Airway epithelial TSLP production of TLR2 drives type 2 immunity in allergic airway inflammation

The receptor for advanced glycation end-products (RAGE) is a multiligand receptor that belongs to the immunoglobulin superfamily. RAGE is reported to be involved in various inflammatory disorders; however, studies that address the role of RAGE in allergic airway disease are inconclusive. RAGE-sufficient (RAGE+/+) and RAGE-deficient (RAGE−/−) mice were sensitized to ovalbumin, and airway responses were monitored after ovalbumin challenge. RAGE−/− mice showed reduced eosinophilic inflammation and goblet cell metaplasia, lower T helper type 2 (Th2) cytokine production from spleen and peribronchial lymph node mononuclear cells, and lower numbers of group 2 innate lymphoid cells in the lung compared with RAGE+/+ mice following sensitization and challenge. Experiments using irradiated, chimeric mice showed that the mice expressing RAGE on radio-resistant structural cells but not hematopoietic cells developed allergic airway inflammation; however, the mice expressing RAGE on hematopoietic cells but not structural cells showed reduced airway inflammation. In contrast, absence of RAGE expression on structural cells enhanced innate airway hyperresponsiveness (AHR). In the absence of RAGE, increased interleukin (IL)-33 levels in the lung were detected, and blockade of IL-33 receptor ST2 suppressed innate AHR in RAGE−/− mice. These data identify the importance of RAGE expressed on lung structural cells in the development of allergic airway inflammation, T helper type 2 cell activation, and group 2 innate lymphoid cell accumulation in the airways. RAGE on lung structural cells also regulated innate AHR, likely through the IL-33-ST2 pathway. Thus manipulating RAGE represents a novel therapeutic target in controlling allergic airway responses.

Download Full-text

Chitinase 3-like-1 protects airway function despite promoting type 2 inflammation during fungal-associated allergic airway inflammation

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00528.2020 ◽

2021 ◽

Author(s):

Joseph J. Mackel ◽

Jaleesa M. Garth ◽

MaryJane Jones ◽

Diandra A. Ellis ◽

Jonathan P. Blackburn ◽

...

Keyword(s):

Airway Inflammation ◽

Periodic Acid ◽

Acute Infection ◽

Allergic Bronchopulmonary Aspergillosis ◽

Allergic Airway Inflammation ◽

Lung Edema ◽

Periodic Acid Schiff ◽

Wide Range ◽

Type 2 Inflammation

Exposure to fungi can result in a wide range of comorbidities depending on the immune status of the host. Chronic exposure and reactivity to fungi such as Aspergillus fumigatus can result in conditions such as severe asthma with fungal sensitization (SAFS) or allergic bronchopulmonary aspergillosis (ABPA). However, the pathophysiology of SAFS and ABPA are not well understood. Here, we report that the chitinase-like protein YKL-40 is elevated in lung lavage fluid from human asthmatics that are sensitized to fungi. Initial studies demonstrated that mice deficient in the murine ortholog of YKL-40, breast regression protein-39 (BRP-39, chitinase-3-like 1, Chi3l1), were not more susceptible to acute infection with A. fumigatus. However, in an experimental model of fungal-associated allergic airway inflammation (fungal asthma), Chi3l1-/- mice had significantly increased airway hyperresponsiveness (AHR). Surprisingly, increased AHR in Chi3l1-/- mice occurred in the presence of significantly lower type 2 responses (decreased eosinophil numbers and decreased IL-4, IL-5, IL-33, CCL17 and CCL22 levels), although type 1 and type 17 responses were not different. Increased AHR was not associated with differences in Periodic-acid-Schiff staining of lung tissue, differences in the expression of Muc5ac and Clca3, nor differences in lung edema. Bone marrow chimera studies revealed that the presence of BRP-39 in either the hematopoietic or non-hematopoietic compartment was sufficient for controlling AHR during fungal asthma. Collectively, these results indicate that BRP-39 protects against AHR during fungal asthma despite contributing to type 2 inflammation, thus highlighting an unexpected protective role for BRP-39 in allergic fungal asthma.

Download Full-text

IFITM proteins drive type 2 T helper cell differentiation and exacerbate allergic airway inflammation

European Journal of Immunology ◽

10.1002/eji.201847692 ◽

2018 ◽

Vol 49 (1) ◽

pp. 66-78 ◽

Cited By ~ 11

Author(s):

Diana C. Yánez ◽

Hemant Sahni ◽

Susan Ross ◽

Anisha Solanki ◽

Ching-In Lau ◽

...

Keyword(s):

Cell Differentiation ◽

Airway Inflammation ◽

Allergic Airway Inflammation ◽

T Helper Cell ◽

Helper Cell ◽

T Helper

Download Full-text

Noncanonical role for Ku70/80 in the prevention of allergic airway inflammation via maintenance of airway epithelial cell organelle homeostasis

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00522.2019 ◽

2020 ◽

Vol 319 (4) ◽

pp. L728-L741

Author(s):

Rakhshinda Rehman ◽

Vijay Elakkya Vijayakumar ◽

Ashish Jaiswal ◽

Vaibhav Jain ◽

Shravani Mukherjee ◽

...

Keyword(s):

Epithelial Cell ◽

Epithelial Cells ◽

Er Stress ◽

Airway Inflammation ◽

Allergic Airway Inflammation ◽

Cell Organelle ◽

Continuous Exposure ◽

Airway Epithelial ◽

Bronchial Epithelial ◽

Ku Proteins

Airway epithelial homeostasis is under constant threat due to continuous exposure to the external environment, and abnormally robust sensitivity to external stimuli is critical to the development of airway diseases, including asthma. Ku is a key nonhomologous end-joining DNA repair protein with diverse cellular functions such as VDJ recombination and telomere length maintenance. Here, we show a novel function of Ku in alleviating features of allergic airway inflammation via the regulation of mitochondrial and endoplasmic reticulum (ER) stress. We first determined that airway epithelial cells derived from both asthmatic lungs and murine asthma models demonstrate increased expression of 8-hydroxy-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage. Ku protein expression was dramatically reduced in the bronchial epithelium of patients with asthma as well as in human bronchial epithelial cells exposed to oxidative stress. Knockdown of Ku70 or Ku80 in naïve mice elicited mitochondrial collapse or ER stress, leading to bronchial epithelial cell apoptosis and spontaneous development of asthma-like features, including airway hyperresponsiveness, airway inflammation, and subepithelial fibrosis. These findings demonstrate an essential noncanonical role for Ku proteins in asthma pathogenesis, likely via maintenance of organelle homeostasis. This novel function of Ku proteins may also be important in other disease processes associated with organelle stress.

Download Full-text

Targeting SIRP-α protects from type 2-driven allergic airway inflammation

European Journal of Immunology ◽

10.1002/eji.201040797 ◽

2010 ◽

Vol 40 (12) ◽

pp. 3510-3518 ◽

Cited By ~ 11

Author(s):

Marianne Raymond ◽

Vu Quang Van ◽

Manuel Rubio ◽

Karl Welzenbach ◽

Marika Sarfati

Keyword(s):

Airway Inflammation ◽

Allergic Airway Inflammation

Download Full-text

Allergen protease-induced Gsdmd p40 controls IL-33 secretion

10.21203/rs.3.rs-140435/v1 ◽

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.

Download Full-text