Allergen-induced DNA release by the airway epithelium amplifies type 2 immunity.
Alternaria
Asthma
allergic inflammation
caspase-3
furin
house dust mite
Journal
The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002
Informations de publication
Date de publication:
02 2023
02 2023
Historique:
received:
25
03
2022
revised:
10
08
2022
accepted:
15
09
2022
pubmed:
29
10
2022
medline:
8
2
2023
entrez:
28
10
2022
Statut:
ppublish
Résumé
Alternaria alternata and house dust mite exposure evokes IL-33 secretion from the airway epithelium, which functions as an alarmin to stimulate type 2 immunity. Extracellular DNA (eDNA) is also an alarmin that intensifies inflammation in cystic fibrosis, chronic obstructive pulmonary disease, and asthma. We investigated the mechanisms underlying allergen-evoked DNA mobilization and release from the airway epithelium and determined the role of eDNA in type 2 immunity. Human bronchial epithelial (hBE) cells were used to characterize allergen-induced DNA mobilization and extracellular release using comet assays to measure DNA fragmentation, Qubit double-stranded DNA assays to measure DNA release, and DNA sequencing to determine eDNA composition. Mice were used to investigate the role of eDNA in type 2 immunity. Alternaria extract rapidly induces mitochondrial and nuclear DNA release from human bronchial epithelial cells, whereas house dust mite extract induces mitochondrial DNA release. Caspase-3 is responsible for nuclear DNA fragmentation and becomes activated after cleavage by furin. Analysis of secreted nuclear DNA showed disproportionally higher amounts of promotor and exon sequences and lower intron and intergenic regions compared to predictions of random DNA fragmentation. In mice, Alternaria-induced type 2 immune responses were blocked by pretreatment with a DNA scavenger. In caspase-3-deficient mice, Alternaria-induced DNA release was suppressed. Furthermore, intranasal administration of mouse genomic DNA with Alternaria amplified secretion of IL-5 and IL-13 into bronchoalveolar lavage fluid while DNA alone had no effect. These findings highlight a novel, allergen-induced mechanism of rapid DNA release that amplifies type 2 immunity in airways.
Sections du résumé
BACKGROUND
Alternaria alternata and house dust mite exposure evokes IL-33 secretion from the airway epithelium, which functions as an alarmin to stimulate type 2 immunity. Extracellular DNA (eDNA) is also an alarmin that intensifies inflammation in cystic fibrosis, chronic obstructive pulmonary disease, and asthma.
OBJECTIVE
We investigated the mechanisms underlying allergen-evoked DNA mobilization and release from the airway epithelium and determined the role of eDNA in type 2 immunity.
METHODS
Human bronchial epithelial (hBE) cells were used to characterize allergen-induced DNA mobilization and extracellular release using comet assays to measure DNA fragmentation, Qubit double-stranded DNA assays to measure DNA release, and DNA sequencing to determine eDNA composition. Mice were used to investigate the role of eDNA in type 2 immunity.
RESULTS
Alternaria extract rapidly induces mitochondrial and nuclear DNA release from human bronchial epithelial cells, whereas house dust mite extract induces mitochondrial DNA release. Caspase-3 is responsible for nuclear DNA fragmentation and becomes activated after cleavage by furin. Analysis of secreted nuclear DNA showed disproportionally higher amounts of promotor and exon sequences and lower intron and intergenic regions compared to predictions of random DNA fragmentation. In mice, Alternaria-induced type 2 immune responses were blocked by pretreatment with a DNA scavenger. In caspase-3-deficient mice, Alternaria-induced DNA release was suppressed. Furthermore, intranasal administration of mouse genomic DNA with Alternaria amplified secretion of IL-5 and IL-13 into bronchoalveolar lavage fluid while DNA alone had no effect.
CONCLUSION
These findings highlight a novel, allergen-induced mechanism of rapid DNA release that amplifies type 2 immunity in airways.
Identifiants
pubmed: 36306937
pii: S0091-6749(22)01416-6
doi: 10.1016/j.jaci.2022.09.034
pmc: PMC10324884
mid: NIHMS1906420
pii:
doi:
Substances chimiques
Allergens
0
Caspase 3
EC 3.4.22.-
Alarmins
0
DNA
9007-49-2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
494-508.e6Subventions
Organisme : NCI NIH HHS
ID : P30 CA015083
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI128729
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI169530
Pays : United States
Informations de copyright
Copyright © 2022. Published by Elsevier Inc.
