Abstract
Candida albicans is the most common opportunistic fungal pathogen and causes local and systemic disease in immunocompromised patients. Alveolar macrophages (AMs) are pivotal for the clearance of C. albicans from the lung. Activated AMs secrete 5-lipoxygenase-derived leukotrienes (LTs), which in turn enhance phagocytosis and microbicidal activity against a diverse array of pathogens. Our aim was to investigate the role of LTB(4) and LTD(4) in AM antimicrobial functions against C. albicans and the signaling pathways involved. Pharmacologic and genetic inhibition of LT biosynthesis as well as receptor antagonism reduced phagocytosis of C. albicans when compared with untreated or WT controls. Conversely, exogenous LTs of both classes augmented base-line C. albicans phagocytosis by AMs. Although LTB(4) enhanced mainly mannose receptor-dependent fungal ingestion, LTD(4) enhanced mainly dectin-1 receptor-mediated phagocytosis. LT enhancement of yeast ingestion was dependent on protein kinase C-δ (PKCδ) and PI3K but not PKCα and MAPK activation. Both LTs reduced activation of cofilin-1, whereas they enhanced total cellular F-actin; however, LTB(4) accomplished this through the activation of LIM kinases (LIMKs) 1 and 2, whereas LTD(4) did so exclusively via LIMK-2. Finally, both exogenous LTB(4) and LTD(4) enhanced AM fungicidal activity in an NADPH oxidase-dependent manner. Our data identify LTB(4) and LTD(4) as key mediators of innate immunity against C. albicans, which act by both distinct and conserved signaling mechanisms to enhance multiple antimicrobial functions of AMs.
Highlights
IntroductionAlveolar macrophages (AMs) are important defenders against opportunistic fungal infections, preventing the hematogenous dissemination of C. albicans in immunocompromised hosts [6]
Phagocytosis of C. albicans by alveolar macrophages (AMs) Requires the Generation of Both Classes of LTs—First, we compared the ability of live and heat-killed C. albicans to induce LTB4 and cysLT synthesis in rat AMs at time points relevant to the process of yeast ingestion
We asked if LTs produced during C. albicans ingestion have a functional role in AM antimicrobial function
Summary
Alveolar macrophages (AMs) are important defenders against opportunistic fungal infections, preventing the hematogenous dissemination of C. albicans in immunocompromised hosts [6]. LT receptor ligation enhances many aspects of AM activation, including leukocyte accumulation [11], microbial ingestion [13] and killing [14], and generation of proinflammatory mediators [10]. We have previously characterized some of the signaling pathways by which LTs enhance AM antimicrobial functions against IgG-opsonized pathogens recognized by the Fc␥ receptor (FcR) [15,16,17]. Leukotrienes Enhance Macrophage Anti-fungal Activity tion of LTs observed in immunosuppressive states [22], the present study was undertaken to investigate the role of LTs and the signaling pathways involved in the anti-fungal activity of AMs against the opportunistic pathogen C. albicans. Our data show that both endogenous as well as exogenous LTB4 and LTD4 enhance phagocytosis of C. albicans by promoting F-actin polymerization and assembly and killing via NADPH oxidase activation and reactive oxygen intermediate (ROI) generation
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