Cockroach protease allergen induces allergic airway inflammation via epithelial cell activation

Abstract

Protease allergens are known to enhance allergic inflammation but their exact role in initiation of allergic reactions at mucosal surfaces still remains elusive. This study was aimed at deciphering the role of serine protease activity of Per a 10, a major cockroach allergen in initiation of allergic inflammation at mucosal surfaces. We demonstrate that Per a 10 increases epithelial permeability by disruption of tight junction proteins, ZO-1 and occludin, and enhances the migration of Monocyte derived dendritic cell precursors towards epithelial layer as exhibited by trans-well studies. Per a 10 exposure also leads to secretion of IL-33, TSLP and intracellular Ca2+ dependent increase in ATP levels. Further, in vivo experiments revealed that Per a 10 administration in mice elevated allergic inflammatory parameters along with high levels of IL-33, TSLP, IL-1α and uric acid in the mice lungs. We next demonstrated that Per a 10 cleaves CD23 (low affinity IgE receptor) from the surface of PBMCs and purified B cells and CD25 (IL-2 receptor) from the surface of PBMCs and purified T cells in an activity dependent manner, which might favour Th2 responses. In conclusion, protease activity of Per a 10 plays a significant role in initiation of allergic airway inflammation at the mucosal surfaces.

Characterization of a novel, papain‐inducible murine model of eosinophilic rhinosinusitis

“…We hypothesized that the observed induction of type 2 inflammation was due to protease‐induced damage to the sinonasal epithelium. Proteolytic damage to the sinonasal epithelium is known to induce the release of the alarmin IL‐33 . IL‐33 potently activates a variety of cell types involved in initiating and propagating type 2 responses, such as ILC2s, mast cells, basophils, and Th2 cells .…”

“…In addition, papain has limited relevance to ECRS in humans. Many common human allergens, however, demonstrate intrinsic protease activity, which is essential to their immunogenicity . Therefore, this model provides a valuable, physiologically relevant experimental system to study eosinophilic rhinosinusitis pathophysiology.…”

Spectrum of Allergens and Allergen Biology in India

“…The protease activity of natural Per a 10 was also important to initiate the allergic reaction at the mucosal surface. It increased the permeability of lung epithelium by the disintegration of cell junction proteins to enhance the migration of monocyte- derived dendritic cell precursors [119]. The functional property of native Per a 10 was also responsible for dislodging the CD23 and CD25 from the surface of PBMC, purified B cells and purified T cells.…”

“…Although cyclophilin has been reported to be IgE reactive, this is not likely to represent an important allergen as the pollen grains of periwinkle are not essentially airborne. The cockroach allergen Per a 10 was also expressed as a recombinant allergen [119, 124]. The rPer a 10 was IgE-reactive; however, it was observed that the protease activity in rPer a 10 was somehow attenuated, which resulted in reduced allergenic properties.…”

“…It was shown that the protease activity of Per a 10 was crucial for activation of alveolar epithelium (A549 cell line) via PAR-2 receptor cleavage to expose the ligand peptide ‘SLIGKV’ that ultimately led to the mobilization of the intracellular calcium level and production of proinflammatory cytokines like IL-6, IL-8, and GM-CSF [118]. This proteolytic activity modulated the dendritic cells towards the Th2 phenotype by upregulation of CD86 and IL6, but downregulated IL12 secretion [119]. The protease activity of natural Per a 10 was also important to initiate the allergic reaction at the mucosal surface.…”