scholarly journals The chemokine CX3CL1/fractalkine regulates immunopathogenesis during fungal-associated allergic airway inflammation

2020 ◽  
Author(s):  
Matthew S. Godwin ◽  
MaryJane Jones ◽  
Jonathan P. Blackburn ◽  
Zhihong Yu ◽  
Sadis Matalon ◽  
...  
Keyword(s):  
Lung Function ◽  
Airway Inflammation ◽  
Severe Asthma ◽  
Inflammatory Responses ◽  
Allergic Airway Inflammation ◽  
Lavage Fluid ◽  
Asthma Severity ◽  
Survival Factors ◽  
Inflammatory Monocytes ◽  
Elevated Type

Individuals that present with difficult-to-control asthma and sensitivity to one or more fungal species are categorized as a subset of severe asthma patients belonging to a group herein referred to as severe asthma with fungal sensitization (SAFS). We have previously reported the identification of numerous cytokines and chemokines that were elevated in human asthmatics that were sensitized to fungi vs. non-fungal sensitized asthmatics. Here, we show that the unique chemokine CX3CL1 (fractalkine) is elevated in both bronchoalveolar lavage fluid and sputum from human asthmatics sensitized to fungi, implicating an association with CX3CL1 in fungal asthma severity. In an experimental model of fungal-associated allergic airway inflammation, we demonstrate that the absence of CX3CR1 signaling unexpectedly resulted in a profound impairment in lung function. Histological assessment of lung tissue revealed an unrestricted inflammatory response that was subsequently characterized by enhanced levels of neutrophils, eosinophils and inflammatory monocytes. Neutrophilic inflammation correlated with elevated IL-17A, proinflammatory cytokines (TNF-α, IL-1α IL-1β), neutrophil survival factors (G-CSF) and neutrophil-targeting chemokines (CCL3, CCL4). Eosinophilia correlated with elevated type 2 responses (IL-5, IL-13) whereas inflammatory monocyte levels correlated with elevated type 1 responses (IFN-γ, CXCL9) and survival factors (M-CSF). Despite enhanced inflammatory responses, the immunoregulatory cytokine IL-10 and the natural inhibitor of IL-1 signaling, IL-1RA, were significantly elevated rather than impaired. Regulatory T cell levels were unchanged, as were levels of the anti-inflammatory cytokines IL-35 and IL-38. Taken together, the CX3CL1/CX3CR1 axis preserves lung function during fungal-associated allergic airway inflammation through a non-classical immunoregulatory mechanism.

scholarly journals FSTL1 aggravates cigarette smoke-induced airway inflammation and airway remodeling by regulating autophagy

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ying Liu ◽  
Jiawei Xu ◽  
Tian Liu ◽  
Jinxiang Wu ◽  
Jiping Zhao ◽  
...  
Keyword(s):  
Lung Function ◽  
Airway Inflammation ◽  
Cigarette Smoke ◽  
Airway Remodeling ◽  
Critical Factor ◽  
Lavage Fluid ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients ◽  
Impaired Lung Function

Abstract Background Cigarette smoke (CS) is a major risk factor for Chronic Obstructive Pulmonary Disease (COPD). Follistatin-like protein 1 (FSTL1), a critical factor during embryogenesis particularly in respiratory lung development, is a novel mediator related to inflammation and tissue remodeling. We tried to investigate the role of FSTL1 in CS-induced autophagy dysregulation, airway inflammation and remodeling. Methods Serum and lung specimens were obtained from COPD patients and controls. Adult female wild-type (WT) mice, FSTL1± mice and FSTL1flox/+ mice were exposed to room air or chronic CS. Additionally, 3-methyladenine (3-MA), an inhibitor of autophagy, was applied in CS-exposed WT mice. The lung tissues and serum from patients and murine models were tested for FSTL1 and autophagy-associated protein expression by ELISA, western blotting and immunohistochemical. Autophagosome were observed using electron microscope technology. LTB4, IL-8 and TNF-α in bronchoalveolar lavage fluid of mice were examined using ELISA. Airway remodeling and lung function were also assessed. Results Both FSTL1 and autophagy biomarkers increased in COPD patients and CS-exposed WT mice. Autophagy activation was upregulated in CS-exposed mice accompanied by airway remodeling and airway inflammation. FSTL1± mice showed a lower level of CS-induced autophagy compared with the control mice. FSTL1± mice can also resist CS-induced inflammatory response, airway remodeling and impaired lung function. CS-exposed WT mice with 3-MA pretreatment have a similar manifestation with CS-exposed FSTL1± mice. Conclusions FSTL1 promotes CS-induced COPD by modulating autophagy, therefore targeting FSTL1 and autophagy may shed light on treating cigarette smoke-induced COPD.

