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1.
Cell ; 176(5): 982-997.e16, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30712873

RESUMO

Immune cells and epithelium form sophisticated barrier systems in symbiotic relationships with microbiota. Evidence suggests that immune cells can sense microbes through intact barriers, but regulation of microbial commensalism remain largely unexplored. Here, we uncovered spatial compartmentalization of skin-resident innate lymphoid cells (ILCs) and modulation of sebaceous glands by a subset of RORγt+ ILCs residing within hair follicles in close proximity to sebaceous glands. Their persistence in skin required IL-7 and thymic stromal lymphopoietin, and localization was dependent on the chemokine receptor CCR6. ILC subsets expressed TNF receptor ligands, which limited sebocyte growth by repressing Notch signaling pathway. Consequently, loss of ILCs resulted in sebaceous hyperplasia with increased production of antimicrobial lipids and restricted commensalism of Gram-positive bacterial communities. Thus, epithelia-derived signals maintain skin-resident ILCs that regulate microbial commensalism through sebaceous gland-mediated tuning of the barrier surface, highlighting an immune-epithelia circuitry that facilitates host-microbe symbiosis.


Assuntos
Linfócitos/imunologia , Glândulas Sebáceas/metabolismo , Glândulas Sebáceas/microbiologia , Animais , Bactérias/metabolismo , Citocinas/metabolismo , Epitélio/imunologia , Folículo Piloso/metabolismo , Folículo Piloso/microbiologia , Imunidade Inata , Interleucina-7/metabolismo , Linfócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microbiota/imunologia , Receptores CCR6/metabolismo , Receptores Notch/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo , Glândulas Sebáceas/imunologia , Pele/metabolismo , Fenômenos Fisiológicos da Pele , Simbiose , Linfopoietina do Estroma do Timo
2.
Immunity ; 55(10): 1756-1758, 2022 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-36223723

RESUMO

The overall contribution of type 2 immunity to cutaneous barrier integrity is poorly understood. In this issue of Immunity, Ricardo-Gonzalez et al. demonstrate the mechanisms by which type 2 cytokines and group 2 innate lymphoid cells (ILC2s) regulate Demodex mite colonization and maintain skin homeostasis.


Assuntos
Imunidade Inata , Linfócitos , Citocinas
3.
Immunity ; 52(4): 635-649.e4, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32240600

RESUMO

The intestinal microbiota shapes and directs immune development locally and systemically, but little is known about whether commensal microbes in the stomach can impact their immunological microenvironment. Here, we report that group 2 innate lymphoid cells (ILC2s) were the predominant ILC subset in the stomach and show that their homeostasis and effector functions were regulated by local commensal communities. Microbes elicited interleukin-7 (IL-7) and IL-33 production in the stomach, which in turn triggered the propagation and activation of ILC2. Stomach ILC2s were also rapidly induced following infection with Helicobacter pylori. ILC2-derived IL-5 resulted in the production of IgA, which coated stomach bacteria in both specific pathogen-free (SPF) and H. pylori-infected mice. Our study thus identifies ILC2-dependent IgA response that is regulated by the commensal microbiota, which is implicated in stomach protection by eliminating IgA-coated bacteria including pathogenic H. pylori.


Assuntos
Microbioma Gastrointestinal/imunologia , Infecções por Helicobacter/imunologia , Helicobacter pylori/patogenicidade , Imunoglobulina A/biossíntese , Interleucina-5/imunologia , Estômago/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Feminino , Regulação da Expressão Gênica , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Helicobacter pylori/crescimento & desenvolvimento , Helicobacter pylori/imunologia , Imunidade Humoral , Imunidade Inata , Interleucina-33/genética , Interleucina-33/imunologia , Interleucina-5/genética , Interleucina-7/genética , Interleucina-7/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Cultura Primária de Células , Transdução de Sinais , Estômago/microbiologia , Simbiose/imunologia , Subpopulações de Linfócitos T/classificação
4.
Nat Immunol ; 17(1): 76-86, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26595888

RESUMO

Group 2 innate lymphoid cells (ILC2 cells) are type 2 cytokine-producing cells of the innate immune system with important roles in helminth infection and allergic inflammation. Here we found that tissue-resident ILC2 cells proliferated in situ without migrating during inflammatory responses. Both type I and type II interferons and interleukin 27 (IL-27) suppressed ILC2 function in a manner dependent on the transcription factor STAT1. ILC2-mediated lung inflammation was enhanced in the absence of the interferon-γ (IFN-γ) receptor on ILC2 cells in vivo. IFN-γ effectively suppressed the function of tissue-resident ILC2 cells but not that of inflammatory ILC2 cells, and IL-27 suppressed tissue-resident ILC2 cells but not tissue-resident TH2 cells during lung inflammation induced by Alternaria alternata. Our results demonstrate that suppression mediated by interferon and IL-27 is a negative feedback mechanism for ILC2 function in vivo.


