Studies in both humans and rodents have suggested that CD8+ T cells contribute to the development of airway hyperresponsiveness (AHR) and that leukotriene B4 (LTB4) is involved in the chemotaxis of effector CD8+ T cells (TEFF) to the lung by virtue of their expression of BLT1, the receptor for LTB4. In the present study, we used a mast cell-CD8-dependent model of AHR to further define the role of BLT1 in CD8+ T cell-mediated AHR. C57BL/6+/+ and CD8-deficient (CD8−/−) mice were passively sensitized with anti-OVA IgE and exposed to OVA via the airways. Following passive sensitization and allergen exposure, C57BL/6+/+ mice developed altered airway function, whereas passively sensitized and allergen-exposed CD8−/− mice failed to do so. CD8−/− mice reconstituted with CD8+ TEFF developed AHR in response to challenge. In contrast, CD8−/− mice reconstituted with BLT1-deficient effector CD8+ T cells did not develop AHR. The induction of increased airway responsiveness following transfer of CD8+ TEFF or in wild-type mice could be blocked by administration of an LTB4 receptor antagonist confirming the role of BLT1 in CD8+ T cell-mediated AHR. Together, these data define the important role for mast cells and the LTB4-BLT1 pathway in the development of CD8+ T cell-mediated allergic responses in the lung.
The contribution of CD8 + T cells to the development of airway hyperresponsiveness and airway inflammation has received increased attention recently. CD8 + T cells, which are capable of secreting T H 2 cytokines, including IL-4, IL-5, and IL-13, have been described in asthmatic subjects and in animals sensitized and challenged with allergen. A subset of these IL-13–producing CD8 + T cells, effector memory CD8 + T cells in the mouse, express a high-affinity receptor for leukotriene B 4 (BLT1), an...
Last. Peter J. Sterk(LUMC: Leiden University Medical Center)H-Index: 31
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Rationale: Patients with asthma have an accelerated decline in lung function, which can lead to irreversible airway obstruction. It is generally assumed that this is related to specific aspects of airway inflammation and/or remodeling.Objective: We investigated the prognostic significance of bronchial eosinophil and CD8+ cell counts and subepithelial reticular layer thickness for the subsequent decline in lung function in patients with asthma after 7.5 years of follow-up.Methods: In a prospectiv...
Recent studies in both human and rodents have indicated that in addition to CD4+ T cells, CD8+ T cells play an important role in allergic inflammation. We previously demonstrated that allergen-sensitized and -challenged CD8-deficient (CD8−/−) mice develop significantly lower airway hyperresponsiveness (AHR), eosinophilic inflammation, and IL-13 levels in bronchoalveolar lavage fluid compared with wild-type mice, and that all these responses were restored by adoptive transfer of in vivo-primed CD...
Allergic asthma is a complex syndrome characterized by airway obstruction, airway inflammation and airway hyper-responsiveness (AHR). Using a mouse model of allergen-induced AHR, we previously demonstrated that CD8-deficient mice develop significantly lower AHR, eosinophilic inflammation and interleukin (IL)-13 levels in bronchoalveolar lavage fluid compared with wild-type mice. These responses were restored by adoptive transfer of antigen-primed CD8 + T cells 1 . Previously, two distinct popula...
In certain models of allergic airway disease, mast cells facilitate the development of inflammation and airway hyper-responsiveness (AHR). To define the role of the high affinity IgE receptor (FceRI) in the development of AHR, mice with a disruption of the α subunit of the high affinity IgE receptor (FceRI −/− ) were exposed on 10 consecutive days to nebulized OVA. Forty-eight hours after the last nebulization, airway responsiveness was monitored by the contractile response of tracheal smooth mu...
The role of Th2/CD4 T cells, which secrete IL-4, IL-5, and IL-13, in allergic disease is well established; however, the role of CD8+ T cells (allergen-induced airway hyperresponsiveness (AHR) and inflammation) is less clear. This study was conducted to define the role of Ag-primed CD8+ T cells in the development of these allergen-induced responses. CD8-deficient (CD8−/−) mice and wild-type mice were sensitized to OVA by i.p. injection and then challenged with OVA via the airways. Compared with w...
Leukotriene B4 (LTB4) was originally described as a potent lipid myeloid cell chemoattractant, rapidly generated from innate immune cells, that activates leukocytes through the G protein–coupled receptor BLT1. We report here that BLT1 is expressed on effector CD4+ T cells generated in vitro as well as in vivo when effector T cells migrate out of the lymphoid compartment and are recruited into peripheral tissues. BLT1 mediated LTB4-induced T helper type 1 (TH1) and TH2 cell chemotaxis and firm ad...