scholarly journals 2215

2017 ◽  
Vol 1 (S1) ◽  
pp. 3-3
Author(s):  
Timothy P. Moran ◽  
Robert M. Immormino ◽  
Hideki Nakano ◽  
David Peden ◽  
Donald N. Cook
Keyword(s):  
Flow Cytometry ◽  
Airway Inflammation ◽  
Allergic Asthma ◽  
Immune Cells ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Allergic Airway Inflammation ◽  
Surface Protein ◽  
Fold Increase ◽  
Deficient Mice

OBJECTIVES/SPECIFIC AIMS: Allergic asthma is a chronic lung disease driven by inappropriate inflammatory responses against inhaled allergens. Neuropilin-2 (NRP2) is a pleiotropic transmembrane receptor expressed in the lung, but its role in allergic airway inflammation is unknown. Here, we characterized NRP2 expression in lung immune cells and investigated the effects of NRP2 deficiency on airway inflammation. METHODS/STUDY POPULATION: NRP2 expression by lung immune cells from NRP2 reporter mice was determined by flow cytometry. NRP2 expression by human alveolar macrophages (AM) from healthy individuals was determined by mRNA analysis and flow cytometry. Airway inflammation in NRP2-deficient mice was assessed by bronchoalveolar lavage (BAL) cytology and inflammatory gene expression in lung tissue. RESULTS/ANTICIPATED RESULTS: NRP2 expression in lung immune cells was negligible under steady-state conditions. In contrast, inhalational exposure to lipopolysaccharide (LPS) adjuvant dramatically induced NRP2 expression in AM, as 63.3% of AM from LPS-treated mice were NRP2+ compared with 1.5% of AM from control mice. Ex vivo treatment of human AM with LPS resulted in a 1.5-fold and 2.6-fold increase in NRP2 mRNA and surface protein expression, respectively. Compared to littermate controls, NRP2-deficient mice had greater numbers of BAL leukocytes and increased lung expression of the T helper type 2 cytokines IL-4 and IL-5. Furthermore, NRP2 deficiency resulted in stochastic development of allergic airway inflammation, as spontaneous airway eosinophilia was detected in 25% (2/8) of NRP2-deficient mice compared with 0% (0/8) of littermate controls. DISCUSSION/SIGNIFICANCE OF IMPACT: NRP2 is expressed by activated human and murine AM and suppresses the spontaneous development of allergic airway inflammation. These findings suggest that NRP2 may play a key role in allergic asthma pathogenesis, and could prove to be an important therapeutic target in patients with asthma and other allergic diseases.

scholarly journals Diabetes Downregulates Allergen-Induced Airway Inflammation in Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Vinicius F. Carvalho ◽  
Emiliano O. Barreto ◽  
Ana Carolina S. Arantes ◽  
Magda F. Serra ◽  
Tatiana Paula T. Ferreira ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Bronchoalveolar Lavage Fluid ◽  
Allergic Airway Inflammation ◽  
Allergic Diseases ◽  
Lavage Fluid ◽  
Airway Hyperreactivity ◽  
Eosinophil Infiltration ◽  
Mucus Production ◽  
Diabetes Induction

