Acrolein and thiol-reactive electrophiles suppress allergen-induced innate airway epithelial responses by inhibition of DUOX1 and EGFR.
Acrolein is a major thiol-reactive component of cigarette smoke (CS) that is thought to contribute to increased asthma incidence associated with smoking. Here, we explored the effects of acute acrolein exposure on innate airway responses to two common airborne allergens, house dust mite and Alternaria alternata, and observed that acrolein exposure of C57BL/6 mice (5 ppm, 4 h) dramatically inhibited innate airway responses to subsequent allergen challenge, demonstrated by attenuated release of the epithelial-derived cytokines IL-33, IL-25, and IL-1α. Acrolein and other anti-inflammatory thiol-reactive electrophiles, cinnamaldehyde, curcumin, and sulforaphane, similarly inhibited allergen-induced production of these cytokines from human or murine airway epithelial cells in vitro. Based on our previous observations indicating the importance of Ca2+-dependent signaling, activation of the NADPH oxidase DUOX1, and Src/EGFR-dependent signaling in allergen-induced epithelial secretion of these cytokines, we explored the impact of acrolein on these pathways. Acrolein and other thiol-reactive electrophiles were found to dramatically prevent allergen-induced activation of DUOX1 as well as EGFR, and acrolein was capable of inhibiting EGFR tyrosine kinase activity via modification of C797. Biotin-labeling strategies indicated increased cysteine modification and carbonylation of Src, EGFR, as well as DUOX1, in response to acrolein exposure in vitro and in vivo, suggesting that direct alkylation of these proteins on accessible cysteine residues may be responsible for their inhibition. Collectively, our findings indicate a novel anti-inflammatory mechanism of CS-derived acrolein and other thiol-reactive electrophiles, by directly inhibiting DUOX1- and EGFR-mediated airway epithelial responses to airborne allergens.
Department of Pathology and Laboratory Medicine, College of Medicine, University of Vermont, Burlington, Vermont.
Karamatullah
K
Danyal
Department of Pathology and Laboratory Medicine, College of Medicine, University of Vermont, Burlington, Vermont.
Willem
W
de Jong
Department of Pathology and Laboratory Medicine, College of Medicine, University of Vermont, Burlington, Vermont.
Edmund
E
O'Brien
Department of Pathology and Laboratory Medicine, College of Medicine, University of Vermont, Burlington, Vermont.
Robert A
RA
Bauer
Department of Pathology and Laboratory Medicine, College of Medicine, University of Vermont, Burlington, Vermont.
David E
DE
Heppner
Department of Pathology and Laboratory Medicine, College of Medicine, University of Vermont, Burlington, Vermont.
Andrew C
AC
Little
Department of Pathology and Laboratory Medicine, College of Medicine, University of Vermont, Burlington, Vermont.
Milena
M
Hristova
Department of Pathology and Laboratory Medicine, College of Medicine, University of Vermont, Burlington, Vermont.
Aida
A
Habibovic
Department of Pathology and Laboratory Medicine, College of Medicine, University of Vermont, Burlington, Vermont albert.van-der-vliet@uvm.edu.
Albert
A
van der Vliet
D000171:Acrolein / Q000737:chemistry / Q000494:pharmacology*; D000280:Administration, Inhalation; D000485:Allergens / Q000009:adverse effects*; D000818:Animals; D001980:Bronchi / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism; D000074623:Dual Oxidases; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007113:Immunity, Innate / Q000187:drug effects; D000067596:Interleukin-33 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050050:Protein Carbonylation / Q000187:drug effects; D039981:Pyroglyphidae / Q000187:drug effects / Q000502:physiology; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000494:pharmacology*; D019061:src-Family Kinases / Q000378:metabolism
D000485:Allergens; D000067596:Interleukin-33; D013438:Sulfhydryl Compounds; D000171:Acrolein; D006861:Hydrogen Peroxide; D000074623:Dual Oxidases; D019255:NADPH Oxidases; C519130:Duox1 protein, mouse; D066246:ErbB Receptors; D019061:src-Family Kinases; D003545:Cysteine; D002118:Calcium
IL-33; airway epithelium; asthma; cigarette smoke; cysteine oxidation; dual oxidase 1