scholarly journals The Role of PPAR-γ in Allergic Disease

2021 ◽  
Vol 21 (11) ◽  
Author(s):  
Julian M. Stark ◽  
Jonathan M. Coquet ◽  
Christopher A. Tibbitt
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
Immune Responses ◽  
Allergic Disease ◽  
Allergic Inflammation ◽  
Allergic Diseases ◽  
Lymphoid Cells ◽  
Th2 Cells ◽  
Ppar Γ

Abstract Purpose of Review The incidence of allergic diseases such as asthma, rhinitis and atopic dermatitis has risen at an alarming rate over the last century. Thus, there is a clear need to understand the critical factors that drive such pathologic immune responses. Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a nuclear receptor that has emerged as an important regulator of multiple cell types involved in the inflammatory response to allergens; from airway epithelial cells to T Helper (TH) cells. Recent Findings Initial studies suggested that agonists of PPAR-γ could be employed to temper allergic inflammation, suppressing pro-inflammatory gene expression programs in epithelial cells. Several lines of work now suggest that PPAR-γ plays an essential in promoting ‘type 2’ immune responses that are typically associated with allergic disease. PPAR-γ has been found to promote the functions of TH2 cells, type 2 innate lymphoid cells, M2 macrophages and dendritic cells, regulating lipid metabolism and directly inducing effector gene expression. Moreover, preclinical models of allergy in gene-targeted mice have increasingly implicated PPAR-γ in driving allergic inflammation. Summary Herein, we highlight the contrasting roles of PPAR-γ in allergic inflammation and hypothesize that the availability of environmental ligands for PPAR-γ may be at the heart of the rise in allergic diseases worldwide.

scholarly journals Prostaglandin D2 Selectively Induces Chemotaxis in T Helper Type 2 Cells, Eosinophils, and Basophils via Seven-Transmembrane Receptor Crth2

2001 ◽  
Vol 193 (2) ◽  
pp. 255-262 ◽  
Author(s):  
Hiroyuki Hirai ◽  
Kazuya Tanaka ◽  
Osamu Yoshie ◽  
Kazuyuki Ogawa ◽  
Kazumi Kenmotsu ◽  
...  
Keyword(s):  
Allergic Inflammation ◽  
Allergic Diseases ◽  
Th2 Cells ◽  
Prostaglandin D2 ◽  
Dependent Manner ◽  
T Helper ◽  
Dependent Cell ◽  
Blood Eosinophils ◽  
Helper Type

Prostaglandin (PG)D2, which has long been implicated in allergic diseases, is currently considered to elicit its biological actions through the DP receptor (DP). Involvement of DP in the formation of allergic asthma was recently demonstrated with DP-deficient mice. However, proinflammatory functions of PGD2 cannot be explained by DP alone. We show here that a seven-transmembrane receptor, CRTH2, which is preferentially expressed in T helper type 2 (Th2) cells, eosinophils, and basophils in humans, serves as the novel receptor for PGD2. In response to PGD2, CRTH2 induces intracellular Ca2+ mobilization and chemotaxis in Th2 cells in a Gαi-dependent manner. In addition, CRTH2, but not DP, mediates PGD2-dependent cell migration of blood eosinophils and basophils. Thus, PGD2 is likely involved in multiple aspects of allergic inflammation through its dual receptor systems, DP and CRTH2.

scholarly journals Epigenetic regulation of epithelial dectin-1 through an IL-33-STAT3 axis in allergic disease

2020 ◽  
Author(s):  
Hwan Mee Yong ◽  
Naina Gour ◽  
Deepika Sharma ◽  
Syed Muaz Khalil ◽  
Andrew P. Lane ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Allergic Disease ◽  
Epigenetic Regulation ◽  
Allergic Diseases ◽  
Respiratory Epithelium ◽  
Fine Tuning ◽  
Proximal Promoter ◽  
Epigenetic Repression ◽  
Inflammatory Molecules

AbstractAllergic diseases arise in susceptible individuals in part because of decrements in protective pathways. The mechanism by which these anti-inflammatory molecules become repressed remains unclear. We have previously reported that epithelial dectin-1 prevents aberrant type 2 responses and is downregulated in the epithelium of allergic patients. Here we report that dectin-1 is constitutively expressed by the respiratory epithelium in humans, and that IL-33 specifically acts as a repressor of dectin-1. Mechanistically, this occurs via IL-33-dependent STAT3 activation and the subsequent repression of the dectin-1 gene, CLEC7A. We have identified a novel enhancer region upstream of the proximal promoter of CLEC7A that is only accessible in epithelial cells, but not in hematopoietic cells. Epigenetic repression of CLEC7A through this newly identified locus, downstream of an aberrant IL-33-STAT3 axis, occurs in the epithelium of allergic individuals. Collectively, our data identify a mechanism of epigenetic fine-tuning of dectin-1 expression in epithelial cells that may participate in allergenicity.

