Profibrotic function of pulmonary group 2 innate lymphoid cells is controlled by Regnase-1

2020 ◽  
pp. 2000018
Author(s):  
Yoshinari Nakatsuka ◽  
Ai Yaku ◽  
Tomohiro Handa ◽  
Alexis Vandenbon ◽  
Yuki Hikichi ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Mouse Model ◽  
Immune Cell ◽  
Cell Types ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Posttranscriptional Control ◽  
Protein Levels ◽  
Spontaneous Proliferation ◽  
Group 2

Regnase-1 is an RNase critical for posttranscriptional control of pulmonary immune homeostasis in mice by degrading immune-related mRNAs. However, little is known about the cell types Regnase-1 controls in the lung, and its relevance to human pulmonary diseases.Regnase-1-dependent changes in lung immune cell types were examined by a competitive bone marrow transfer mouse model, and group 2 innate lymphoid cells (ILC2s) were identified. Then the associations between Regnase-1 in ILC2s and human diseases were investigated by transcriptome analysis and a bleomycin-induced pulmonary fibrosis mouse model. The clinical significance of Regnase-1 in ILC2s was further assessed using patients-derived cells.Regnase-1-deficiency resulted in the spontaneous proliferation and activation of ILC2s in the lung. Intriguingly, genes associated with pulmonary fibrosis were highly upregulated in Regnase1-deficient ILC2s compared with wild-type, and supplementation of Regnase-1-deficient ILC2s augmented bleomycin-induced pulmonary fibrosis in mice. Regnase-1 suppresses mRNAs encoding transcription factors Gata3 and Egr1, which are potent to regulate fibrosis-associated genes. Clinically, Regnase-1 protein levels in ILC2 negatively correlated with the ILC2 population in bronchoalveolar lavage (BAL) fluid. Furthermore, idiopathic pulmonary fibrosis (IPF) patients with more than 1500 cells·mL−1 peripheral blood ILC2s exhibited poorer prognosis than patients with lower numbers, implying the contribution of Regnase-1 in ILC2s for the progression of IPF.Collectively, Regnase-1 was identified as a critical posttranscriptional regulator of the pro-fibrotic function of ILC2s both in mouse and human, suggesting that Regnase-1 may be a novel therapeutic target for IPF.

scholarly journals An ST2-dependent role of bone marrow-derived group 2 innate lymphoid cells in pulmonary fibrosis

2018 ◽  
Vol 245 (4) ◽  
pp. 399-409 ◽  
Author(s):  
Yuyue Zhao ◽  
Francina Gonzalez De Los Santos ◽  
Zhe Wu ◽  
Tianju Liu ◽  
Sem H Phan
Keyword(s):  
Bone Marrow ◽  
Pulmonary Fibrosis ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Group 2

scholarly journals Cell type–specific actions of Bcl11b in early T-lineage and group 2 innate lymphoid cells

2019 ◽  
Vol 217 (1) ◽  
Author(s):  
Hiroyuki Hosokawa ◽  
Maile Romero-Wolf ◽  
Qi Yang ◽  
Yasutaka Motomura ◽  
Ditsa Levanon ◽  
...  
Keyword(s):  
T Cells ◽  
Target Genes ◽  
Cell Types ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Cell Type ◽  
Distal Enhancer ◽  
Distinct Cell Type ◽  
Cell Type Specific ◽  
Group 2

The zinc finger transcription factor, Bcl11b, is expressed in T cells and group 2 innate lymphoid cells (ILC2s) among hematopoietic cells. In early T-lineage cells, Bcl11b directly binds and represses the gene encoding the E protein antagonist, Id2, preventing pro-T cells from adopting innate-like fates. In contrast, ILC2s co-express both Bcl11b and Id2. To address this contradiction, we have directly compared Bcl11b action mechanisms in pro-T cells and ILC2s. We found that Bcl11b binding to regions across the genome shows distinct cell type–specific motif preferences. Bcl11b occupies functionally different sites in lineage-specific patterns and controls totally different sets of target genes in these cell types. In addition, Bcl11b bears cell type–specific post-translational modifications and organizes different cell type–specific protein complexes. However, both cell types use the same distal enhancer region to control timing of Bcl11b activation. Therefore, although pro-T cells and ILC2s both need Bcl11b for optimal development and function, Bcl11b works substantially differently in these two cell types.