Assuntos
Helmintíase Animal/imunologia , Imunidade Inata/imunologia , Interferons/imunologia , Interleucinas/imunologia , Linfócitos/imunologia , Transferência Adotiva , Animais , Modelos Animais de Doenças , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pneumonia/imunologia , Reação em Cadeia da Polimerase em Tempo Real
5.
Immunity ; 51(4): 598-600, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31618650

RESUMO

In this issue of Immunity, Nagashima et al., Wallrapp et al., and Xu et al. demonstrate that the neuropeptide calcitonin gene-related peptide (CGRP) fine tunes type 2 innate immune response via suppressing group 2 innate lymphoid cells (ILC2s).


Assuntos
Transtorno Bipolar , Peptídeo Relacionado com Gene de Calcitonina , Calcitonina , Humanos , Imunidade Inata , Inflamação , Linfócitos
6.
Nat Immunol ; 16(3): 276-85, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25599561

RESUMO

Foxp3(+) regulatory T (Treg) cells in visceral adipose tissue (VAT-Treg cells) are functionally specialized tissue-resident cells that prevent obesity-associated inflammation and preserve insulin sensitivity and glucose tolerance. Their development depends on the transcription factor PPAR-γ; however, the environmental cues required for their differentiation are unknown. Here we show that interleukin 33 (IL-33) signaling through the IL-33 receptor ST2 and myeloid differentiation factor MyD88 is essential for development and maintenance of VAT-Treg cells and sustains their transcriptional signature. Furthermore, the transcriptional regulators BATF and IRF4 were necessary for VAT-Treg differentiation through direct regulation of ST2 and PPAR-γ expression. IL-33 administration induced vigorous population expansion of VAT-Treg cells, which tightly correlated with improvements in metabolic parameters in obese mice. Human omental adipose tissue Treg cells also showed high ST2 expression, suggesting an evolutionarily conserved requirement for IL-33 in VAT-Treg cell homeostasis.


Assuntos
Tecido Adiposo/citologia , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Fatores Reguladores de Interferon/metabolismo , Interleucinas/metabolismo , Linfócitos T Reguladores/citologia , Tecido Adiposo/metabolismo , Animais , Diferenciação Celular/fisiologia , Humanos , Interleucina-33 , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fator 88 de Diferenciação Mieloide/metabolismo , Obesidade/metabolismo , PPAR gama/metabolismo , Receptores de Superfície Celular/metabolismo , Linfócitos T Reguladores/metabolismo
7.
Nat Immunol ; 13(8): 744-52, 2012 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-22729248

RESUMO

Langerhans cells (LCs) are epidermal dendritic cells with incompletely understood origins that associate with hair follicles for unknown reasons. Here we show that in response to external stress, mouse hair follicles recruited Gr-1(hi) monocyte-derived precursors of LCs whose epidermal entry was dependent on the chemokine receptors CCR2 and CCR6, whereas the chemokine receptor CCR8 inhibited the recruitment of LCs. Distinct hair-follicle regions had differences in their expression of ligands for CCR2 and CCR6. The isthmus expressed the chemokine CCL2; the infundibulum expressed the chemokine CCL20; and keratinocytes in the bulge produced the chemokine CCL8, which is the ligand for CCR8. Thus, distinct hair-follicle keratinocyte subpopulations promoted or inhibited repopulation with LCs via differences in chemokine production, a feature also noted in humans. Pre-LCs failed to enter hairless skin in mice or humans, which establishes hair follicles as portals for LCs.


