Abstract
Cysteinyl leukotrienes (CysLTs) and lipoxins (LXs) are lipid mediators that control inflammation, with the former inducing and the latter inhibiting this process. Because the role played by these mediators in paracoccidioidomycosis was not investigated, we aimed to characterize the role of CysLT in the pulmonary infection developed by resistant (A/J) and susceptible (B10.A) mice. 48 h after infection, elevated levels of pulmonary LTC4 and LXA4 were produced by both mouse strains, but higher levels were found in the lungs of susceptible mice. Blocking the CysLTs receptor by MTL reduced fungal loads in B10.A, but not in A/J mice. In susceptible mice, MLT treatment led to reduced influx of PMN leukocytes, increased recruitment of monocytes, predominant synthesis of anti-inflammatory cytokines, and augmented expression of 5- and 15-lipoxygenase mRNA, suggesting a prevalent LXA4 activity. In agreement, MTL-treated macrophages showed reduced fungal burdens associated with decreased ingestion of fungal cells. Furthermore, the addition of exogenous LX reduced, and the specific blockade of the LX receptor increased the fungal loads of B10.A macrophages. This study showed for the first time that inhibition of CysLTs signaling results in less severe pulmonary paracoccidioidomycosis that occurs in parallel with elevated LX activity and reduced infection of macrophages.
Highlights
Paracoccidioidomycosis (PCM) is a chronic systemic infectious disease of Latin America caused by the dimorphic fungus Paracoccidioides brasiliensis
To further elucidate the role of LTs in murine paracoccidioidomycosis, we aimed to investigate the role of Cysteinyl leukotrienes (CysLTs) in the in vitro and in vivo infections caused by P. brasiliensis
Before studying the effect of CysLT1 blockade in pulmonary PCM, we first asked if P. brasiliensis infection induces the production of lipid mediators
Summary
Paracoccidioidomycosis (PCM) is a chronic systemic infectious disease of Latin America caused by the dimorphic fungus Paracoccidioides brasiliensis. High antibody titers and suppressed T cell mediated immunity characterize the severe forms of the disease whereas the opposite pattern of immunity is associated with mild PCM [2]. Our laboratory developed an isogenic murine model of paracoccidioidomycosis where A/J and B10.A mice mimic the benign and severe forms of the disease, respectively. A/J mice develop a regressive infection characterized by intense cellular immunity and organized lesions. B10.A mice show a progressive disease associated with suppressed T cell immunity and intense tissue pathology caused by fungirich disorganized lesions [3, 4]. IFN-γ is the main protective cytokine to pulmonary PCM, and IFN-γ depletion causes more severe disease in both, susceptible and resistant mice [5]. The innate response of resistant mice is predominantly TGF-β mediated, resulting in an M2
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