scholarly journals Group 2 Innate Lymphoid Cells and the House Dust Mite-Induced Asthma Mouse Model

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1178
Author(s):  
Yuichiro Yasuda ◽  
Tatsuya Nagano ◽  
Kazuyuki Kobayashi ◽  
Yoshihiro Nishimura
Keyword(s):  
Epithelial Cells ◽  
Mouse Model ◽  
House Dust ◽  
Innate Lymphoid Cells ◽  
Airway Epithelial Cells ◽  
Lymphoid Cells ◽  
House Dust Mites ◽  
Airway Epithelial ◽  
Group 2 ◽  
Asthma Mouse Model

Asthma is an important issue not only in health but also in economics worldwide. Therefore, asthma animal models have been frequently used to understand the pathogenesis of asthma. Recently, in addition to acquired immunity, innate immunity has also been thought to be involved in asthma. Among innate immune cells, group 2 innate lymphoid cells (ILC2s) have been considered to be crucial for eosinophilic airway inflammation by releasing T helper 2 cytokines. Moreover, house dust mites (HDMs) belonging to group 1 act on airway epithelial cells not only as allergens but also as cysteine proteases. The production of interleukin-25 (IL-25), IL-33, and thymic stromal lymphopoietin (TSLP) from airway epithelial cells was induced by the protease activity of HDMs. These cytokines activate ILC2s, and activated ILC2s produce IL-5, IL-9, IL-13, and amphiregulin. Hence, the HDM-induced asthma mouse model greatly contributes to understanding asthma pathogenesis. In this review, we highlight the relationship between ILC2s and the HDM in the asthma mouse model to help researchers and clinicians not only choose a proper asthma mouse model but also to understand the molecular mechanisms underlying HDM-induced asthma.

scholarly journals IL-25 simultaneously elicits distinct populations of innate lymphoid cells and multipotent progenitor type 2 (MPPtype2) cells

2013 ◽  
Vol 210 (9) ◽  
pp. 1823-1837 ◽  
Author(s):  
Steven A. Saenz ◽  
Mark C. Siracusa ◽  
Laurel A. Monticelli ◽  
Carly G.K. Ziegler ◽  
Brian S. Kim ◽  
...  
Keyword(s):  
Immune Cell ◽  
Extramedullary Hematopoiesis ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Cell Populations ◽  
Helper Cells ◽  
Th2 Cytokine ◽  
Natural Helper ◽  
Group 2

The predominantly epithelial cell–derived cytokines IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) can promote CD4+ Th2 cell–dependent immunity, inflammation, and tissue repair at barrier surfaces through the induction of multiple innate immune cell populations. IL-25 and IL-33 were previously shown to elicit four innate cell populations, named natural helper cells, nuocytes, innate type 2 helper cells, and multipotent progenitor type 2 (MPPtype2) cells, now collectively termed group 2 innate lymphoid cells (ILC2). In contrast to other types of ILC2, MPPtype2 cells exhibit multipotent potential and do not express T1/ST2 or IL-7Rα, suggesting that MPPtype2 cells may be a distinct population. Here, we show that IL-33 elicits robust ILC2 responses, whereas IL-25 predominantly promotes MPPtype2 cell responses at multiple tissue sites with limited effects on ILC2 responses. MPPtype2 cells were distinguished from ILC2 by their differential developmental requirements for specific transcription factors, distinct genome-wide transcriptional profile, and functional potential. Furthermore, IL-25–induced MPPtype2 cells promoted Th2 cytokine–associated inflammation after depletion of ILC2. These findings indicate that IL-25 simultaneously elicits phenotypically and functionally distinct innate lymphoid– and nonlymphoid-associated cell populations and implicate IL-25–elicited MPPtype2 cells and extramedullary hematopoiesis in the promotion of Th2 cytokine responses at mucosal surfaces.

scholarly journals Innate Lymphoid Cells in Response to Intracellular Pathogens: Protection Versus Immunopathology

2021 ◽  
Vol 11 ◽  
Author(s):  
Anna A. Korchagina ◽  
Ekaterina Koroleva ◽  
Alexei V. Tumanov
Keyword(s):  
Cytokine Production ◽  
Immune Cell ◽  
Cell Types ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Mucosal Barrier ◽  
Intracellular Pathogens ◽  
Pathogen Invasion ◽  
And Function ◽  
Mucosal Pathogens