Assuntos
Quimiocinas/biossíntese , Folículo Piloso/imunologia , Células de Langerhans/fisiologia , Estresse Fisiológico , Alopecia , Animais , Movimento Celular , Quimiocina CCL20/biossíntese , Quimiocina CCL8/biossíntese , Quimiocinas/metabolismo , Folículo Piloso/metabolismo , Humanos , Queratinócitos/metabolismo , Células de Langerhans/imunologia , Camundongos , Camundongos Pelados , Receptores CCR2/metabolismo , Receptores CCR6/metabolismo , Receptores CCR8/metabolismo , Pele/imunologia
8.
Immunity ; 43(1): 175-86, 2015 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-26200013

RESUMO

House dust mite-derived proteases contribute to allergic disorders in part by disrupting epithelial barrier function. Interleukin-33 (IL-33), produced by lung cells after exposure to protease allergens, can induce innate-type airway eosinophilia by activating natural helper (NH) cells, a member of group 2 innate lymphoid cells (ILC2), to secrete Th2 type-cytokines. Because IL-33 also can induce mast cells (MCs) to secrete Th2 type-cytokines, MCs are thought to cooperate with NH cells in enhancing protease or IL-33-mediated innate-type airway eosinophilia. However, we found that MC-deficient Kit(W-sh/W-sh) mice exhibited exacerbated protease-induced lung inflammation associated with reduced numbers of regulatory T (Treg) cells. Moreover, IL-2 produced by IL-33-stimulated MCs promoted expansion of numbers of Treg cells, thereby suppressing development of papain- or IL-33-induced airway eosinophilia. We have thus identified a unique anti-inflammatory pathway that can limit induction of innate-type allergic airway inflammation mediated by NH cells.


Assuntos
Inflamação/imunologia , Interleucina-2/imunologia , Interleucinas/imunologia , Mastócitos/imunologia , Linfócitos T Reguladores/imunologia , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Células Cultivadas , Eosinofilia/induzido quimicamente , Humanos , Interleucina-10/imunologia , Interleucina-2/genética , Interleucina-33 , Interleucinas/genética , Interleucinas/farmacologia , Pulmão/citologia , Pulmão/imunologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Papaína/farmacologia , Proteínas Proto-Oncogênicas c-kit/genética , Pyroglyphidae/imunologia , Células Th2/imunologia
9.
Trends Immunol ; 41(2): 100-112, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31948873

RESUMO

Skin is the largest barrier organ and an important interface between the body and the outside environment. Immune surveillance and homeostatic regulation of skin function are governed by complex interactions between resident lymphoid and myeloid cells and their communications with the surrounding parenchyma. Recent studies have provided exciting insights about the unique characteristics of skin-resident innate lymphoid cells (ILCs). Here, we discuss advances demonstrating how skin ILCs contribute to tissue homeostasis by regulating microbiome balance in steady-state and how their dysregulation can trigger and promote inflammatory skin diseases such as atopic dermatitis and psoriasis. We review the phenotypic and functional similarities and differences of ILCs between the skin and other organs and highlight future areas of investigation for this field.


Assuntos
Imunidade Inata , Linfócitos , Pele , Dermatite Atópica/imunologia , Humanos , Imunidade Inata/imunologia , Linfócitos/imunologia , Psoríase/imunologia , Pele/citologia , Pele/imunologia
10.
Immunity ; 40(5): 758-71, 2014 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24837103

RESUMO

Allergic asthma is an inflammatory disease characterized by lung eosinophilia controlled by type 2 cytokines. Cysteine proteases are potent triggers of allergic inflammation by causing barrier disruption in lung epithelial cells inducing the elevation of interleukin-5 (IL-5) and IL-13 from natural helper (NH) cells, a member of ILC2s, which leads to lung eosinophilia. In this study, we found that basophils play a crucial role in NH cell-mediated eosinophilic inflammation induced by protease allergens. Conditional deletion of basophils caused a resolution of the papain-induced eosinophilia and mucus production. Resolution of eosinophilia was also observed in mice lacking IL-4 specifically in basophils, indicating that basophil-derived IL-4 enhanced expression of the chemokine CCL11, as well as IL-5, IL-9, and IL-13 in NH cells, thus attracting eosinophils. These results demonstrate that IL-4 from basophils has an important role in the NH-derived cytokine and chemokine expression, subsequently leading to protease allergen-induced airway inflammation.


