Cytosolic phospholipase A2 contributes to innate immune defense against Candida albicans lung infection

Abstract

BackgroundThe lung is exposed to airborne fungal spores, and fungi that colonize the oral cavity such as Candida albicans, but does not develop disease to opportunistic fungal pathogens unless the immune system is compromised. The Group IVA cytosolic phospholipase A2 (cPLA2α) is activated in response to Candida albicans infection resulting in the release of arachidonic acid for eicosanoid production. Although eicosanoids such as prostaglandins and leukotrienes modulate inflammation and immune responses, the role of cPLA2α and eicosanoids in regulating C. albicans lung infection is not understood.MethodsThe responses of cPLA2α+/+ and cPLA2α−/− Balb/c mice to intratracheal instillation of C. albicans were compared. After challenge, we evaluated weight loss, organ fungal burden, and the recruitment of cells and the levels of cytokines and eicosanoids in bronchoalveolar lavage fluid. The ability of macrophages and neutrophils from cPLA2α+/+ and cPLA2α−/− mice to recognize and kill C. albicans was also compared.ResultsAfter C. albicans instillation, cPLA2α+/+ mice recovered a modest weight loss by 48 h and completely cleared fungi from the lung by 12 h with no dissemination to the kidneys. In cPLA2α−/− mice, weight loss continued for 72 h, C. albicans was not completely cleared from the lung and disseminated to the kidneys. cPLA2α−/− mice exhibited greater signs of inflammation including higher neutrophil influx, and elevated levels of albumin and pro-inflammatory cytokines/chemokines (IL1α, IL1β, TNFα, IL6, CSF2, CXCL1, CCL20) in bronchoalveolar lavage fluid. The amounts of cysteinyl leukotrienes, thromboxane B2 and prostaglandin E2 were significantly lower in bronchoalveolar lavage fluid from C. albicans-infected cPLA2α−/− mice compared to cPLA2α+/+ mice. Alveolar macrophages and neutrophils from uninfected cPLA2α−/− mice exhibited less killing of C. albicans in vitro than cells from cPLA2α+/+ mice. In addition alveolar macrophages from cPLA2α−/− mice isolated 6 h after instillation of GFP-C. albicans contained fewer internalized fungi than cPLA2α+/+ macrophages.ConclusionsThe results demonstrate that cPLA2α contributes to immune surveillance and host defense in the lung to prevent infection by the commensal fungus C. albicans and to dampen inflammation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12865-016-0165-9) contains supplementary material, which is available to authorized users.

Host-Derived Leukotriene B4 Is Critical for Resistance against Invasive Pulmonary Aspergillosis

“…Following challenge of alveolar macrophages or resident mouse peritoneal macrophages with Candida albicans arachidonic acid is effectively mobilized by cPLA2 ( 15 – 17 ), which is necessary for production of both prostaglandins and leukotrienes. cPLA2 is critical for host resistance against C. albicans challenge, through the regulation of macrophage transcriptional responses and likely through increased anti-fungal activity of alveolar macrophages ( 17 , 18 ). Moreover, exogenous LTB 4 and LTD 4 can enhance phagocytosis and killing of C. albicans by macrophages ( 19 ).…”

Candida Albicans Lung Abscess in an Illicit Drugs User With Hepatitis C Virus Chronic Infection

“…Two mechanisms have been hypothesized to play a role in their onset: the first one is the direct inhalation of pathogens contaminating the substance, the second one is the direct action of cocaine on alveolar macrophages, resulting in an inhibited response by leukocytes [ 14 ]. In this regard, a study conducted on animal models from Jayaraja et al is interesting [ 15 ]. The researchers, after having intratracheally instilled Candida albicans in mice, performed an analysis on the bronchoalveolar lavage, which contained macrophages alveolar, and neutrophils [ 15 ].…”

Comparative Metabolomics Analysis of Cervicitis in Human Patients and a Phenol Mucilage-Induced Rat Model Using Liquid Chromatography Tandem Mass Spectrometry

“…The polyunsaturated, essential fatty acid AA and its metabolites play a central role in regulating inflammatory signaling pathways (Ma et al, 2016 ). AA is the substrate for the synthesis of biologically active compounds, such as leukotrienes, prostaglandins, thromboxanes, which act as regulators of inflammatory cytokine production and immune function (Jayaraja et al, 2016 ; Monk et al, 2016 ). In addition, linoleic acid metabolism was identified as a metabolic pathway linked to cervicitis (Figure 9 ).…”