Dysregulated invertebrate tropomyosin–dectin-1 interaction confers susceptibility to allergic diseases

Naina Gour, Stephane Lajoie, Ursula Smole, Marquitta White, Donglei Hu, Pagé Goddard, Scott Huntsman, Celeste Eng, Angel Mak, Sam Oh, Jung Hyun Kim, Annu Sharma, Sophie Plante, Ikhlass Haj Salem, Yvonne Resch, Xiao Xiao, Nu Yao, Anju Singh, Susanne Vrtala, Jamila ChakirEsteban G. Burchard, Andrew P. Lane, Marsha Wills-Karp

Research output: Contribution to journalArticlepeer-review

Abstract

The key factors underlying the development of allergic diseases—the propensity for a minority of individuals to develop dysfunctional responses to harmless environmental molecules—remain undefined. We report a pathway of immune counter-regulation that suppresses the development of aeroallergy and shrimp-induced anaphylaxis. In mice, signaling through epithelially expressed dectin-1 suppresses the development of type 2 immune responses through inhibition of interleukin-33 (IL-33) secretion and the subsequent recruitment of IL-13–producing innate lymphoid cells. Although this homeostatic pathway is functional in respiratory epithelial cells from healthy humans, it is dramatically impaired in epithelial cells from asthmatic and chronic rhinosinusitis patients, resulting in elevated IL-33 production. Moreover, we identify an association between a single-nucleotide polymorphism (SNP) in the dectin-1 gene loci and reduced pulmonary function in two cohorts of asthmatics. This intronic SNP is a predicted eQTL (expression quantitative trait locus) that is associated with reduced dectin-1 expression in human tissue. We identify invertebrate tropomyosin, a ubiquitous arthropod-derived molecule, as an immunobiologically relevant dectin-1 ligand that normally serves to restrain IL-33 release and dampen type 2 immunity in healthy individuals. However, invertebrate tropomyosin presented in the context of impaired dectin-1 function, as observed in allergic individuals, leads to unrestrained IL-33 secretion and skewing of immune responses toward type 2 immunity. Collectively, we uncover a previously unrecognized mechanism of protection against allergy to a conserved recognition element omnipresent in our environment.

Original languageEnglish (US)
Article numbereaam9841
JournalScience Immunology
Volume3
Issue number20
DOIs
StatePublished - 2018

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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