Th17-Inducing Cytokines IL-6 and IL-23 Are Crucial for Granuloma Formation during Experimental Paracoccidioidomycosis

Abstract

Paracoccidioidomycosis (PCM), a chronic granulomatous disease caused by the thermally dimorphic fungus Paracoccidioides brasiliensis and Paracoccidioides lutzii, has the highest mortality rate among systemic mycosis. The T helper 1-mediated immunity is primarily responsible for acquired resistance during P. brasiliensis infection, while susceptibility is associated with Th2 occurrence. Th17 is a population of T CD4+ cells that, among several chemokines and cytokines, produces IL-17A and requires the presence of IL-1, IL-6, and TGF-β for differentiation in mice and IL-23 for its maintenance. Th17 has been described as an arm of the immune system that enhances host protection against several bacterial and fungal infections, as Pneumocystis carinii and Candida albicans. In this study, we aimed to evaluate the Th17 immune response and the role of Th17-associated cytokines (IL-6, IL-23, and IL-17A) during experimental PCM. First, we observed that P. brasiliensis infection [virulent yeast strain 18 of P. brasiliensis (Pb18)] increased the IL-17A production in vitro and all the evaluated Th17-associated cytokines in the lung tissue from C57BL/6 wild-type mice. In addition, the deficiency of IL-6, IL-23, or IL-17 receptor A (IL-17RA) impaired the compact granuloma formation and conferred susceptibility during infection, associated with reduced tumor necrosis factor-α, IFN-γ, and inducible nitric oxide synthase enzyme expression. Our data suggest that IL-6 production by bone marrow-derived macrophages (BMDMs) is important to promote the Th17 differentiation during Pb18 infection. In accordance, the adoptive transfer of BMDMs from C57BL/6 to infected IL-6−/− or IL-17RA−/− mice reduced the fungal burden in the lungs compared to nontransferred mice and reestablished the pulmonary granuloma formation. Taken together, these results suggest that Th17-associated cytokines are involved in the modulation of immune response and granuloma formation during experimental PCM.

Th17 lymphocytes in atypical cutaneous leishmaniasis caused by Leishmania (L.) infantum chagasi in Central America

“…[25][26][27][28] Activation of naïve T cells in the presence of specific cytokines, such as TGF-β, IL-6, IL-1β and IL-23, in addition to the transcription factor ROR-γt, mediates Th17 cell development and maintenance. [28][29][30][31] In protozoal, fungal and bacterial infections, IL-17 has been extensively studied in the murine model 26,29,[31][32][33][34][35][36][37][38][39] ; however, its role in human parasitic infections, especially leishmaniasis, is still unclear.…”

“…12,15,25,27,28,38,40 In experimental paracoccidioidomycosis, it was demonstrated that IL-6 and IL-23 are essential to induce a Th17 immune profile, which positively regulates TNFα, IFN-γ and iNOS expression, contributing to modulation of the immune response and granuloma formation. 38 In mycobacterial infections 35,36,39 and sarcoidosis, 37 it has been observed that IL-17 is involved in granuloma formation and its stability by increasing chemokine production, which helps to recruit inflammatory cells to the site of infection. Therefore, based on these reports, we speculate that Th17 cells could be involved in the granuloma organization in skin lesions of 60% of patients affected by NUCL in the present study.…”

NLRP3 inflammasome contributes to host defense against Talaromyces marneffei infection

“…As neither IL-12 nor IL-23 could be detectable upon co-culture of T. marneffei-stimulated human CD14 + monocytes (Fig 5I and J), this suggests that cytokines other than IL-12 and IL-23 might be secreted by human monocytes for the differentiation of Th1 and Th17 cells in response to T. marneffei infection. For example, it was found that IL-6 contributes to IFN- expression in lung tissues in a murine model of systemic P. brasiliensis infection (Tristão et al, 2017). Alternatively, Th17 cells against T. marneffei could originate from memory T cells that are cross-reactive to C. albicans instead of being differentiated de novo, since Th17 cells cross-reactive to C. albicans have been demonstrated to contribute to Th17 response towards A. fumigatus (Bacher et al, 2019).…”

“…The activation of Dectin-1 also triggers the induction of IL-23 through the Syk-CARD9 signaling pathway and drives robust Th17 response (LeibundGut-Landmann et al, 2007). The IL-17/IL-23 axis has been shown to promote immunity to C. albicans, Aspergillus and dimorphic fungi such as H. capsulatum (Deepe Jr. & Gibbons, 2009;Chamilos et al, 2010;Wu et al, 2013) and Paracoccidioides brasiliensis (Tristão et al, 2017). In a murine model of disseminated candidiasis, NLRP3 inflammasome exerts antifungal activity through driving protective Th1 and Th17 immune responses (van de Veerdonk et al, 2011).…”

Avaliação do efeito terapêutico de plasmídeos vacinais contendo o gene da proteína de estresse térmico de 60kDa de <i>Paracoccidioides brasiliensis</i> na paracoccidioidomicose experimental em camundongos

“…Componentes fúngicos podem se ligar a esses receptores e promover a ação das células dendríticas no sentido de diferenciar os linfócitos em células produtoras de IL-17 (LOURES et al, 2015). Esses resultados corroboram o conhecimento atual sobre imunidade na PCM onde os padrões de resposta Th1 e Th17 tem um papel importante no controle da infecção (FELONATO et al, 2012;FERIOTTI et al, 2017;LOURES et al, 2011;TRISTÃO et al, 2017) . Tristão et al (2017)…”