The Effect of a TLR3 Agonist on Airway Allergic Inflammation and Viral Infection in Immunoproteasome-Deficient Mice.

Allergic asthma is characterized by increased type 2 inflammation, including eosinophils. Subjects with allergic asthma have recurrent symptoms due to their constant exposure to environmental allergens, such as house dust mite (HDM), which can be further exacerbated by respiratory infections like rhinovirus. The immunoproteasome (IP) is a proteolytic machinery that is induced by inflammatory mediators during virus infection, but the role of the IP in airway allergic inflammation during rhinovirus infection remains unknown.

Cooperation of immune regulators Tollip and surfactant protein A inhibits influenza A virus infection in mice.

Background: Influenza A virus (IAV) infection is a significant risk factor for respiratory diseases, but the host defense mechanisms against IAV remain to be defined. Immune regulators such as surfactant protein A (SP-A) and Toll-interacting protein (Tollip) have been shown to be involved in IAV infection, but whether SP-A and Tollip cooperate in more effective host defense against IAV infection has not been investigated.

Methods: Wild-type (WT), Tollip knockout (KO), SP-A KO, and Tollip/SP-A double KO (dKO) mice were infected with IAV for four days.

Tollip deficiency exaggerates airway type 2 inflammation in mice exposed to allergen and influenza A virus: role of the ATP/IL-33 signaling axis.

Toll-interacting protein (Tollip) is a negative regulator of the pro-inflammatory response to viruses, including influenza A virus (IAV). Genetic variation of Tollip has been associated with reduced airway epithelial Tollip expression and poor lung function in patients with asthma. Whether Tollip deficiency exaggerates type 2 inflammation (e.

Parkin Promotes Airway Inflammatory Response to Interferon Gamma.

Purpose: Increased type 2 interferon (i.e., IFN-γ) signaling has been shown to be involved in airway inflammation in a subset of asthma patients who often show high levels of airway neutrophilic inflammation and poor response to corticosteroid treatment.

Desert particulate matter from Afghanistan increases airway obstruction in human distal lungs exposed to type 2 cytokine IL-13.

Introduction: Deployment related asthma-like symptoms including distal airway obstruction have been described in U.S. military personnel who served in Iraq and Afghanistan.

Single cell RNA-sequencing of human precision-cut lung slices: A novel approach to study the effect of vaping and viral infection on lung health.

Vaping is an increasing health threat in the US and worldwide. The damaging impact of vaping on the human distal lung has been highlighted by the recent epidemic of electronic cigarette or vaping use-associated lung injury (EVALI). The pathogenesis of EVALI remains incompletely understood, due to a paucity of models that recapitulate the structural and functional complexity of the human distal lung and the still poorly defined culprit exposures to vaping products and respiratory viral infections.

High-fat diet and palmitic acid amplify airway type 2 inflammation.

Introduction: Metabolic dysfunction such as elevated levels of saturated fatty acids (SFA) may play a role in obese asthma, but its contribution to airway inflammation remains unclear. We sought to determine the role of high-fat diet (HFD) and palmitic acid (PA), a major form of SFA, in regulating type 2 inflammation.

Methods: Airway samples from asthma patients with or without obesity, mouse models and human airway epithelial cell culture were utilized to test if SFA amplify type 2 inflammation.

Parkin promotes airway inflammatory response to interferon gamma.

Background: Increased type 2 interferon (i.e., IFN-γ) signaling has been shown to be involved in airway inflammation in a subset of asthma patients who often show high levels of airway neutrophilic inflammation and poor response to corticosteroid treatment.

Electronic Cigarette Exposure Increases the Severity of Influenza a Virus Infection via TRAIL Dysregulation in Human Precision-Cut Lung Slices.

The use of electronic nicotine dispensing systems (ENDS), also known as electronic cigarettes (ECs), is common among adolescents and young adults with limited knowledge about the detrimental effects on lung health such as respiratory viral infections and underlying mechanisms. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a protein of the TNF family involved in cell apoptosis, is upregulated in COPD patients and during influenza A virus (IAV) infections, but its role in viral infection during EC exposures remains unclear. This study was aimed to investigate the effect of ECs on viral infection and TRAIL release in a human lung precision-cut lung slices (PCLS) model, and the role of TRAIL in regulating IAV infection.

Bacterial DNA amplifies neutrophilic inflammation in IL-17-exposed airways.

Background: Neutrophilic asthma (NA) is associated with increased airway interleukin (IL)-17 and abnormal bacterial community such as dominance of nontypeable (NTHi), particularly during asthma exacerbations. Bacteria release various products including DNA, but whether they cooperate with IL-17 in exaggerating neutrophilic inflammation is unclear. We sought to investigate the role of bacteria-derived DNA in airway neutrophilic inflammation related to IL-17-high asthma and underlying mechanisms ( Toll-like receptor 9 (TLR9)/IL-36γ signalling axis).