scholarly journals Leukotrienes provide an NFAT-dependent signal that synergizes with IL-33 to activate ILC2s

2016 ◽  
Vol 214 (1) ◽  
pp. 27-37 ◽  
Author(s):  
Jakob von Moltke ◽  
Claire E. O’Leary ◽  
Nora A. Barrett ◽  
Yoshihide Kanaoka ◽  
K. Frank Austen ◽  
...  
Keyword(s):  
T Cells ◽  
Allergic Inflammation ◽  
Primary Source ◽  
Cell Receptor ◽  
Lymphoid Cells ◽  
Th2 Cells ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Deficient Mice

Group 2 innate lymphoid cells (ILC2s) and type 2 helper T cells (Th2 cells) are the primary source of interleukin 5 (IL-5) and IL-13 during type 2 (allergic) inflammation in the lung. In Th2 cells, T cell receptor (TCR) signaling activates the transcription factors nuclear factor of activated T cells (NFAT), nuclear factor κB (NF-κB), and activator protein 1 (AP-1) to induce type 2 cytokines. ILC2s lack a TCR and respond instead to locally produced cytokines such as IL-33. Although IL-33 induces AP-1 and NF-κB, NFAT signaling has not been described in ILC2s. In this study, we report a nonredundant NFAT-dependent role for lipid-derived leukotrienes (LTs) in the activation of lung ILC2s. Using cytokine reporter and LT-deficient mice, we find that complete disruption of LT signaling markedly diminishes ILC2 activation and downstream responses during type 2 inflammation. Type 2 responses are equivalently attenuated in IL-33– and LT-deficient mice, and optimal ILC2 activation reflects potent synergy between these pathways. These findings expand our understanding of ILC2 regulation and may have important implications for the treatment of airways disease.

scholarly journals House Dust Mite Induces Bone Marrow IL-33-Responsive ILC2s and TH Cells

2020 ◽  
Vol 21 (11) ◽  
pp. 3751
Author(s):  
Emma Boberg ◽  
Kristina Johansson ◽  
Carina Malmhäll ◽  
Julie Weidner ◽  
Madeleine Rådinger
Keyword(s):  
Bone Marrow ◽  
House Dust ◽  
House Dust Mite ◽  
Allergic Diseases ◽  
Lymphoid Cells ◽  
Th2 Cells ◽  
Initial Increase ◽  
Th Cells ◽  
Dust Mite

Type 2 innate lymphoid cells (ILC2s) and their adaptive counterpart type 2 T helper (TH2) cells respond to interleukin-33 (IL-33) by producing IL-5, which is a crucial cytokine for eosinophil development in the bone marrow. The aim of this study was to determine if bone marrow ILC2s, TH cells, and eosinophils are locally regulated by IL-33 in terms of number and activation upon exposure to the common aeroallergen house dust mite (HDM). Mice that were sensitized and challenged with HDM by intranasal exposures induced eosinophil development in the bone marrow with an initial increase of IL5Rα+ eosinophil progenitors, following elevated numbers of mature eosinophils and the induction of airway eosinophilia. Bone marrow ILC2s, TH2, and eosinophils all responded to HDM challenge by increased IL-33 receptor (ST2) expression. However, only ILC2s, but not TH cells, revealed increased ST2 expression at the onset of eosinophil development, which significantly correlated with the number of eosinophil progenitors. In summary, our findings suggest that airway allergen challenges with HDM activates IL-33-responsive ILC2s, TH cells, and eosinophils locally in the bone marrow. Targeting the IL-33/ST2 axis in allergic diseases including asthma may be beneficial by decreasing eosinophil production in the bone marrow.

scholarly journals MicroRNA regulation of type 2 innate lymphoid cell homeostasis and function in allergic inflammation

