Leukotrienes target F-actin/cofilin-1 to enhance alveolar macrophage anti-fungal activity.

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 (5-LO)-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 LTB4 and LTD4 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 to untreated or WT controls. Conversely, exogenous LTs of both classes augmented baseline C. albicans phagocytosis by AMs. While LTB4 enhanced mainly mannose receptor-dependent fungal ingestion, LTD4 enhanced mainly dectin-1 receptor-mediated phagocytosis. LT enhancement of yeast ingestion was dependent on protein kinase C (PKC)-δ and PI3K, but not PKC-α and MAPK activation. Both LTs reduced activation of cofilin-1 while they enhanced total cellular F-actin; however, LTB4 accomplished this through the activation of LIM kinase (LIMK)-1 and -2, while LTD4 did so exclusively via LIMK-2. Finally, both exogenous LTB4 and LTD4 enhanced AM fungicidal activity in a NADPH oxidase-dependent manner. Our data identify LTB4 and LTD4 as key mediators of innate immunity against C. albicans that act by both distinct and conserved signaling mechanisms to enhance multiple antimicrobial functions of AMs.