Invasive infections caused by Aspergillus fumigatus can be life-threatening, but phagocytic leukocytes like macrophages defend the host against this fungus. Besides phagocytosis, A. fumigatus-activated macrophages produce cytokines, chemokines, and pro-inflammatory lipid mediators including leukotriene (LT)B4. LTB4 is essential for defense against A. fumigatus, however, the mechanisms regulating its biosynthesis in innate immune cells upon A. fumigatus infection remain unclear. Here, we reveal that pro-inflammatory M1-monocyte-derived macrophages display highest 5-lipoxygenase (LOX)-mediated LTB4 production in response to A. fumigatus, which depends on fungal morphology and viability, where fungal cell wall structural polysaccharides via dectin-1 receptor, followed by phagocytosis of A. fumigatus are determinants. LTB4 biosynthesis depends on cytosolic phospholipase A2, intracellular Ca²⁺, functionality of the 5-LOX-activating protein, and the activation of mitogen-activated protein kinases, p38 MAPK and ERK-1/2. Finally, screening of Aspergillus spp. mycotoxins reveals that inhibition of the sarcoplasmic/endoplasmic reticulum Ca2+-dependent ATPase by cyclopiazonic acid-like toxins mediates LTB4 biosynthesis following phagocytosis.
2026-10-30
Dectin-1-dependent phagocytosis of Aspergillus fumigatus triggers robust leukotriene B4 formation in human pro-inflammatory macrophages
Kerstin Günther, Tom Schöne, Zoltan Cseresnyés, Corissa Visser, Vivien Nischang, Jethro L. Hemmann, Slavica Janevska, Francisco Páez Larios, Zahraa Abboud, Dalia Sheta, Thorsten Heinekamp, Olaf Kniemeyer, Christian Eggeling, Andreas Beilhack, Axel A. Brakhage, Marc Thilo Figge, Oliver Werz#, Paul M. Jordan#
#Correspondence: paul.jordan@uni-jena.de and oliver.werz@uni-jena.de
Cell Reports