2017 ◽  
Vol 214 (12) ◽  
pp. 3627-3643 ◽  
Author(s):  
Priti B. Singh ◽  
Heather H. Pua ◽  
Hannah C. Happ ◽  
Christoph Schneider ◽  
Jakob von Moltke ◽  
...  
Keyword(s):  
Target Genes ◽  
Therapeutic Potential ◽  
Allergic Inflammation ◽  
Lymphoid Cells ◽  
Th2 Cells ◽  
Signaling Inhibitors ◽  
Regulated Gene Expression ◽  
And Function

MicroRNAs (miRNAs) exert powerful effects on immunity through coordinate regulation of multiple target genes in a wide variety of cells. Type 2 innate lymphoid cells (ILC2s) are tissue sentinel mediators of allergic inflammation. We established the physiological requirements for miRNAs in ILC2 homeostasis and immune function and compared the global miRNA repertoire of resting and activated ILC2s and T helper type 2 (TH2) cells. After exposure to the natural allergen papain, mice selectively lacking the miR-17∼92 cluster in ILC2s displayed reduced lung inflammation. Moreover, miR-17∼92–deficient ILC2s exhibited defective growth and cytokine expression in response to IL-33 and thymic stromal lymphopoietin in vitro. The miR-17∼92 cluster member miR-19a promoted IL-13 and IL-5 production and inhibited expression of several targets, including SOCS1 and A20, signaling inhibitors that limit IL-13 and IL-5 production. These findings establish miRNAs as important regulators of ILC2 biology, reveal overlapping but nonidentical miRNA-regulated gene expression networks in ILC2s and TH2 cells, and reinforce the therapeutic potential of targeting miR-19 to alleviate pathogenic allergic responses.

scholarly journals Maintenance of Type 2 Response by CXCR6-Deficient ILC2 in Papain-Induced Lung Inflammation

2019 ◽  
Vol 20 (21) ◽  
pp. 5493 ◽  
Author(s):  
Meunier ◽  
Chea ◽  
Garrido ◽  
Perchet ◽  
Petit ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Nk Cell ◽  
Lymphoid Cells ◽  
Inflammatory Conditions ◽  
Airway Diseases ◽  
Type 2 Cytokines ◽  
Lymphoid Organogenesis ◽  
Deficient Mice

Innate lymphoid cells (ILC) are important players of early immune defenses in situations like lymphoid organogenesis or in case of immune response to inflammation, infection and cancer. Th1 and Th2 antagonism is crucial for the regulation of immune responses, however mechanisms are still unclear for ILC functions. ILC2 and NK cells were reported to be both involved in allergic airway diseases and were shown to be able to interplay in the regulation of the immune response. CXCR6 is a common chemokine receptor expressed by all ILC, and its deficiency affects ILC2 and ILC1/NK cell numbers and functions in lungs in both steady-state and inflammatory conditions. We determined that the absence of a specific ILC2 KLRG1+ST2– subset in CXCR6-deficient mice is probably dependent on CXCR6 for its recruitment to the lung under inflammation. We show that despite their decreased numbers, lung CXCR6-deficient ILC2 are even more activated cells producing large amount of type 2 cytokines that could drive eosinophilia. This is strongly associated to the decrease of the lung Th1 response in CXCR6-deficient mice.

scholarly journals Selective deletion of SHIP-1 in hematopoietic cells in mice leads to severe lung inflammation involving ILC2 cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xujun Ye ◽  
Fengrui Zhang ◽  
Li Zhou ◽  
Yadong Wei ◽  
Li Zhang ◽  
...  
Keyword(s):  
Lung Inflammation ◽  
Airway Remodeling ◽  
Pulmonary Inflammation ◽  
Hematopoietic Cells ◽  
Cell Lineage ◽  
Allergic Inflammation ◽  
Cell Types ◽  
Lymphoid Cells ◽  
Whole Body