Role of Myeloid Cell-Specific TLR9 in Mitochondrial DNA-Induced Lung Inflammation in Mice.

Mitochondrial dysfunction is common in various pathological conditions including obesity. Release of mitochondrial DNA (mtDNA) during mitochondrial dysfunction has been shown to play a role in driving the pro-inflammatory response in leukocytes including macrophages. However, the mechanisms by which mtDNA induces leukocyte inflammatory responses in vivo are still unclear.

Airway epithelial immunoproteasome subunit LMP7 protects against rhinovirus infection.

Immunoproteasomes (IP) serve as an important modulator of immune responses to pathogens and other pathological factors. LMP7/β5i, one of the IP subunits, plays a critical role in autoimmune diseases by downregulating inflammation. Rhinovirus (RV) infection is a major risk factor in the exacerbations of respiratory inflammatory diseases, but whether LMP7 regulates RV-mediated inflammation in the lung particularly in the airway epithelium, the first line of defense against RV infection, remains unclear.

Human Bronchial Epithelial Cell Culture Models for Cigarette Smoke and Vaping Studies.

Despite the continuing public health efforts to stop or reduce smoking, cigarette smoke use remains popular in the youth and adult population. A recent surge in the use of electronic cigarette and vaping products has created another major health challenge in public health. There is an urgent need to use physiologically relevant models to study the health effect of smoking or vaping in human subjects.

Tollip Inhibits IL-33 Release and Inflammation in Influenza A Virus-Infected Mouse Airways.

Respiratory influenza A virus (IAV) infection continues to pose significant challenges in healthcare of human diseases including asthma. IAV infection in mice was shown to increase IL-33, a key cytokine in driving airway inflammation in asthma, but how IL-33 is regulated during viral infection remains unclear. We previously found that a genetic mutation in Toll-interacting protein (Tollip) was linked to less airway epithelial Tollip expression, increased neutrophil chemokines, and lower lung function in asthma patients.

Electronic cigarette vapor exposure exaggerates the pro-inflammatory response during influenza A viral infection in human distal airway epithelium.

Electronic cigarettes or vaping products have been marketed as a safer alternative to smoking, but very little is known about the health effects in the human lung, particularly in the distal airways, a key site of airway obstruction and destruction in chronic obstructive pulmonary disease that is often exacerbated by viral infections. The aim of this study was to investigate the effects of electronic cigarette vapor (e-vapor) on human distal airway epithelial responses to influenza A virus (IAV) infection. We isolated primary small airway epithelial cells (SAECs) from donor lungs free of lung disease, and cultured them at air-liquid interface (ALI).

Tollip interaction with STAT3: a novel mechanism to regulate human airway epithelial responses to type 2 cytokines.

Background: Toll-interacting protein (Tollip) is one of the key negative regulators in host innate immunity. Genetic variation of Tollip has been associated with less Tollip expression and poor lung function in asthmatic patients, but little is known about the role of Tollip in human airway type 2 inflammatory response, a prominent feature in allergic asthma.

Objective: Our goal was to determine the role and underlying mechanisms of Tollip in human airway epithelial responses such as eotaxin to type 2 cytokine IL-13.

Parkin, an E3 ubiquitin ligase, enhances airway mitochondrial DNA release and inflammation.

Introduction: Parkin (Park2), an E3 ubiquitin ligase, is critical to maintain mitochondrial function by regulating mitochondrial biogenesis and degradation (mitophagy), but recent evidence suggests the involvement of Parkin in promoting inflammation. In the present study, we determined if Parkin regulates airway mitochondrial DNA (mtDNA) release and inflammatory responses to type 2 cytokine interleukin (IL)-13 and allergens.

Methods: We measured Parkin mRNA expression in brushed bronchial epithelial cells and mtDNA release in the paired bronchoalveolar lavage fluid (BALF) from normal subjects and asthmatics.

Interleukin 1 Receptor-Like 1 (IL1RL1) Promotes Airway Bacterial and Viral Infection and Inflammation.

Interleukin 1 receptor-like 1 (IL1RL1), also known as suppression of tumorigenicity 2 (ST2), is the receptor for interleukin 33 (IL-33) and has been increasingly studied in type 2 inflammation. An increase in airway IL-33/ST2 signaling in asthma has been associated with eosinophilic inflammation, but little is known about the role of ST2 in neutrophilic inflammation. Airway and human rhinovirus (HRV) infections are linked to neutrophilic inflammation during acute exacerbations of asthma.