We aimed at evaluating TLR2 and TLR4 expression on human neutroph

We aimed at evaluating TLR2 and TLR4 expression on human neutrophils activated with GM-CSF, IL-15, TNF-α or IFN-γ and challenged with a virulent strain of P. brasiliensis (Pb18). Moreover, we

asked if these receptors have a role buy STI571 on fungicidal activity, H2O2 and IL-6, IL-8, TNF-α and IL-10 production by activated and challenged cells. All cytokines increased TLR2 and TLR4 expression. Pb18 also increased TLR2 expression inducing an additional effect to that of cytokines. On the contrary, it inhibited TLR4 expression. All cytokines increased neutrophil fungicidal activity and H2O2 production, but this process was not associated with TLR2 or TLR4. Neutrophils activation with GM-CSF and TNF-α resulted in a significative increase in IL-8 production, while IL-15 and IFN-γ have no effect. Pb18 alone also increased IL-8 production. None of the cytokines activated neutrophils for Ruxolitinib nmr IL-10 release. This cytokine was only detected after Pb18 challenge. Interestingly, IL-8 and IL-10 production involved TLR2 and mainly TLR4 modulation. Our data suggest that Pb18 uses TLR4 to gain access to human neutrophils. This interaction results in IL-8 and IL-10 production that may be considered as a pathogenic mechanism in paracoccidioidomycosis. Paracoccidioides brasiliensis (Pb) is the aetiological agent of paracoccidioidomycosis, a systemic mycosis endemic in Latin America.

The infection can be acquired by inhalation of airborne conidia that reach the lung alveoli, where they transform into yeast cells, the infective form [1]. Many people are exposed to the fungus, but only a small number develop clinical symptoms, suggesting that both innate and adaptive mechanisms are important

in fungus clearance [2–5]. The host innate immune response against fungus has been well characterized, and several studies have clearly shown the role of phagocytic cells. In this context, in last years, various studies have focused on the role of neutrophils [6]. Some in vitro studies suggest that Pb-infected macrophages induce the onset of extravascular neutrophilia by releasing chemotactic peptides [7]. Heavy neutrophil infiltration in the lungs of Pb-infected mice at early acute infection was correlated with the release of keratinocyte-derived chemokine (KC) and macrophage inflammatory protein-1α (MIP-1α), two important neutrophil EGFR inhibitor chemoattractants [8]. In consequence of these chemotactic processes, massive neutrophil infiltration is found in infected tissues from patients with paracoccidioidomycosis [9] and in the early lesions of experimentally infected animals [10, 11]. Neutrophils from infected individuals can kill Pb [12]. However, experiments using more sensitive methods showed that despite their phagocytic capacity, these neutrophils are unable to digest Pb in vitro, indicating that a defect of neutrophil function may represent a susceptibility factor [13].

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