Innate lymphoid cells (ILCs) are a heterogeneous group of cytokine-producing lymphocytes which are predominantly located at mucosal barrier surfaces, such as skin, lungs, and gastrointestinal tract. ILCs contribute to tissue homeostasis, regulate microbiota-derived signals, and protect against mucosal pathogens. ILCs are classified into five major groups by their developmental origin and distinct cytokine production. A recently emerged intriguing feature of ILCs is their ability to alter their phenotype and function in response to changing local environmental cues such as pathogen invasion. Once the pathogen crosses host barriers, ILCs quickly activate cytokine production to limit the spread of the pathogen. However, the dysregulated ILC responses can lead to tissue inflammation and damage. Furthermore, the interplay between ILCs and other immune cell types shapes the outcome of the immune response. Recent studies highlighted the important role of ILCs for host defense against intracellular pathogens. Here, we review recent advances in understanding the mechanisms controlling protective and pathogenic ILC responses to intracellular pathogens. This knowledge can help develop new ILC-targeted strategies to control infectious diseases and immunopathology.

scholarly journals Stomach microbiota, Helicobacter pylori, and group 2 innate lymphoid cells

2020 ◽  
Vol 52 (9) ◽  
pp. 1377-1382 ◽  
Author(s):  
Hiroshi Ohno ◽  
Naoko Satoh-Takayama
Keyword(s):  
Helicobacter Pylori ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Receptor Protein ◽  
Protein Levels ◽  
Culture Independent ◽  
Microbial Analysis ◽  
Group 2 ◽  
Iga Production

Abstract The stomach has been thought to host few commensal bacteria because of the existence of barriers, such as gastric acid. However, recent culture-independent, sequencing-based microbial analysis has shown that the stomach also harbors a wide diversity of microbiota. Although the stomach immune system, especially innate lymphoid cells (ILCs), has not been well elucidated, recent studies have shown that group 2 ILCs (ILC2s) are the dominant subtype in the stomach of both humans and mice. Stomach ILC2s are unique in that their existence is dependent on stomach microbiota, in sharp contrast to the lack of an impact of commensal microbiota on ILC2s in other tissues. The microbiota dependency of stomach ILC2s is partly explained by their responsiveness to interleukin (IL)-7. Stomach ILC2s express significantly higher IL-7 receptor protein levels on their surface and proliferate more in response to IL-7 stimulation in vitro than small intestinal ILC2s. Consistently, the stomach expresses much higher IL-7 protein levels than the small intestine. IL-5 secreted from stomach ILC2s promotes immunoglobulin (Ig) A production by plasma B cells. In a murine model, stomach ILC2s are important in containing Helicobacter pylori infection, especially in the early phase of infection, by promoting IgA production.

scholarly journals Group 2 innate lymphoid cells are numerically and functionally deficient in the triple transgenic mouse model of Alzheimer’s disease

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Ivan Ting Hin Fung ◽  
Yuanyue Zhang ◽  
Damian S. Shin ◽  
Poornima Sankar ◽  
Xiangwan Sun ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Wild Type ◽  
Model Of Alzheimer’S Disease ◽  
Group 2 ◽  
Resident Group ◽  
And Function

Abstract Background The immune pathways in Alzheimer’s disease (AD) remain incompletely understood. Our recent study indicates that tissue-resident group 2 innate lymphoid cells (ILC2) accumulate in the brain barriers of aged mice and that their activation alleviates aging-associated cognitive decline. The regulation and function of ILC2 in AD, however, remain unknown. Methods In this study, we examined the numbers and functional capability of ILC2 from the triple transgenic AD mice (3xTg-AD) and control wild-type mice. We investigated the effects of treatment with IL-5, a cytokine produced by ILC2, on the cognitive function of 3xTg-AD mice. Results We demonstrate that brain-associated ILC2 are numerically and functionally defective in the triple transgenic AD mouse model (3xTg-AD). The numbers of brain-associated ILC2 were greatly reduced in 7-month-old 3xTg-AD mice of both sexes, compared to those in age- and sex-matched control wild-type mice. The remaining ILC2 in 3xTg-AD mice failed to efficiently produce the type 2 cytokine IL-5 but gained the capability to express a number of proinflammatory genes. Administration of IL-5, a cytokine produced by ILC2, transiently improved spatial recognition and learning in 3xTg-AD mice. Conclusion Our results collectively indicate that numerical and functional deficiency of ILC2 might contribute to the cognitive impairment of 3xTg-AD mice.

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