Cytosolic phospholipase A 2 contributes to innate immune defense against Candida albicans lung infection

摘要

Background The 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. Methods The 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. Results After 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. Conclusions The 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.