与其他真菌感染一致,肺副球孢子菌病(PCM)的免疫保护是由Th1/Th17细胞介导的,而疾病进展是由普遍的Th2/Th9免疫介导的。Treg细胞发挥双重作用,抑制免疫力,但也控制过度的组织炎症。我们最近的研究表明,吲哚胺2,3双加氧酶(IDO)和转录因子芳基烃受体(AhR)在PCM的免疫调节中起重要作用。为了进一步评估AhR在这种真菌感染中的免疫调节活性,用两种不同的AhR激动剂治疗巴西副球菌感染的小鼠,L-Kynurenin(L-Kyn)或6-甲酰吲哚[3,2-b]咔唑(FICZ),和一种AhR特异性拮抗剂(CH223191)。在感染后96小时和2周评估治疗和未治疗小鼠的疾病严重程度和免疫应答。FICZ和L-Kyn对宿主反应有一些类似的影响,比如减少真菌负荷,表达活化标志物的CD11c+肺髓样细胞数量减少(IA,CD40,CD80,CD86),以及早期增加的IDO和AhR的表达。相比之下,AhR拮抗剂CH223191诱导真菌负荷增加,表达活化标志物的肺CD11c+白细胞数量增加,以及减少AhR和IDO产量。虽然FICZ处理促进了ILC3的大量增加,但L-Kyn和CH223191显著减少了该细胞群。这些AhR配体中的每一种诱导特征性的适应性免疫。FICZ诱导的骨髓的大量扩张,淋巴样,和浆细胞样树突状细胞(DC)导致所有CD4+T细胞亚群(Th1,Th2,Th17,Th22和Treg)的扩增增加,但Th17和Th22亚群明显占优势。另一方面,L-Kyn,优先激活的浆细胞样DC,减少Th1/Th22发育,但引起Treg细胞的强烈扩增。AhR拮抗剂CH223191诱导髓样DC的优先扩增,减少Th1、Th22和Treg细胞的数量,但增加Th17分化。总之,本研究表明,AhR配体可以调节肺部PCM中的病原体负荷和免疫反应。然而,需要进一步的研究来确定这些化合物作为这种真菌感染的辅助疗法的可能用途。
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.