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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

The IDO-Ahr axis controls Th17/Treg Immunity in a Pulmonary Model of Fungal Infection

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Author(s):
de Araujo, Eliseu Frank ; Feriotti, Claudia ; de Lima Galdino, Nayane Alves ; Preite, Nycolas Willian ; Garcia Calich, Vera Lucia ; Loures, Flavio Vieira
Total Authors: 6
Document type: Journal article
Source: FRONTIERS IN IMMUNOLOGY; v. 8, JUL 24 2017.
Web of Science Citations: 14
Abstract

In infectious diseases, the enzyme indoleamine 2,3 dioxygenase-1 (IDO1) that catalyzes the tryptophan (Trp) degradation along the kynurenines (Kyn) pathway has two main functions, the control of pathogen growth by reducing available Trp and immune regulation mediated by the Kyn-mediated expansion of regulatory T (Treg) cells via aryl hydrocarbon receptor (AhR). In pulmonary paracoccidioidomycosis (PCM) caused by the dimorphic fungus Paracoccidioides brasiliensis, IDO1 was shown to control the disease severity of both resistant and susceptible mice to the infection; however, only in resistant mice, IDO1 is induced by TGF-beta signaling that confers a stable tolerogenic phenotype to dendritic cells (DCs). In addition, in pulmonary PCM, the tolerogenic function of plasmacytoid dendritic cells was linked to the IDO1 activity. To further evaluate the function of IDO1 in pulmonary PCM, IDO1-deficient (IDO1(-/-)) C57BL/6 mice were intratracheally infected with P. brasiliensis yeasts and the infection analyzed at three postinfection periods regarding several parameters of disease severity and immune response. The fungal loads and tissue pathology of IDO1(-/-) mice were higher than their wild-type controls resulting in increased mortality rates. The evaluation of innate lymphoid cells showed an upregulated differentiation of the innate lymphoid cell 3 phenotype accompanied by a decreased expansion of ILC1 and NK cells in the lungs of infected IDO1(-/-) mice. DCs from these mice expressed elevated levels of costimulatory molecules and cytokine IL-6 associated with reduced production of IL-12, TNF-alpha, IL-1 beta, TGF-beta, and IL-10. This response was concomitant with a marked reduction in AhR production. The absence of IDO1 expression caused an increased influx of activated Th17 cells to the lungs with a simultaneous reduction in Th1 and Treg cells. Accordingly, the suppressive cytokines IL-10, TGF-beta, IL-27, and IL-35 appeared in reduced levels in the lungs of IDO1(-/-) mice. In conclusion, the immunological balance mediated by the axis IDO/AhR is fundamental to determine the balance between Th17/Treg cells and control the severity of pulmonary PCM. (AU)

FAPESP's process: 11/51258-2 - Influence of the enzyme indoleamine-2,3-dioxygenase (IDO) in the differentiation and function of dendritic cells and regulatory T cells in the pulmonary paracoccidioidomycosis of resistant and susceptible mice to P. brasiliensis infection
Grantee:Vera Lucia Garcia Calich
Support type: Regular Research Grants
FAPESP's process: 14/04783-2 - Study of the plasmacytoid and myeloid dendritic cells function during Paracoccidioides brasiliensis infection
Grantee:Flávio Vieira Loures
Support type: Research Grants - Young Investigators Grants