Dr. Silvio Antoniak is part of a multidisciplinary investigator team on a newly funded collaborative NIH-NIEHS R01 under the lead of PI James C. Bonner (NCSU) and investigators Dr. Christine K. Payne and Dr. Loretta G. Que both at Duke University.
Project Narrative: Multi-walled carbon nanotubes (MWCNTs) are engineered nanoparticles with numerous applications. Their expanding use represents an emerging risk for lung diseases, including asthma. MWCNTs by design have extremely high surface area and avidly bind biomolecules, including allergens, to form a protein corona that can modify the biological responses of innate and adaptive immune cells that interact with them. We have shown inhalation of MWCNTs exacerbate HDM-induced allergic airway disease in mice and discovered that proteolytic allergens in HDM extract form a corona on MWCNTs. While a variety of allergens are known to increase proteolytic activity when adsorbed onto nanoparticles, it is not known if proteolytic allergens in the corona mediate exacerbation of allergic airway disease or if functionalization of MWCNTs alters the corona.
The protease-activated receptor 2 (PAR2) is a cell surface G-protein-coupled receptor activated by serine proteases, including those in HDM extract. PAR2 activation leads to suppression of interferon (IFN)-induced STAT1 signaling. STAT transcription factors are important regulators of allergic lung disease. The Bonner lab reported that STAT1 knockout (KO) mice are susceptible to exacerbation of allergic airway disease by MWCNTs. STAT1 opposes the pro-fibrotic and allergic effects of STAT3 and STAT6, respectively. PAR2 KO mice have reduced HDM-induced airway disease. Therefore, we propose a mechanism of nanoparticle exacerbation of allergic airway disease mediated by the allergen corona that results in increased PAR2 activation in macrophages. Preliminary studies show that allergens from HDM form a corona around MWCNTs with increased proteolytic activity that is reduced by a PAR2 inhibitor (PAR2i). Moreover, we discovered that MWCNTs exacerbate HDM-induced airway disease in mice. Finally, PAR2 KO mice have enhanced STAT3 activation in lung compared to wild type (WT) mice.
This led us to hypothesize that MWCNTs exacerbate allergic airway disease by enhancing the proteolytic activity of allergens to increase PAR2 activation on macrophages leading to induction of STAT3 signaling and suppression of STAT1 signaling.
Preliminary studies were supported by a NC TraCS grant (550KR252003).