scholarly journals The Role of Histamine in the Pathophysiology of Asthma and the Clinical Efficacy of Antihistamines in Asthma Therapy

2019 ◽  
Vol 20 (7) ◽  
pp. 1733 ◽  
Author(s):  
Kohei Yamauchi ◽  
Masahito Ogasawara
Keyword(s):  
Mast Cells ◽  
Allergic Asthma ◽  
Clinical Efficacy ◽  
Critical Role ◽  
Allergic Airway Inflammation ◽  
Specific Ige ◽  
Smooth Muscle Contraction ◽  
Lymphoid Cells ◽  
Group 2 ◽  
Perennial Allergens

Mast cells play a critical role in the pathogenesis of allergic asthma. Histamine is a central mediator released from mast cells through allergic reactions. Histamine plays a role in airway obstruction via smooth muscle contraction, bronchial secretion, and airway mucosal edema. However, previous clinical trials of H1 receptor antagonists (H1RAs) as a treatment for asthma were not successful. In recent years, type 2 innate immunity has been demonstrated to be involved in allergic airway inflammation. Allergic asthma is defined by IgE antibody-mediated mast cell degranulation, while group 2 innate lymphoid cells (ILC2) induce eosinophilic inflammation in nonallergic asthma without allergen-specific IgE. Anti-IgE therapy has demonstrated prominent efficacy in the treatment of severe allergic asthmatics sensitized with specific perennial allergens. Furthermore, recent trials of specific cytokine antagonists indicated that these antagonists were effective in only some subtypes of asthma. Accordingly, H1RAs may show significant clinical efficacy for some subtypes of allergic asthma in which histamine is deeply associated with the pathophysiology.

scholarly journals Allergen protease-induced Gsdmd p40 controls IL-33 secretion

2021 ◽  
Author(s):  
Bing Sun ◽  
Bin Wu ◽  
Dong Wu ◽  
Feng Shao ◽  
Yaguang Zhang ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Critical Role ◽  
Allergic Airway Inflammation ◽  
Airway Epithelial Cells ◽  
Allergen Exposure ◽  
Lymphoid Cells ◽  
House Dust Mites ◽  
Airway Epithelial ◽  
Group 2 ◽  
Inflammatory Caspases

Abstract Interleukin (IL)-33, an epithelial cell-derived cytokine that responds rapidly to environmental insult, has a critical role in initiating airway inflammation, such as that in asthma. However, the molecular mechanism underlying IL-33 secretion following allergen exposure is not clear. Here, we demonstrated that Gasdermin D (Gsdmd) functions as a conduit for IL-33 secretion following allergen protease exposure. Gsdmd was rapidly cleaved into a functional neo-form, the N-terminal p40 fragment (p40 NT-Gsdmd), in the murine airway epithelium when cells were exposed to allergen proteases from fungi, house dust mites (HDMs), or bacteria. This cleavage event that produces the p40 Gsdmd fragment was independent of inflammatory caspases-1/11, as it could not be inhibited by caspase-1 and caspase-11 deficiency in murine cells. The functional p40 NT-Gsdmd fragment directly contributed to the secretion of both the nuclear full-length form and cytosolic mature form of IL-33. Both Gsdmd deficiency and blockade of the generation of p40 by amino acid mutation or deletion of residues 308–313 (ELRQQ) in the Gsdmd sequence could efficiently prevent IL-33 release in airway epithelial cells. In mice, Gsdmd deficiency prevented IL-33 release and hindered the activation of group 2 innate lymphoid cells (ILC2s), thus alleviating airway inflammation and lung tissue damage after stimulation with HDMs or papain. Our findings uncovered a mechanism of Gsdmd-mediated IL-33 release under allergen exposure and offer insight into Gsdmd cleavage prevention as a potential approach to reduce allergic airway inflammation.

scholarly journals Mast cell function in prostate inflammation, fibrosis, and smooth muscle cell dysfunction

2021 ◽  
Author(s):  
Goutham Pattabiraman ◽  
Ashlee J Bell-Cohn ◽  
Stephen F. Murphy ◽  
Daniel J Mazur ◽  
Anthony J Schaeffer ◽  
...  
Keyword(s):  
Mast Cell ◽  
Smooth Muscle ◽  
Mast Cells ◽  
Cell Activation ◽  
Cell Function ◽  
Critical Role ◽  
Smooth Muscle Contraction ◽  
Urinary Dysfunction ◽  
Mast Cell Activation ◽  
Prostate Inflammation