Assuntos
Basófilos/imunologia , Eosinófilos/imunologia , Interleucina-13/imunologia , Interleucina-4/imunologia , Interleucina-5/imunologia , Animais , Asma/imunologia , Quimiocina CCL11/biossíntese , Interleucina-13/biossíntese , Interleucina-4/deficiência , Interleucina-4/genética , Interleucina-5/biossíntese , Interleucina-9/biossíntese , Interleucina-9/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pneumonia/imunologia , Eosinofilia Pulmonar/imunologia , Linfócitos T Auxiliares-Indutores/imunologia
11.
Allergol Int ; 72(2): 187-193, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36646561

RESUMO

Group 2 innate lymphoid cells (ILC2s) are tissue-resident innate lymphoid cells that express the transcription factor GATA3 as a master regulator, which leads to the production of large amounts of type 2 cytokines, such as IL-5 and IL-13. ILC2s are activated by epithelial cell-derived cytokines, including IL-33 and IL-25, and play a key role in parasite expulsion, allergic responses, tissue repair, and metabolism. In the first five years after the discovery of ILC2s, research mainly focused on their function through cytokine receptors. However, in recent years, their regulatory mechanisms through not only cytokine receptors but also lipids, neuropeptides, and hormones have become a hot topic. For ILC2s that do not recognize foreign antigens, receptor expression of such endogenous factors is important, and the diverse expression patterns create the individuality of ILC2s in each organ. By considering the mechanisms of differentiation and regulation of ILC2s and their role in disease while taking into account spatio-temporal information, it is expected that new therapeutic strategies targeting ILC2s will be developed. Herein, we summarize the current understanding of ILC2s in lung homeostasis and pathology and provide valuable insights that will help to guide the future development of therapeutic methods for ILC2-mediated lung diseases.


Assuntos
Imunidade Inata , Pesquisa Translacional Biomédica , Humanos , Linfócitos , Citocinas/metabolismo , Receptores de Citocinas/metabolismo
13.
Int Immunol ; 33(5): 251-259, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33403383

RESUMO

Group 2 innate lymphoid cells (ILC2s) are novel lymphocytes discovered in 2010. Unlike T or B cells, ILC2s are activated non-specifically by environmental factors and produce various cytokines, thus playing a role in tissue homeostasis, diseases including allergic diseases, and parasite elimination. ILC2s were first reported as cells abundantly present in fat-associated lymphoid clusters in adipose tissue. However, subsequent studies revealed their presence in various tissues throughout the body, acting as key players in tissue-specific diseases. Recent histologic analyses revealed that ILC2s are concentrated in specific regions in tissues, such as the lamina propria and perivascular regions, with their function being controlled by the surrounding cells, such as epithelial cells and other immune cells, via cytokine and lipid production or by cell-cell interactions through surface molecules. Especially, some stromal cells have been identified as the niche cells for ILC2s, both in the steady state and under inflammatory conditions, through the production of IL-33 or extracellular matrix factors. Additionally, peripheral neurons reportedly co-localize with ILC2s and alter their function directly through neurotransmitters. These findings suggest that the different localizations or different cell-cell interactions might affect the function of ILC2s. Furthermore, generally, ILC2s are thought to be tissue-resident cells; however, they occasionally migrate to other tissues and perform a new role; this supports the importance of the microenvironment for their function. We summarize here the current understanding of how the microenvironment controls ILC2 localization and function with the aim of promoting the development of novel diagnostic and therapeutic methods.


Assuntos
Comunicação Celular/imunologia , Imunidade Inata/imunologia , Linfócitos/imunologia , Animais , Microambiente Celular , Citocinas/imunologia , Células Epiteliais/imunologia , Humanos , Inflamação/imunologia
14.
Int Immunol ; 33(12): 705-709, 2021 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-34498700

RESUMO

Group 2 innate lymphoid cells (ILC2s), discovered in 2010, have been recognized as immune cells with unique functions and their involvement in various diseases has been clarified. Before 2010, the antigen-specific response was a primary focus of immunology research, and immune responses were considered almost equivalent to biological responses to foreign antigens. However, with the emergence of ILC2s, the importance of 'antigen-independent responses' was confirmed, and this concept has permeated basic and clinical research as well as drug development. When ILC2s were discovered, their function in the acute phase of diseases garnered attention because of their rapid and potent type 2 immune response. However, several studies have revealed that the main role of ILC2s is more closely related to the chronicity of diseases, such as allergy and fibrosis, than to the induction of diseases. In this review, we discuss how ILC2 research has affected the concept of 'Taishitsu', a Japanese term describing the overall nature of an individual as determined by the interaction of genetic and acquired predisposition.


