Irg1/itaconate metabolic pathway is a crucial determinant of dendritic cells immune-priming function and contributes to resolute allergen-induced airway inflammation
| Autor: | Jyoti Yadav, Maninder Sandey, Suman Mazumder, Amol Suryawanshi, Sangeet Makhija, Amit Kumar Mitra, Amarjit Mishra, Anil Kumar Jaiswal |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
Adoptive cell transfer
Immunology Priming (immunology) medicine.disease_cause Allergic sensitization Mice Th2 Cells Immune system Allergen Antigen medicine Animals Immunology and Allergy Hydro-Lyases Inflammation House dust mite biology Chemistry Pyroglyphidae Succinates Dendritic Cells Allergens Acquired immune system biology.organism_classification Metabolic Networks and Pathways |
| Zdroj: | Mucosal Immunology. 15:301-313 |
| ISSN: | 1933-0219 |
| DOI: | 10.1038/s41385-021-00462-y |
| Popis: | Itaconate is produced from the mitochondrial TCA cycle enzyme aconitase decarboxylase (encoded by immune responsive gene1; Irg1) that exerts immunomodulatory function in myeloid cells. However, the role of the Irg1/itaconate pathway in dendritic cells (DC)-mediated airway inflammation and adaptive immunity to inhaled allergens, which are the primary antigen-presenting cells in allergic asthma, remains largely unknown. House dust mite (HDM)-challenged Irg1-/- mice displayed increases in eosinophilic airway inflammation, mucous cell metaplasia, and Th2 cytokine production with a mechanism involving impaired mite antigen presentations by DC. Adoptive transfer of HDM-pulsed DC from Irg1-deficient mice into naive WT mice induced a similar phenotype of elevated type 2 airway inflammation and allergic sensitization. Untargeted metabolite analysis of HDM-pulsed DC revealed itaconate as one of the most abundant polar metabolites that potentially suppress mitochondrial oxidative damage. Furthermore, the immunomodulatory effect of itaconate was translated in vivo, where intranasal administration of 4-octyl itaconate 4-OI following antigen priming attenuated the manifestations of HDM-induced airway disease and Th2 immune response. Taken together, these data demonstrated for the first time a direct regulatory role of the Irg1/itaconate pathway in DC for the development of type 2 airway inflammation and suggest a possible therapeutic target in modulating allergic asthma. |
| Databáze: | OpenAIRE |
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