AhR Ligands Modulate the Differentiation of Innate Lymphoid Cells and T Helper Cell Subsets That Control the Severity of a Pulmonary Fungal Infection

Abstract

In agreement with other fungal infections, immunoprotection in pulmonary paracoccidioidomycosis (PCM) is mediated by Th1/Th17 cells whereas disease progression by prevalent Th2/Th9 immunity. Treg cells play a dual role, suppressing immunity but also controlling excessive tissue inflammation. Our recent studies have demonstrated that the enzyme indoleamine 2,3 dioxygenase (IDO) and the transcription factor aryl hydrocarbon receptor (AhR) play an important role in the immunoregulation of PCM. To further evaluate the immunomodulatory activity of AhR in this fungal infection, Paracoccidioides brasiliensis infected mice were treated with two different AhR agonists, L-Kynurenin (L-Kyn) or 6-formylindole [3,2-b] carbazole (FICZ), and one AhR specific antagonist (CH223191). The disease severity and immune response of treated and untreated mice were assessed 96 hours and 2 weeks after infection. Some similar effects on host response were shared by FICZ and L-Kyn, such as the reduced fungal loads, decreased numbers of CD11c+ lung myeloid cells expressing activation markers (IA, CD40, CD80, CD86), and early increased expression of IDO and AhR. In contrast, the AhR antagonist CH223191 induced increased fungal loads, increased number of pulmonary CD11c+ leukocytes expressing activation markers, and a reduction in AhR and IDO production. While FICZ treatment promoted large increases in ILC3, L-Kyn and CH223191 significantly reduced this cell population. Each of these AhR ligands induced a characteristic adaptive immunity. The large expansion of FICZ-induced myeloid, lymphoid, and plasmacytoid dendritic cells (DCs) led to the increased expansion of all CD4+ T cell subpopulations (Th1, Th2, Th17, Th22, and Treg), but with a clear predominance of Th17 and Th22 subsets. On the other hand, L-Kyn, that preferentially activated plasmacytoid DCs, reduced Th1/Th22 development but caused a robust expansion of Treg cells. The AhR antagonist CH223191 induced a preferential expansion of myeloid DCs, reduced the number of Th1, Th22, and Treg cells, but increased Th17 differentiation. In conclusion, the present study showed that the pathogen loads and the immune response in pulmonary PCM can be modulated by AhR ligands. However, further studies are needed to define the possible use of these compounds as adjuvant therapy for this fungal infection.

Pharmacological blockage of the AHR-CYP1A1 axis: a call for in vivo evidence

“…The number of CD11c + cells expressing membrane (IAb, CD80, CD86) markers was also increased. CH-223191 also augmented the migration of myeloid dendritic cells to the lungs and promoted the expansion of Th17 lymphocytes associated with concomitant reduction of Treg cells, Th1, and Th22 [87,88]. The results strongly suggest that fungal infections can be modulated by AHR signaling, unveiling new perspectives to treat these infections.…”

Aryl hydrocarbon receptor involved in Th17/Treg imbalance in chronic hepatitis B via the AhR–RORγt–FoxP3 axis

“…AhR expresses innate and adaptive immune cells and can participate in the activation and functional development of the immune system [29]. Th17 and Treg cells, belonging to CD4 + T lymphocytes, play a role in promoting and reducing in ammation in cellular immunity.…”

“…Th17/Treg imbalance is involved in the pathogenesis of many autoimmune [30], metabolic [31], and infectious diseases [32]. Therefore, AhR plays an important role in Th17 and Treg cell differentiation and function [17,29] and is involved in Th17/Treg imbalance mechanism. However, the immunopathogenic role (especially Th17/Treg balance) of AhR in CHB remained unknown.…”

The key player in the pathogenesis of environmental influence of systemic lupus erythematosus: Aryl hydrocarbon receptor

“…Eliseu et al. reported that both AhR agonist Kyn and AhR antagonist CH223191 decreased the number of Th1 cells in a mice pulmonary fungal infection model, while agonist FICZ resulted in the expansion of all CD4+ T cell subsets (Th1, Th2, Th17, Th22, and Treg) ( 65 ). In addition, AhR-deficient mice displayed a decrease in Th1, Th22, and other immune cells in their lungs ( 66 ).…”