Proteolytic Cleavage by House Dust Mite Impairs SPLUNC1's Ability to Modulate TH2 Inflammation in the Airway

Abstract

Lung epithelial cells are often on of the first lines of defense against inhaled allergens. They also work in concert with other airway cell types to orchestrate innate immune responses, keeping inflammation under control. In allergic asthma, allergens (e.g., HDM) disrupts the normal barrier function of epithelia, as well as its interaction with other airway cells via various mechanisms. Proteolytic enzyme activity of allergen components is thought to be one of top contributors of allergic inflammation in the lung. A large body of evidence supports that the biologic activity of HDM proteases augment allergic activity by 1) directly promoting IgE synthesis; 2) damaging the lung epithelium, increasing bronchial permeability; 3) degrading epithelial tight junctions and increasing accessibility to dendritic antigen presenting cells that lie beneath the epithelium; and 4) causing the release of pro‐inflammatory cytokines from epithelial cells, mast cells and basophils.Short palate, lung and nasal epithelial clone 1 (SPLUNC1) is a 256‐amino acid, secretive protein in polarized epithelia and is present at high levels in normal airway surface liquid (ASL). SPLUNC1 is a multi‐functional protein, which regulates ion channel activity, has anti‐microbial activity and affects surface tension. We observed that 1) SPLUNC1 is reduced in asthmatic patients' sputum as well as HDM challenged human bronchial epithelial cells (HBECs). 2)SPLUNC1 was degraded by HDM in both time‐ and dose‐ dependent manners. 3) SPLUNC1 knockout (KO) mice showed more severe inflammatory phenotypes in their airways when challenged with HDM, compared to their wildtype (WT) littermate controls.Overall, we conclude that SPLUNC1 is an epithelial‐derived factor that plays a major role in dampening TH2 inflammation in airways, which is deranged in asthma patients. SPLUNC1 deficiency is partially due to its proteolytical cleavage by HDM. Identifying strategies to increase SPLUNC1 resistance to HDM proteolytic activities or SPLUNC1 in ASL may lead to novel therapies to treat allergic asthma.Support or Funding InformationAmerican Asthma Foundation NCCU‐DUKE CTSIThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.