Pathways Regulating Cytosolic Phospholipase A2 Activation and Eicosanoid Production in Macrophages by Candida albicans

Abstract

Resident tissue macrophages are activated by the fungal pathogen Candida albicans to release eicosanoids, which are important modulators of inflammation and immune responses. Our objective was to identify the macrophage receptors engaged by C. albicans that mediate activation of group IVA cytosolic phospholipase A2 (cPLA2α), a regulatory enzyme that releases arachidonic acid (AA) for production of prostaglandins and leukotrienes. A comparison of peritoneal macrophages from wild type and knock-out mice demonstrates that the β-glucan receptor Dectin-1 and MyD88 regulate early release of AA and eicosanoids in response to C. albicans. However, cyclooxygenase 2 (COX2) expression and later phase eicosanoid production are defective in MyD88−/− but not Dectin-1−/− macrophages. Furthermore, C. albicans-stimulated activation of MAPK and phosphorylation of cPLA2α on Ser-505 are regulated by MyD88 and not Dectin-1. In contrast, Dectin-1 mediates MAPK activation, cPLA2α phosphorylation, and COX2 expression in response to particulate β-glucan suggesting that other receptors engaged by C. albicans preferentially mediate these responses. Results also implicate the mannan-binding receptor Dectin-2 in regulating cPLA2α. C. albicans-stimulated MAPK activation and AA release are blocked by d-mannose and Dectin-2-specific antibody, and overexpression of Dectin-2 in RAW264.7 macrophages enhances C. albicans-stimulated MAPK activation, AA release, and COX2 expression. In addition, calcium mobilization is enhanced in RAW264.7 macrophages overexpressing Dectin-1 or -2. The results demonstrate that C. albicans engages both β-glucan and mannan-binding receptors on macrophages that act with MyD88 to regulate the activation of cPLA2α and eicosanoid production.

Eicosanoid biosynthesis influences the virulence of Candida parapsilosis

“…For example, nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin or ibuprofen, target mainly the COX enzymes, thus prostaglandin biosynthesis, to alleviate inflammation [1–3]. Interestingly, the recognition of the C. albicans cell wall β-glucan by dectin-1 on the surface of macrophages enhances macrophage cytosolic phospholipase A2 activity and COX expression, thus promoting prostaglandin biosynthesis in the host [4,5]. Prostaglandin E 2 (PGE 2 ) is known to inhibit the Th1 response and promote Th2 immune responses [6,7].…”

Activation of Cytosolic Phospholipase A2 Downstream of the Src-Phospholipase D1 (PLD1)-Protein Kinase C γ (PKCγ) Signaling Axis Is Required for Hypoxia-induced Pathological Retinal Angiogenesis

“…Together, these observations show that VEGF-induced cPLA 2 phosphorylation and AA release require activation of Src-PLD1-PKC␥ signaling. Previous studies had demonstrated that MAPKs play a role in agonist-induced cPLA 2 activation (38,39). Therefore, to find whether MAPKs play a role in VEGFinduced cPLA 2 activation, we also studied the role of ERK1/2, JNK1, and p38MAPK.…”

Low Molecular Weight Hyaluronan Activates Cytosolic Phospholipase A2α and Eicosanoid Production in Monocytes and Macrophages

“…3C). Various MAPKs were previously reported to take part in cPLA 2 ␣ phosphorylation (57)(58)(59). Therefore, we analyzed the phosphorylation patterns of ERK1/2, p38, JNK, and PI3K-Akt kinases after HA (100 g/ml) treatment over time.…”