AbstractSrc homology 2 domain–containing inositol 5-phosphatase 1 (SHIP-1) regulates the intracellular levels of phosphotidylinositol-3, 4, 5-trisphosphate, a phosphoinositide 3–kinase (PI3K) product. Emerging evidence suggests that the PI3K pathway is involved in allergic inflammation in the lung. Germline or induced whole-body deletion of SHIP-1 in mice led to spontaneous type 2-dominated pulmonary inflammation, demonstrating that SHIP-1 is essential for lung homeostasis. However, the mechanisms by which SHIP-1 regulates lung inflammation and the responsible cell types are still unclear. Deletion of SHIP-1 selectively in B cells, T cells, dendritic cells (DC) or macrophages did not lead to spontaneous allergic inflammation in mice, suggesting that innate immune cells, particularly group 2 innate lymphoid cells (ILC2 cells) may play an important role in this process. We tested this idea using mice with deletion of SHIP-1 in the hematopoietic cell lineage and examined the changes in ILC2 cells. Conditional deletion of SHIP-1 in hematopoietic cells in Tek-Cre/SHIP-1 mice resulted in spontaneous pulmonary inflammation with features of type 2 immune responses and airway remodeling like those seen in mice with global deletion of SHIP-1. Furthermore, when compared to wild-type control mice, Tek-Cre/SHIP-1 mice displayed a significant increase in the number of IL-5/IL-13 producing ILC2 cells in the lung at baseline and after stimulation by allergen Papain. These findings provide some hints that PI3K signaling may play a role in ILC2 cell development at baseline and in response to allergen stimulation. SHIP-1 is required for maintaining lung homeostasis potentially by restraining ILC2 cells and type 2 inflammation.

scholarly journals Transcription Factors in the Development and Function of Group 2 Innate Lymphoid Cells

2019 ◽  
Vol 20 (6) ◽  
pp. 1377 ◽  
Author(s):  
Takashi Ebihara ◽  
Ichiro Taniuchi
Keyword(s):  
Transcription Factors ◽  
Physiological State ◽  
Allergic Inflammation ◽  
Allergic Diseases ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Th2 Cytokine ◽  
Parasitic Worm ◽  
Group 2 ◽  
And Function

Group 2 innate lymphoid cells (ILC2s) are tissue-resident cells and are a major source of innate TH2 cytokine secretion upon allergen exposure or parasitic-worm infection. Accumulating studies have revealed that transcription factors, including GATA-3, Bcl11b, Gfi1, RORα, and Ets-1, play a role in ILC2 differentiation. Recent reports have further revealed that the characteristics and functions of ILC2 are influenced by the physiological state of the tissues. Specifically, the type of inflammation strongly affects the ILC2 phenotype in tissues. Inhibitory ILC2s, memory-like ILC2s, and ex-ILC2s with ILC1 features acquire their characteristic properties following exposure to their specific inflammatory environment. We have recently reported a new ILC2 population, designated as exhausted-like ILC2s, which emerges after a severe allergic inflammation. Exhausted-like ILC2s are featured with low reactivity and high expression of inhibitory receptors. Therefore, for a more comprehensive understanding of ILC2 function and differentiation, we review the recent knowledge of transcriptional regulation of ILC2 differentiation and discuss the roles of the Runx transcription factor in controlling the emergence of exhausted-like ILC2s. The concept of exhausted-like ILC2s sheds a light on a new aspect of ILC2 biology in allergic diseases.

scholarly journals Miquelianin Inhibits Allergic Responses in Mice by Suppressing CD4+ T Cell Proliferation

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1120
Author(s):  
Dae Woon Choi ◽  
Sun Young Jung ◽  
Gun-Dong Kim ◽  
So-Young Lee ◽  
Hee Soon Shin
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Mouse Model ◽  
Immune Responses ◽  
Reactive Oxygen Species Generation ◽  
Allergic Diseases ◽  
Cd4 T Cell ◽  
Th2 Cells ◽  
T Cell Proliferation ◽  
Heme Oxygenase 1

Allergic diseases, including atopic dermatitis (AD), induce type 2 helper T (Th2) cell-dominant immune responses. Miquelianin (quercetin 3-O-glucuronide, MQL) is an active compound in Rosae multiflorae fructus extract with anti-allergic properties. Here, we investigate the anti-allergic effects of MQL in an ovalbumin (OVA)-induced Th2-dominant mouse model and the associated mechanisms. Oral MQL suppressed cytokine and IL-2 production and proliferation of Th2 cells and upregulated heme oxygenase-1 (HO-1) in splenocytes. Ex vivo MQL suppressed Th1- and Th2-related immune responses by inhibiting CD4+ T cell proliferation, and upregulated HO-1 in CD4+ T cells by activating C-Raf–ERK1/2–Nrf2 pathway via induction of reactive oxygen species generation. In a trimellitic anhydride-induced AD-like mouse model, both topical and oral MQL ameliorated AD symptoms by suppressing Th2 immune responses. Our results suggest that MQL is a potential therapeutic agent for CD4+ T cell-mediated diseases, including allergic diseases.

Sign in / Sign up

Export Citation Format

Share Document