Assuntos
Doenças do Sistema Imunitário/imunologia , Imunidade Inata/imunologia , Linfócitos/imunologia , Animais , Humanos
15.
Int Immunol ; 33(11): 573-585, 2021 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-34498703

RESUMO

Group 2 innate lymphoid cells (ILC2s) are tissue-resident cells that play different roles in different organs by sensing surrounding environmental factors. Initially, it was thought that ILC2s in bone marrow (BM) are progenitors for systemic ILC2s, which migrate to other organs and acquire effector functions. However, accumulating evidence that ILC2s differentiate in peripheral tissues suggests that BM ILC2s may play a specific role in the BM as a unique effector per se. Here, we demonstrate that BM ILC2s highly express the receptor activator of nuclear factor κB ligand (RANKL), a robust cytokine for osteoclast differentiation and activation, and RANKL expression on ILC2s is up-regulated by interleukin (IL)-2, IL-7 and all-trans retinoic acid (ATRA). BM ILC2s co-cultured with BM-derived monocyte/macrophage lineage cells (BMMs) in the presence of IL-7 induce the differentiation of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts in a RANKL-dependent manner. In contrast, BM ILC2s stimulated with IL-33 down-regulate RANKL expression and convert BMMs differentiation into M2 macrophage-like cells rather than osteoclasts by granulocyte macrophage colony-stimulating factor (GM-CSF) and IL-13 production. Intravital imaging using two-photon microscopy revealed that a depletion of ILC2s prominently impaired in vivo osteoclast activity in an IL-7 plus ATRA-induced bone loss mouse model. These results suggest that ILC2s regulate osteoclast activation and contribute to bone homeostasis in both steady state and IL-33-induced inflammation.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Imunidade Inata/imunologia , Interleucina-13/imunologia , Linfócitos/imunologia , Osteoclastos/imunologia , Ligante RANK/imunologia , Animais , Diferenciação Celular/imunologia , Células Cultivadas , Técnicas de Cocultura , Inflamação/imunologia , Interleucina-13/biossíntese , Linfócitos/citologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Osteogênese/imunologia
16.
Adv Exp Med Biol ; 1365: 75-95, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35567742

RESUMO

The recent discovery of new innate lymphoid cells (ILCs) has revolutionized the field of allergies. Since most allergic diseases induce a type 2 immune response, Th2 cells, which produce IL-4, IL-5, and IL-13 in an antigen-dependent manner, in addition to basophils and mast cells which are activated by antigen-specific IgE, are thought to play a major role in the pathogenesis. However, since group 2 innate lymphoid cells (ILC2s) produce type 2 cytokines (i.e., IL-2, IL-4, IL-5, IL-6, IL-9, IL-13, GM-CSF, and amphiregulin) in response to various cytokines, including IL-33 in the surrounding environment, the possibility has emerged that there are two types of allergies: allergies induced in an antigen-dependent manner by Th2 cells and allergies induced in an antigen-independent manner by ILC2s. In order to make an impact on the increasing incidence of allergic diseases in the world, it is essential to research and develop new treatments that focus not only on Th2 cells but also on ILC2s. In this chapter, the role of ILCs in allergic diseases, which has rapidly changed with the discovery of ILCs, is discussed, focusing mainly on ILC2s.


Assuntos
Hipersensibilidade , Interleucina-13 , Citocinas , Humanos , Imunidade Inata , Interleucina-4 , Interleucina-5 , Linfócitos
17.
Immunol Rev ; 286(1): 37-52, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30294963

RESUMO

Group 2 innate lymphoid cells (ILC2s) play critical roles in the induction of type 2 inflammation, response to parasite infection, metabolic homeostasis, and tissue repair. These multifunctional roles of ILC2s are tightly controlled by complex regulatory systems in the local microenvironment, the disruption of which may cause various health problems. This review summarizes up-to-date knowledge regarding positive and negative regulators for ILC2s based on their function and signaling pathways, including activating cytokines (IL-33, IL-25; MAPK, NF-κB pathways), co-stimulatory cytokines (IL-2, IL-7, IL-9, TSLP; STAT5, IL-4; STAT6, TNF superfamily; MAPK, NF-κB pathways), suppressive cytokines (type1 IFNs, IFN-γ, IL-27; STAT1, IL-10, TGF-ß), transdifferentiation cytokines (IL-12; STAT4, IL-1ß, IL-18), lipid mediators (LTC4, LTD4, LTE4, PGD2; Ca2+ -NFAT pathways, PGE2, PGI2; AC/cAMP/PKA pathways, LXA4, LTB4), neuropeptides (NMU; Ca2+ -NFAT, MAPK pathways, VIP, CGRP, catecholamine, acetylcholine), sex hormones (androgen, estrogen), nutrients (butyrate; HDAC inhibitors, vitamins), and cell-to-cell interactions (ICOSL-ICOS; STAT5, B7-H6-NKp30, E-cadherin-KLRG1). This comprehensive review affords a better understanding of the regulatory network system for ILC2s, providing impetus to develop new treatment strategies for ILC2-related health problems.