Intraurethral inoculation of mice with uropathogenic E. coli (CP1) results in prostate inflammation, fibrosis, and urinary dysfunction, recapitulating some but not all of the pathognomonic clinical features associated with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). In both patients with LUTS and in CP1-infected mice, we observed increased numbers and activation of mast cells and elevated levels of prostate fibrosis. Therapeutic inhibition of mast cells using a combination of mast cell stabilizer (MCS), cromolyn sodium, and the histamine 1 receptor antagonist (H1RA), cetirizine di-hydrochloride, in the mouse model resulted in reduced mast cell activation in the prostate and significant alleviation of urinary dysfunction. Treated mice showed reduced prostate fibrosis, less infiltration of immune cells, and decreased inflammation. In addition, as opposed to symptomatic CP1-infected mice, treated mice showed reduced myosin light chain (MLC)-2 phosphorylation, a marker of prostate smooth muscle contraction. These results show that mast cells play a critical role in the pathophysiology of urinary dysfunction and may be an important therapeutic target for men with BPH/LUTS.

scholarly journals Runx/Cbfβ complexes protect group 2 innate lymphoid cells from exhausted-like hyporesponsiveness during allergic airway inflammation

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Chizuko Miyamoto ◽  
Satoshi Kojo ◽  
Motoi Yamashita ◽  
Kazuyo Moro ◽  
Georges Lacaud ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Allergic Airway Inflammation ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Group 2

scholarly journals T-bet fate mapping identifies a novel ILC1-ILC2 subset in vivo

2020 ◽  
Author(s):  
J-H Schroeder ◽  
N Garrido-Mesa ◽  
T Zabinski ◽  
AL Gallagher ◽  
L Campbell ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Immune Responses ◽  
Critical Role ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Fate Mapping ◽  
Functional Roles ◽  
Mucosal Surfaces ◽  
Group 2

ABSTRACTInnate lymphoid cells (ILC) play a critical role in regulating immune responses at mucosal surfaces. Various subsets exist resembling T cell lineages defined by the expression of specific transcription factors. Thus, T-bet is expressed in ILC1 and Th1 cells. In order to further understand the functional roles of T-bet in ILC, we generated a fate-mapping mouse model that permanently marks cells and their progeny that are expressing, or have ever expressed T-bet. Here we have identified and characterised a novel ILC with characteristics of ILC1 and ILC2 that are “fate-mapped” for T-bet expression and arise early in neonatal life prior to establishment of a mature microbiome. These ILC1-ILC2 cells are critically dependent on T-bet and are able to express type 1 and type 2 cytokines at steady state, but not in the context of inflammation. These findings refine our understanding of ILC lineage regulation and stability and have important implications for the understanding of ILC biology at mucosal surfaces.SUMMARYInnate lymphoid cells (ILC) play a critical role in regulating immune responses at mucosal surfaces. Three distinct ILC groups have been described according to expression of subset defining transcription factors and other markers. In this study we characterize a novel ILC subset with characteristics of group 1 and group 2 ILC in vivo.

Group 2 Innate Lymphoid Cells: Team Players in Regulating Asthma

2021 ◽  
Vol 39 (1) ◽  
Author(s):  
Noe Rodriguez-Rodriguez ◽  
Mayuri Gogoi ◽  
Andrew N.J. McKenzie
Keyword(s):  
Allergic Asthma ◽  
Cell Activation ◽  
Innate Lymphoid Cells ◽  
Experimental Models ◽  
Lymphoid Cells ◽  
Annual Review ◽  
Publication Date ◽  
Effector Cytokines ◽  
Group 2

Type 2 immunity helps protect the host from infection, but it also plays key roles in tissue homeostasis, metabolism, and repair. Unfortunately, inappropriate type 2 immune reactions may lead to allergy and asthma. Group 2 innate lymphoid cells (ILC2s) in the lungs respond rapidly to local environmental cues, such as the release of epithelium-derived type 2 initiator cytokines/alarmins, producing type 2 effector cytokines such as IL-4, IL-5, and IL-13 in response to tissue damage and infection. ILC2s are associated with the severity of allergic asthma, and experimental models of lung inflammation have shown how they act as playmakers, receiving signals variously from stromal and immune cells as well as the nervous system and then disseminating cytokine cues to elicit effector functions and potentiate CD4+ T helper cell activation, both of which characterize the pathology of allergic asthma. Recent breakthroughs identifying stromal- and neuronal-derived microenvironmental cues that regulate ILC2s, along with studies recognizing the potential plasticity of ILC2s, have improved our understanding of the immunoregulation of asthma and opened new avenues for drug discovery. Expected final online publication date for the Annual Review of Immunology, Volume 39 is April 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Androgen signaling negatively controls group 2 innate lymphoid cells

