Neutrophils are the most abundant leukocytes in circulation playing a key role in acute inflammation during microbial infections. Phagocytosis, one of the crucial defence mechanisms of neutrophils against pathogens, is amplified by chemotactic leukotriene (LT)B₄, which is biosynthesized via 5-lipoxygenase (5-LOX). However, extensive liberation of LTB₄ can be destructive by over-intensifying the inflammatory process. While enzymatic biosynthesis of LTB₄ is well characterized, less is known about molecular mechanisms that activate 5-LOX and lead to LTB₄ formation during host–pathogen interactions. Here, we investigated the ability of the common opportunistic fungal pathogen Candida albicans to induce LTB₄ formation in neutrophils, and elucidated pathogen-mediated drivers and cellular processes that activate this pathway. We revealed that C. albicans-induced LTB₄ biosynthesis requires both the morphological transition from yeast cells to hyphae and the expression of hyphae-associated genes, as exclusively viable hyphae or yeast-locked mutant cells expressing hyphae-associated genes stimulated 5-LOX by [Ca²⁺]_i mobilization and p38 MAPK activation. LTB₄ biosynthesis was orchestrated by synergistic activation of dectin-1 and Toll-like receptor 2, and corresponding signaling via SYK and MYD88, respectively. Conclusively, we report hyphae-specific induction of LTB₄ biosynthesis in human neutrophils. This highlights an expanding role of neutrophils during inflammatory processes in the response to C. albicans infections.

中文翻译：

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中性粒细胞中白色念珠菌诱导的白三烯生物合成仅限于菌丝形态

中性粒细胞是循环中最丰富的白细胞，在微生物感染期间的急性炎症中起关键作用。吞噬作用是中性粒细胞对抗病原体的重要防御机制之一，通过5-脂氧合酶 (5-LOX)生物合成的趋化性白三烯 (LT)B ₄放大。然而，LTB _{4 的}大量释放可通过过度加剧炎症过程而具有破坏性。虽然 LTB _{4 的}酶促生物合成已得到充分表征，但在宿主-病原体相互作用期间激活 5-LOX 并导致 LTB ₄形成的分子机制知之甚少。在这里，我们研究了常见的机会性真菌病原体白色念珠菌的能力在中性粒细胞中诱导 LTB ₄形成，并阐明了病原体介导的驱动因素和激活该途径的细胞过程。我们发现，白色念珠菌诱导的 LTB ₄生物合成需要从酵母细胞到菌丝的形态转变和菌丝相关基因的表达，因为只有活菌丝或表达菌丝相关基因的酵母锁定突变细胞受到 5-LOX 的刺激。 [Ca ²⁺ ] _i动员和 p38 MAPK 激活。LTB _{4 的}生物合成是通过 dectin-1 和 Toll 样受体 2 的协同激活以及相应的信号传导来协调的分别是 SYK 和 MYD88。最后，我们报告了人中性粒细胞中 LTB ₄生物合成的菌丝特异性诱导。这突出了嗜中性粒细胞在炎症过程中对白色念珠菌感染的反应中不断扩大的作用。