Références
Nature. 2010 Apr 29;464(7293):1367-70
pubmed: 20200518
Immunity. 2015 Jul 21;43(1):29-40
pubmed: 26200011
J Pathol. 2019 Apr;247(4):505-512
pubmed: 30506885
Nat Med. 2012 Sep;18(9):1386-93
pubmed: 22922410
Science. 2019 Mar 8;363(6431):
pubmed: 30846571
Nat Med. 2017 Jun;23(6):681-691
pubmed: 28459437
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Int J Mol Sci. 2021 Aug 23;22(16):
pubmed: 34445774
Curr Allergy Asthma Rep. 2016 Nov;16(11):78
pubmed: 27796793
Allergy. 2017 Oct;72(10):1521-1531
pubmed: 28273344
Nat Med. 2008 Sep;14(9):949-53
pubmed: 18690244
Protein Eng Des Sel. 2004 Jan;17(1):107-12
pubmed: 14985543
Allergy. 2013 Apr;68(4):409-16
pubmed: 23409745
J Allergy Clin Immunol. 2012 Jul;130(1):241-7.e9
pubmed: 22664167
Bioinformatics. 2017 Oct 01;33(19):3088-3090
pubmed: 28575171
Allergy. 2015 Sep;70(9):1184-8
pubmed: 26043360
Cell Rep. 2020 Oct 13;33(2):108254
pubmed: 33007239
Clin Rev Allergy Immunol. 2014 Dec;47(3):354-65
pubmed: 25205364
Nature. 2021 Mar;591(7849):293-299
pubmed: 33494095
J Immunol. 2013 Apr 15;190(8):4136-48
pubmed: 23509360
Physiology (Bethesda). 2020 Mar 1;35(2):112-124
pubmed: 32027562
J Immunol. 2010 Dec 15;185(12):7413-25
pubmed: 21098229
Proc Natl Acad Sci U S A. 2019 Apr 30;116(18):8985-8994
pubmed: 30988194
Nat Med. 2016 Feb;22(2):146-53
pubmed: 26779811
Bioinformatics. 2014 Aug 1;30(15):2114-20
pubmed: 24695404
Blood. 2013 Oct 17;122(16):2784-94
pubmed: 24009232
J Immunol Methods. 2015 Aug;423:104-10
pubmed: 26003624
Ann Am Thorac Soc. 2015 Nov;12 Suppl 2:S137-43
pubmed: 26595729
J Allergy Clin Immunol. 2018 Nov;142(5):1423-1436
pubmed: 30213625
Biol Rev Camb Philos Soc. 2019 Oct;94(5):1685-1700
pubmed: 31134732
J Allergy Clin Immunol. 2018 Aug;142(2):353-363
pubmed: 30080527
Onco Targets Ther. 2018 Aug 17;11:4945-4953
pubmed: 30154663
FEBS Lett. 2005 Apr 25;579(11):2364-8
pubmed: 15848173
Dev Cell. 2018 Mar 12;44(5):542-553
pubmed: 29533770
Eur J Immunol. 2019 Feb;49(2):221-227
pubmed: 30629284
Front Immunol. 2018 Jul 30;9:1507
pubmed: 30100902
J Immunol. 2009 Feb 15;182(4):2502-10
pubmed: 19201906
J Pharmacol Exp Ther. 2003 Jan;304(1):433-40
pubmed: 12490620
Scand J Immunol. 2016 Dec;84(6):317-322
pubmed: 27667737
J Physiol. 2020 May;598(10):1829-1845
pubmed: 32103508
Nat Med. 2011 Jul 17;17(8):996-1002
pubmed: 21765404
J Allergy Clin Immunol. 2022 Mar;149(3):1044-1059.e5
pubmed: 34428519
Mol Biol Rep. 2020 Aug;47(8):6239-6246
pubmed: 32803501
Oxid Med Cell Longev. 2019 Jul 14;2019:9372182
pubmed: 31396308
Phys Chem Chem Phys. 2016 Jan 28;18(4):2981-92
pubmed: 26740332
Cancer Res. 2004 Dec 15;64(24):9027-34
pubmed: 15604268
BMC Bioinformatics. 2010 May 11;11:237
pubmed: 20459804
J Biol Chem. 1998 Jul 10;273(28):17559-64
pubmed: 9651349
Nature. 2004 Apr 1;428(6982):522-8
pubmed: 15057823
Cell. 1997 Apr 18;89(2):175-84
pubmed: 9108473
Allergol Int. 2015 Oct;64(4):304-11
pubmed: 26433526
J Physiol. 2013 Sep 15;591(18):4595-609
pubmed: 23858006
Int Arch Allergy Immunol. 2012;158 Suppl 1:19-29
pubmed: 22627362
J Immunol. 2007 Apr 15;178(8):5237-44
pubmed: 17404307
Sci Signal. 2008 May 27;1(21):pe25
pubmed: 18506034
J Investig Allergol Clin Immunol. 2017;27(6):346-355
pubmed: 29199961
J Cell Biochem. 2005 Apr 15;94(6):1078-87
pubmed: 15723341
J Immunol. 2009 Jul 15;183(2):1427-34
pubmed: 19561109
Parasitology. 2020 Apr;147(4):401-409
pubmed: 31840621
J Cell Sci. 2014 May 15;127(Pt 10):2135-44
pubmed: 24833670
Sci Rep. 2016 Sep 16;6:33468
pubmed: 27633190
J Allergy Clin Immunol. 2016 Jul;138(1):84-96.e1
pubmed: 27157131
Eur J Immunol. 2013 Apr;43(4):907-17
pubmed: 23319328
Am J Respir Crit Care Med. 2019 May 1;199(9):1076-1085
pubmed: 30888839