Research ArticleALLERGY

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

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Science Immunology  23 Feb 2018:
Vol. 3, Issue 20, eaam9841
DOI: 10.1126/sciimmunol.aam9841

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Dectin-1 limits allergic responses

Aberrant activation of pattern recognition receptors (PRRs) drives inflammation in autoimmune and allergic diseases. Here, Gour et al. have identified invertebrate tropomyosin from house dust mite and shrimp as a ligand for dectin-1. Dectin-1 is a PRR that has been demonstrated to recognize fungal β-glucans to antifungal immune responses. Here, the authors report that engagement of dectin-1 by invertebrate tropomyosins limits type 2 inflammation and that dectin-1–deficient mice are more prone to allergic airway inflammation. They have also established that expression of dectin-1 is repressed in allergic individuals. By identifying invertebrate tropomyosin orthologs as dectin-1 ligands, the study establishes the importance of dectin-1 in limiting allergic responses.

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.

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