Assuntos
Imunidade Inata , Linfócitos/imunologia , Células Th2/imunologia , Animais , Comunicação Celular , Microambiente Celular , Citocinas/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hormônios Esteroides Gonadais/metabolismo , Homeostase , Humanos , NF-kappa B/metabolismo , Transdução de Sinais
18.
Eur Respir J ; 57(3)2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32978308

RESUMO

Regnase-1 is an RNase critical for post-transcriptional 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 patient-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 Regnase-1-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 fluid. Furthermore, idiopathic pulmonary fibrosis (IPF) patients with ILC2s >1500 cells·mL-1 peripheral blood 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 post-transcriptional regulator of the profibrotic function of ILC2s both in mouse and human, suggesting that Regnase-1 may be a novel therapeutic target for IPF.


Assuntos
Linfócitos , Fibrose Pulmonar , Animais , Líquido da Lavagem Broncoalveolar , Humanos , Imunidade Inata , Pulmão , Camundongos , Camundongos Knockout , Fibrose Pulmonar/induzido quimicamente
19.
Allergy ; 76(9): 2785-2796, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33792078

RESUMO

BACKGROUND: Tiotropium bromide, a long-acting muscarinic antagonist, reduces the frequency of exacerbation in patients with moderate to severe asthma, but its underlying mechanism is not clear. Asthma exacerbations are associated with exposure to external stimuli, and group 2 innate lymphoid cells (ILC2s) are considered to be involved in the pathophysiology of asthma exacerbation. We investigated whether tiotropium modulates airway inflammation through ILC2 functions. METHODS: Mice were administered papain intranasally to induce innate-type airway inflammation with or without tiotropium pretreatment, and bronchoalveolar lavage fluids (BALF) and lung tissues were collected. Lung-derived ILC2s and bone marrow-derived basophils were stimulated in vitro with IL-33 in the presence or absence of tiotropium. Muscarinic M3 receptor (M3R) expression on immune cells was assessed by RNA sequence. RESULTS: Papain induced airway eosinophilic inflammation, and tiotropium reduced the numbers of eosinophils in BALF. The concentrations of IL-4, IL-5, and IL-13, and the numbers of ILC2s in BALF were also reduced by tiotropium treatment. However, tiotropium did not affect IL-33-induced IL-5 and IL-13 production from ILC2s, suggesting that tiotropium regulates ILC2s indirectly. Gene-expression analysis showed that basophils predominantly expressed M3R mRNA among murine immune cells. Tiotropium reduced IL-4 production from basophils derived from mouse bone marrow and human basophils after stimulation with IL-33. CONCLUSIONS: These findings suggest that tiotropium attenuates ILC2-dependent airway inflammation by suppressing IL-4 production from basophils and, subsequently, regulating ILC2 activation. The inhibitory effects of long-acting muscarinic antagonists on the innate response may contribute to reducing asthma exacerbation.


Assuntos
Imunidade Inata , Linfócitos , Animais , Citocinas , Humanos , Inflamação , Pulmão , Camundongos , Antagonistas Muscarínicos
20.
Int Immunol ; 32(6): 407-419, 2020 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-32147688

RESUMO

Group 2 innate lymphoid cells (ILC2s) are type 2 cytokine-producing cells that have important roles in helminth infection and allergic inflammation. ILC2s are tissue-resident cells, and their phenotypes and roles are regulated by tissue-specific environmental factors. While the role of ILC2s in the lung, intestine and bone marrow has been elucidated in many studies, their role in adipose tissues is still unclear. Here, we report on the role of ILC2-derived bone morphogenetic protein 7 (BMP7) in adipocyte differentiation and lipid accumulation. Co-culture of fat-derived ILC2s with pluripotent mesenchymal C3H10T1/2 cells and committed white preadipocyte 3T3-L1 cells resulted in their differentiation to adipocytes and induced lipid accumulation. Co-culture experiments using BMP7-deficient ILC2s revealed that BMP7, produced by ILC2s, induces differentiation into brown adipocytes. Our results demonstrate that BMP7, produced by ILC2s, affects adipocyte differentiation, particularly in brown adipocytes.


Assuntos
Adipogenia/imunologia , Proteína Morfogenética Óssea 7/biossíntese , Imunidade Inata , Linfócitos/imunologia , Células 3T3-L1 , Animais , Células Cultivadas , Técnicas de Cocultura , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
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