Mitofusin 2 Deficiency Causes Pro-Inflammatory Effects in Human Primary Macrophages

Frontiers in Immunology

Bernhard Brüne¹  Yannick Schreiber²  Ralf P. Brandes⁴  Vera Khodzhaeva⁵  Dmitry Namgaladze⁵  Gerd Geisslinger⁶ 

[1] Frankfurt Cancer Institute, Goethe-University Frankfurt, Frankfurt, Germany;Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt, Germany;German Cancer Consortium (DKTK), Partner Site Frankfurt, Frankfurt, Germany;Institute for Cardiovascular Physiology, Goethe-University Frankfurt, Frankfurt, Germany;Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany;Institute of Clinical Pharmacology, Pharmazentrum Frankfurt/ZAFES, University Hospital, Goethe-University Frankfurt, Frankfurt, Germany;

关键词: macrophages;    mitochondria;    zymosan;    inflammation;    mitochondrial dynamics;    endoplasmic reticulum;   

DOI  :  10.3389/fimmu.2021.723683

来源: DOAJ

【 摘 要 】

Mitofusin 2 (MFN2) is a mitochondrial outer membrane GTPase, which modulates mitochondrial fusion and affects the interaction between endoplasmic reticulum and mitochondria. Here, we explored how MFN2 influences mitochondrial functions and inflammatory responses towards zymosan in primary human macrophages. A knockdown of MFN2 by small interfering RNA decreased mitochondrial respiration without attenuating mitochondrial membrane potential and reduced interactions between endoplasmic reticulum and mitochondria. A MFN2 deficiency potentiated zymosan-elicited inflammatory responses of human primary macrophages, such as expression and secretion of pro-inflammatory cytokines interleukin-1β, -6, -8 and tumor necrosis factor α, as well as induction of cyclooxygenase 2 and prostaglandin E2 synthesis. MFN2 silencing also increased zymosan-induced nuclear factor kappa-light-chain-enhancer of activated B cells and mitogen-activated protein kinases inflammatory signal transduction, without affecting mitochondrial reactive oxygen species production. Mechanistic studies revealed that MFN2 deficiency enhanced the toll-like receptor 2-dependent branch of zymosan-triggered responses upstream of inhibitor of κB kinase. This was associated with elevated, cytosolic expression of interleukin-1 receptor-associated kinase 4 in MFN2-deficient cells. Our data suggest pro-inflammatory effects of MFN2 deficiency in human macrophages.

【 授权许可】

Unknown