2017 ◽  
Vol 214 (6) ◽  
pp. 1581-1592 ◽  
Author(s):  
Sophie Laffont ◽  
Eve Blanquart ◽  
Magali Savignac ◽  
Claire Cénac ◽  
Gilles Laverny ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Lung Inflammation ◽  
Inflammatory Responses ◽  
Allergic Airway Inflammation ◽  
Innate Lymphoid Cells ◽  
Protective Role ◽  
Lymphoid Cells ◽  
Peripheral Tissues ◽  
Group 2

Prevalence of asthma is higher in women than in men, but the mechanisms underlying this sex bias are unknown. Group 2 innate lymphoid cells (ILC2s) are key regulators of type 2 inflammatory responses. Here, we show that ILC2 development is greatly influenced by male sex hormones. Male mice have reduced numbers of ILC2 progenitors (ILC2Ps) and mature ILC2s in peripheral tissues compared with females. In consequence, males exhibit reduced susceptibility to allergic airway inflammation in response to environmental allergens and less severe IL-33–driven lung inflammation, correlating with an impaired expansion of lung ILC2s. Importantly, orchiectomy, but not ovariectomy, abolishes the sex differences in ILC2 development and restores IL-33–mediated lung inflammation. ILC2Ps express the androgen receptor (AR), and AR signaling inhibits their differentiation into mature ILC2s. Finally, we show that hematopoietic AR expression limits IL-33–driven lung inflammation through a cell-intrinsic inhibition of ILC2 expansion. Thus, androgens play a crucial protective role in type 2 airway inflammation by negatively regulating ILC2 homeostasis, thereby limiting their capacity to expand locally in response to IL-33.

Acupuncture inhibited airway inflammation and group 2 innate lymphoid cells in the lung in an ovalbumin-induced murine asthma model

2020 ◽  
pp. 096452842092403
Author(s):  
Jie Cui ◽  
Ming Dong ◽  
La Yi ◽  
Ying Wei ◽  
Weifeng Tang ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Acupuncture Treatment ◽  
Allergic Airway Inflammation ◽  
Dynamic Compliance ◽  
Lavage Fluid ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
Apparent Decrease ◽  
Group 2

Background Group 2 innate lymphoid cells (ILC2s) are known to serve important functions in the pathogenesis of allergic airway inflammation. Studies have shown that acupuncture has an anti-inflammatory effect in the airways. However, how acupuncture treatment affects innate immunity, especially with regard to the function of ILC2s in ovalbumin (OVA)-induced allergic airway inflammation, is poorly understood. Methods BALB/c mice were injected and subsequently challenged with OVA ± treated with manual acupuncture. At the end of the experimental course, lung function was assessed by measurement of airway resistance (RL) and lung dynamic compliance (Cdyn). Cytokine levels were detected by enzyme-linked immunosorbent assay (ELISA). ILC2 proportions in the lung were analyzed by flow cytometry. Results The results showed that airway inflammation and mucus secretion were significantly suppressed by acupuncture treatment. RL decreased while Cdyn increased after acupuncture treatment. There was an apparent decrease in the bronchoalveolar lavage fluid (BALF) concentrations of interleukin (IL)-5, IL-13, IL-9, IL-25 and IL-33 and an increase in soluble IL-33 receptor (sST2) levels compared with untreated asthmatic mice. Acupuncture also reduced the lin–CD45+KLRG1+ST2+ cell proportion in the lung. Conclusion In conclusion, this study has demonstrated that acupuncture treatment alleviates allergic airway inflammation and inhibits pulmonary ILC2 influx and IL-5, IL-9 and IL-13 production. The inhibition of ILC2s by acupuncture may be associated with the IL-33/ST2-signaling pathway and IL-25 levels, thereby offering protection from the respiratory inflammation associated with asthma.

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