Previous studies described that allergic diseases, including asthma, occur less often than expected in patients with type 1 diabetes. Here, we investigated the influence of diabetes on allergic airway inflammation in a model of experimental asthma in mice. Diabetes was induced by intravenous injection of alloxan into 12 h-fasted A/J mice, followed by subcutaneous sensitization with ovalbumin (OVA) and aluminum hydroxide (Al(OH)3), on days 5 and 19 after diabetes induction. Animals were intranasally challenged with OVA (25 μg), from day 24 to day 26. Alloxan-induced diabetes significantly attenuated airway inflammation as attested by the lower number of total leukocytes in the bronchoalveolar lavage fluid, mainly neutrophils and eosinophils. Suppression of eosinophil infiltration in the peribronchiolar space and generation of eosinophilotactic mediators, such as CCL-11/eotaxin, CCL-3/MIP-1α, and IL-5, were noted in the lungs of diabetic sensitized mice. In parallel, reduction of airway hyperreactivity (AHR) to methacholine, mucus production, and serum IgE levels was also noted under diabetic conditions. Our findings show that alloxan diabetes caused attenuation of lung allergic inflammatory response in A/J mice, by a mechanism possibly associated with downregulation of IgE antibody production.

scholarly journals Changes in Pulmonary Function and Parasite Burden in Rats Infected with Strongyloides venezuelensis Concomitant with Induction of Allergic Airway Inflammation

2003 ◽  
Vol 71 (5) ◽  
pp. 2607-2614 ◽  
Author(s):  
Deborah Negrão-Corrêa ◽  
Micheline R. Silveira ◽  
Cynthia M. Borges ◽  
Danielle G. Souza ◽  
Mauro M. Teixeira
Keyword(s):  
Airway Inflammation ◽  
Mutual Influence ◽  
Pulmonary Inflammation ◽  
Allergic Airway Inflammation ◽  
Parasite Burden ◽  
Allergic Diseases ◽  
Lavage Fluid ◽  
Eosinophil Infiltration ◽  
Asthmatic Patients ◽  
Strongyloides Venezuelensis

ABSTRACT The prevalence of allergic diseases such as asthma has increased markedly over the past few decades. To evaluate the possible mutual influence of helminth infection and allergy, the combined effects of experimental allergic airway inflammation and infection with Strongyloides venezuelensis on various parasitological and inflammatory indices were evaluated in the rat. A challenge of immunized rats with aerosolized ovalbumin (OVA) resulted in eosinophilic inflammation that peaked 48 h after the challenge and was accompanied by airway hyperresponsiveness (AHR) to an intravenous acetylcholine challenge. S. venezuelensis infection concomitant with an OVA challenge of immunized rats resulted in prolonged pulmonary inflammation with increased eosinophil infiltration in bronchoalveolar lavage fluid but not in the lung tissue. These rats also showed a significant parasite burden reduction, especially during parasite migration through the lungs. However, the fecundity rates of worms that reached the intestine were similar in allergic and nonallergic animals. Despite airway inflammation, the increased responsiveness of the airways in the experimental asthma model was suppressed during parasite migration through the lungs (2 days). In contrast, parasite-induced AHR was unchanged 5 days after infection in immunized and challenged rats. In conclusion, infection with S. venezuelensis interfered with the onset of AHR following an antigen challenge of immunized rats. The ability of parasites to switch off functional airway responses is therapeutically relevant because we may learn from parasites how to modulate lung function and, hence, the AHR characteristic of asthmatic patients.