Last. Jae Hong Kim(KU: Korea University)H-Index: 52
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Leukotriene B4 (LTB4) is a lipid mediator of inflammation that is generated from arachidonic acid via the 5-lipoxygenase pathway. Previous studies have reported that the receptors of LTB4, BLT1, and BLT2 play mediatory roles in the allergic airway inflammation induced by ovalbumin (OVA). However, considering that house dust mites (HDMs) are the most prevalent allergen and well-known risk factor for asthmatic allergies, we are interested in elucidating the contributory roles of BLT1/2 in HDM-indu...
The World Health Organization has described the 2019 Coronavirus disease caused by an influenza-like virus called SARS-CoV-2 as a pandemic. Millions of people worldwide are already infected by this virus, and severe infection causes hyper inflammation, thus disrupting lung function, exacerbating breath difficulties, and death. Various inflammatory mediators bio-synthesized through the arachidonic acid pathway play roles in developing cytokine storms, injuring virus-infected cells. Since pro-infl...
SARS-CoV-2 causing coronavirus disease 2019 (COVID-19) has wreaked havoc during the global pandemic of 2020 infecting millions and leaving over a half million dead. As a new virus, not previously in the human population, but with similarities to other coronaviruses causing severe acute respiratory distress syndrome (SARS/ARDS), and no known treatments, the race to re-purpose existing drugs and to enlist novel therapeutics is underway. In the half-year since the first cases, we have acquired subs...
#1Menglu Yang(MEE: Massachusetts Eye and Ear Infirmary)H-Index: 1
#2Jeffrey A. Bair(MEE: Massachusetts Eye and Ear Infirmary)H-Index: 5
Last. Darlene A. Dartt(MEE: Massachusetts Eye and Ear Infirmary)H-Index: 56
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Leukotriene B4 (LTB4) is a major proinflammatory mediator important in host defense whereas resolvins (Rvs) are produced during the resolution phase of inflammation. We determined the actions of both RvE1 and RvD1 on LTB4-induced responses of goblet cells cultured from rat conjunctiva. The responses measured were an increase in the intracellular [Ca2+] ([Ca2+]i) and high molecular weight glycoprotein secretion. Treatment with RvE1 or RvD1 for 30 min significantly blocked the LTB4-induced [Ca2+]i...
Abstract Leukotriene B4 (LTB4) is a major type of lipid mediator that is rapidly generated from arachidonic acid through sequential action of 5-lipoxygenase (5-LO), 5-lipoxygenase-activating protein (FLAP) and LTA4 hydrolase (LTA4H) in response to various stimuli. LTB4 is well known to be a chemoattractant for leukocytes, particularly neutrophils, via interaction with its high-affinity receptor BLT1. Extensive attention has been paid to the role of the LTB4-BLT1 axis in acute and chronic inflamm...
The complexity of asthma is underscored by the number of cell types and mediators implicated in the pathogenesis of this heterogeneous syndrome. Type 2 CD4+ T-cells (Th2) and more recently, type 2 innate lymphoid cells dominate current descriptions of asthma pathogenesis. However, another important source of these type 2 cytokines, especially interleukin (IL)-5 and IL-13, are CD8+ T-cells, which are increasingly proposed to play an important role in asthma pathogenesis, because they are abundant...
It is anticipated that bioactive fragments of the extracellular matrix (matrikines) can influence the development and progression of chronic diseases. The enzyme leukotriene A 4 hydrolase (LTA 4 H) mediates opposing proinflammatory and anti-inflammatory activities, through the generation of leukotriene B 4 (LTB 4 ) and degradation of proneutrophilic matrikine Pro-Gly-Pro (PGP), respectively. We show that abrogation of LTB 4 signaling ameliorated inflammation and airway hyperresponsiveness (AHR) ...
The presence of mast cells in some human colorectal cancers is a positive prognostic factor, but the basis for this association is incompletely understood. Here, we found that mice with a heterozygous mutation in the adenomatous polyposis coli gene (Apc Min/+ ) displayed reduced intestinal tumor burdens and increased survival in a chemokine decoy receptor, ACKR2-null background, which led to discovery of a critical role for mast cells in tumor defense. ACKR2 −/− Apc Min/+ tumors showed increased...
