Protease-activated receptor-2: Role in asthma pathogenesis and utility as a biomarker of disease severity

Abstract

PAR₂, a receptor activated by serine proteases, has primarily pro-inflammatory roles in the airways and may play a role in asthma pathogenesis. PAR₂ exerts its effects in the lungs through activation of a variety of airway cells, but also activation of circulating immune cells. There is evidence that PAR₂ expression increases in asthma and other inflammatory diseases, although the regulation of PAR₂ expression is not fully understood. Here we review the available literature on the potential role of PAR₂ in asthma pathogenesis and propose a model of PAR₂-mediated development of allergic sensitization. We also propose, based on our previous work, that PAR₂ expression on peripheral blood monocyte subsets has the potential to serve as a biomarker of asthma severity and/or control.

Keywords: PAR-2; allergic disease; asthma; biomarker; severity.

FIGURE 1

PAR-2 activated airway epithelial cells release a variety of inflammatory mediators that may induce airway inflammation, airway hyperresponsiveness and airway remodeling. The numbers in brackets after the name of specific inflammatory mediators indicate the reference of the main text where that mediator is discussed. AHR, airway hyperresponsiveness; CCL2, CC motif chemokine ligand 2; DC, dendritic cell; GM-CSF, granulocyte-macrophage colony-stimulating factor; ILC2, type 2 innate lymphoid cells; IL-25, interleukin 25; IL-8, interleukin 8; LTC4, leukotriene C4; MMP-9, matrix metalloproteinase 9; TSLP, thymic stromal lymphopoietin.

FIGURE 2

Model of PAR-2-mediated allergic sensitization. Allergic sensitization requires the recognition of an antigen by DC and also PAR-2 activation by an allergen with serine protease activity, or by an independent serine protease. Other stimuli may facilitate this process. AM, alveolar macrophages; DC, dendritic cells; GM-CSF, granulocyte macrophage colony stimulating factor; LPS, lipopolysaccharide; TNF, tumor necrosis factor; TSLP, thymic stromal lymphopoietin.