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The Major Chromoblastomycosis Etiologic Agent Fonsecaea Pedrosoi Activates the NLRP3 Inflammasome

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The Major Chromoblastomycosis Etiologic Agent Fonsecaea Pedrosoi Activates the NLRP3 Inflammasome ORIGINAL RESEARCH published: 20 November 2017 doi: 10.3389/fimmu.2017.01572 The Major Chromoblastomycosis Etiologic Agent Fonsecaea pedrosoi Activates the NLRP3 Inflammasome Raffael Júnio Araújo de Castro1, Isaque Medeiros Siqueira1, Márcio Sousa Jerônimo1, Angelina Maria Moreschi Basso1, Paulo Henrique de Holanda Veloso Junior1, Kelly Grace Magalhães 2, Luiza Chaves Leonhardt1, Stephan Alberto Machado de Oliveira1, Pedro Henrique Bürgel1, Aldo Henrique Tavares1† and Anamélia Lorenzetti Bocca1*† 1 Laboratory of Applied Immunology, Department of Cellular Biology, Institute of Biological Sciences, University of Brasília, Brasília, Brazil, 2 Laboratory of Immunology and Inflammation, Department of Cellular Biology, Institute of Biological Sciences, University of Brasília, Brasília, Brazil Edited by: Ilse Denise Jacobsen, Leibniz-Institut für Naturstoff- Fonsecaea pedrosoi is the main etiologic agent of chromoblastomycosis (CBM), one of Forschung und Infektionsbiologie, the most prevalent subcutaneous mycosis in tropical and subtropical countries. CBM Hans Knöll Institut, Germany is a poorly characterized chronic infection that commonly starts after transcutaneous Reviewed by: Etienne Meunier, inoculation of conidia and saprophytic hyphae of F. pedrosoi. Recently, we have shown UMR5089 Institut de that unlike conidia, hyphae and muriform cells (the parasitic morphotype) of F. pedrosoi Pharmacologie et de Biologie promotes an intense inflammatory response pattern in vivo, which comprises the pro- Structurale (IPBS), France Leonardo H. Travassos, duction of an inflammasome-derived cytokine, IL-1β. Nonetheless, the mechanisms Federal University of Rio de Janeiro, underlying IL-1β production and maturation upon F. pedrosoi infection and its functional Brazil output in the course of CBM remains unknown. We show here that F. pedrosoi hyphae, *Correspondence: Anamélia Lorenzetti Bocca differently from conidia, induce IL-1β secretion in both bone marrow-derived dendritic [email protected] cells and macrophages. Using inhibitors and knockout cells, we demonstrated that †These authors have contributed the mechanisms underlying IL-1β production by hyphae-infected macrophages were equally and share senior authorship. dependent on dectin-1, -2, and -3 receptors and the Syk-NF-kB signaling pathway. Furthermore, F. pedrosoi promoted a NLRP3-dependent inflammasome activation, Specialty section: This article was submitted to which required potassium efflux, reactive oxygen species production, phagolysosomal Microbial Immunology, acidification, and cathepsin B release as triggers. IL-1β processing and release was a section of the journal Frontiers in Immunology mediated primarily by caspase-1 and, to a lesser extent, by caspase-8-dependent cleavage. Finally, we showed using a murine CBM model that F. pedrosoi elicits a Received: 30 August 2017 Accepted: 01 November 2017 NLRP3-regulated IL-1β and interleukin-18 release in vivo, but without NLRP3 inflam- Published: 20 November 2017 masome activation interfering in the course of the experimental infection. Citation: Castro RJA, Siqueira IM, Keywords: NLRP3 inflammasome, Fonsecaea pedrosoi, chromoblastomycosis, hyphae, macrophages, Jerônimo MS, Basso AMM, dendritic cells Veloso Junior PHH, Magalhães KG, Leonhardt LC, Oliveira SAM, INTRODUCTION Bürgel PH, Tavares AH and Bocca AL (2017) The Major Chromoblastomycosis (CBM) is a chronic, granulomatous, suppurative, and often debilitating Chromoblastomycosis Etiologic Agent Fonsecaea pedrosoi Activates cutaneous and subcutaneous mycosis, caused by dimorphic filamentous fungi belonging to the the NLRP3 Inflammasome. Dematiaceous family (1–3). Multiple dematiaceous fungi are related to the disease etiology; of Front. Immunol. 8:1572. these, Fonsecaea pedrosoi and Cladophialophora carrionii are the most frequently identified doi: 10.3389/fimmu.2017.01572 fungal species in human CBM skin lesions. This disease occurs worldwide; however, it is mostly Frontiers in Immunology | www.frontiersin.org 1 November 2017 | Volume 8 | Article 1572 Castro et al. Inflamassome Activation by F. pedrosoi prevalent in tropical and subtropical areas (4, 5). Clinically, such as potassium efflux, production of reactive oxygen spe- CBM is characterized by the slow development of polymorphic cies (ROS), phagolysosome acidification, and cathepsin B skin lesions, such as nodules, warts, tumors, plaques, and scars, release. Several conditions may lead to DAMPs production, after inoculation of fungal propagules consisting of conidia including metabolic disorders, inflammatory diseases, and and hyphal fragments into host skin, more frequently into