Induction of ferroptosis-like cell death of eosinophils exerts synergistic effects with glucocorticoids in allergic airway inflammation

Thorax ◽  
2020 ◽  
Vol 75 (11) ◽  
pp. 918-927 ◽  
Author(s):  
Yanping Wu ◽  
Haixia Chen ◽  
Nanxia Xuan ◽  
Lingren Zhou ◽  
Yinfang Wu ◽  
...  
Keyword(s):  
Cell Death ◽  
Synergistic Effect ◽  
Airway Inflammation ◽  
Synergistic Effects ◽  
Morphological Characteristics ◽  
Allergic Airway Inflammation ◽  
Lavage Fluid ◽  
Allergic Disorders

IntroductionEosinophils are critical in allergic disorders, and promoting eosinophil death effectively attenuates allergic airway inflammation. Ferroptosis is a recently described novel form of cell death; however, little is known about ferroptosis in eosinophils and related diseases. This study aimed to investigate the effects of ferroptosis-inducing agents (FINs) on eosinophil death and allergic airway inflammation, and to explore their potential synergistic effect with glucocorticoids (GCs).MethodsEosinophils isolated from the peripheral blood of humans or mice were incubated with FINs, and eosinophil ferroptosis was assessed. The in vivo effects of FINs alone or in combination with dexamethasone (DXMS) were examined in a mouse model of allergic airway inflammation. Bronchoalveolar lavage fluid and lung tissue were collected to examine airway inflammation.ResultsTreatment with FINs time and dose dependency induced cell death in human and mouse eosinophils. Interestingly, FINs induced non-canonical ferroptosis in eosinophils, which generated morphological characteristics unique to ferroptosis and was iron dependent but was independent of lipid peroxidation. The antioxidants glutathione and N-acetylcysteine significantly attenuated FIN-induced cell death. Treatment with FINs triggered eosinophil death in vivo and eventually relieved eosinophilic airway inflammation in mice. Furthermore, FINs exerted a synergistic effect with DXMS to induce eosinophil death in vitro and to alleviate allergic airway inflammation in vivo.ConclusionsFINs induced ferroptosis-like cell death of eosinophils, suggesting their use as a promising therapeutic strategy for eosinophilic airway inflammation, especially due to the advantage of their synergy with GCs in the treatment of allergic disorders.

scholarly journals MTOR-Mediated Autophagy Is Involved in the Protective Effect of Ketamine on Allergic Airway Inflammation

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Hongyun Zou ◽  
Li-Xia Wang ◽  
Muzi Wang ◽  
Cheng Cheng ◽  
Shuai Li ◽  
...  
Keyword(s):  
Bronchoalveolar Lavage ◽  
Protective Effect ◽  
Airway Inflammation ◽  
Bronchoalveolar Lavage Fluid ◽  
Mammalian Target Of Rapamycin ◽  
Allergic Airway Inflammation ◽  
Lavage Fluid ◽  
Morphological Findings ◽  
Airway Diseases ◽  
Inflammatory Mechanism

Unresolved inflammation underpins the pathogenesis of allergic airway diseases, such as asthma. Ketamine, accepted as a promising therapy for resistant asthma, has been demonstrated to attenuate allergic airway inflammation. However, the anti-inflammatory mechanism by ketamine in this setting is largely unknown. We aimed to investigate whether autophagy was involved in the protective effect of ketamine on allergic airway inflammation. Female C57BL/6 mice were sensitized to ovalbumin (OVA) and treated with ketamine at 25, 50, or 100 mg/kg prior to OVA challenge. In this model, the pulmonary morphological findings and airway inflammation were significantly inhibited at 50 mg/kg but not at 25 or 100 mg/kg. Moreover, 50 mg/kg ketamine abrogated the increased concentrations of inflammatory cytokines in bronchoalveolar lavage fluid (BALF) of allergic mice, as well as activated the expression of phosphorylated mammalian target of rapamycin (p-MTOR) and inhibited autophagy in allergic mice. To confirm whether the effect of 50 mg/kg ketamine on asthma was mediated by inhibiting autophagy, rapamycin was administered to mice sensitized to OVA and exposed to 50 mg/kg ketamine. All of the effect of 50 mg/kg ketamine was reversed by rapamycin treatment, including increased p-MTOR and decreased autophagy. Taken together, the present study demonstrates that 50 mg/kg ketamine inhibits allergic airway inflammation by suppressed autophagy, and this effect is mediated by the activation of MTOR in the lungs of allergic mice.

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.

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