mouse models of airway inflammation. Transcriptome analysis of acute IL-33 (CD25High) or chronic HDM (CD25Low) activated murine lung ILC2s suggests functional differences between these two ILC2 populations.
2020-05-13 | GSE99780 | GEO