infections. lower limbs (6–8). During infection of mammalian host, these The inflammasome-dependent release of IL-1β and IL-18 primarily saprophyte fungal forms undergo transformation into cytokines has a striking importance in the regulation of innate the intensely melanized and thick-walled muriform (sclerotic) and adaptive response against many different fungal patho- cells, the parasitic morphotype of F. pedrosoi (4). gens, including significant protective roles against Candida Although little is known about the immune response of the albicans, Aspergillus fumigatus, Cryptococcus neoformans, Para­ host to infection by F. pedrosoi, it has been credited that an coccidioides brasiliensis, and Histoplasma capsulatum (16–22). adaptive response mediated by T helper (Th) cell types 1 and One aspect associated with inflammasome activation is fungal 17 might be protective against F. pedrosoi infection (9–11). morphotype diversity and complexity. C. albicans hyphae are In this scenario, the abrogation of IL-12p35 transcription in better inducers and the only fungal form of A. fumigatus that human dendritic cells, leading to Th1-deficient development activates the NLRP3 inflammasome 16( , 17, 23). Indeed, we by several Fonsecaea species, and the Th17-mediated response have recently showed that unlike conidia, the hyphae and muri- suppression in experimentally infected mice, suggest that this form (sclerotic) cells of F. pedrosoi promote intense production fungal pathogen evade host immune response by complex of proinflammatory cytokines in vitro and in vivo (24). Among mechanisms. These mechanisms usually encompass the evasion these cytokines, we observed IL-1β production, suggesting that or subversion of the function of innate pattern recognition recep- F. pedrosoi could activate the inflammasome. In this context, tors (PRRs) in the detection of conserved fungal components or we aimed to evaluate the inflammasome activation by F. pedrosoi pathogen-associated molecular patterns (PAMPs) by phagocytes infective propagules and the role of the inflammasome in CBM (10–12). A number of PRRs families have been associated with experimental disease. F. pedrosoi sensing, including the C-type lectin receptors (CLRs) We show here that F. pedrosoi hyphae, differently from conidia, mincle, dectin-1 and dectin-2, as well as toll-like receptors induce IL-1β secretion in both bone marrow-derived dendritic cells (TLRs). Besides these cytoplasmic membrane-bound receptors, and macrophages. The mechanisms underlying IL-1β production fungal sensing by cytosolic PRRs, such as NOD-like receptors by macrophage-infected hyphae were dependent on dectin-1, -2, (NLRs) and AIM2-like receptors, is becoming increasingly and -3 receptors and the Syk-NF-kB signaling pathway. F. pedrosoi apparent. promoted a NLRP3-dependent inflammasome activation, which The members of the NLR protein family typically share three required K+ efflux, ROS production, pha golysosomal acidifica- functional domains: a C-terminal leucine-rich-repeat putative tion, and cathepsin B release. IL-1β processing and release were ligand-binding domain, a central NACHT nucleotide-binding mediated by caspase-1 and, to a lesser extent, caspase-8-dependent and oligomerization domain and an N-terminal signaling cleavage. Furthermore, we demonstrated using an experimental domain (13). The latter consists of different domains, most CBM model that F. pedrosoi elicits a NLRP3-regulated IL-1β notably a pyrin domain (PYD) or a caspase recruitment and IL-18 release in vivo. However, we did not observe an influ- domain (CARD). Certain NLRP (NLR subfamily with an ence of the NLRP3 inflammasome on the control of the fungal N-terminal PYD), such as NLRP1 and NLRP3, and the infection. NLR family CARD domain-containing protein 4 (NLRC4) associate with inflammatory caspase-1 (in the form of pro- caspase-1) to assemble the inflammasome, a large cytosolic MATERIALS AND METHODS multiprotein complex. Notably, NLRP3-containing inflamma- some formation is dependent on the adaptor protein ASC Fungal Culture and Preparation (apoptosis-associated speck-like protein containing a CARD), Fonsecaea pedrosoi ATCC 46428 were maintained in Sabouraud which promotes the recruitment of pro-caspase-1 through dextrose agar medium (SDA) at 37°C after serial animal pas- CARD–CARD interactions (13). The assembly of the inflam- sages to enhance fungal virulence. In order to obtain purified masome complex leads to the cleavage of pro-caspase-1 into conidia and hyphae for experiments, virulent F. pedrosoi an active cysteine protease, which cleaves the proinflammatory propagules were grown in potato dextrose medium in a rotary cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) shaker (120 rpm) at 30°C. A 15-day-old suspension contain- into their mature forms. NLRP3 inflammasome, the most ing conidia and hyphal fragments was submitted to successive
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