Lipopolysaccharide promotes Drp1-dependent mitochondrial fission and associated inflammatory responses in macrophages
| Autor: | Ronan Kapetanovic, Takashi Okada, Matthew J. Sweet, Kate Schroder, Jost de Bruin, Grace Mep Lawrence, Justin C. St. John, David P. Fairlie, Syeda Farhana Afroz, Divya Ramnath, Antje Blumenthal, James E. B. Curson |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Dynamins Lipopolysaccharides Toll‐like receptor Immunology macrophage Mitochondrion Mitochondrial Dynamics Outstanding Observation Mitochondrial Proteins 03 medical and health sciences DNM1L Mice 0302 clinical medicine Immunology and Allergy Animals Humans Cells Cultured Toll-like receptor Chemistry mitochondrial fission Macrophages lipopolysaccharide Cell Biology Fibroblasts Cell biology Toll-Like Receptor 4 030104 developmental biology Mitochondrial biogenesis mitochondrial fusion Myeloid Differentiation Factor 88 TLR4 Phosphorylation Mitochondrial fission Dynamin‐related protein 1 030215 immunology |
| Zdroj: | Immunology and Cell Biology |
| ISSN: | 1440-1711 |
| Popis: | Mitochondria have a multitude of functions, including energy generation and cell signaling. Recent evidence suggests that mitochondrial dynamics (i.e. the balance between mitochondrial fission and fusion) also regulate immune functions. Here, we reveal that lipopolysaccharide (LPS) stimulation increases mitochondrial numbers in mouse bone marrow‐derived macrophages (BMMs) and human monocyte‐derived macrophages. In BMMs, this response requires Toll‐like receptor 4 (Tlr4) and the TLR adaptor protein myeloid differentiation primary response 88 (MyD88) but is independent of mitochondrial biogenesis. Consistent with this phenomenon being a consequence of mitochondrial fission, the dynamin‐related protein 1 (Drp1) GTPase that promotes mitochondrial fission is enriched on mitochondria in LPS‐activated macrophages and is required for the LPS‐mediated increase in mitochondrial numbers in both BMMs and mouse embryonic fibroblasts. Pharmacological agents that skew toward mitochondrial fusion also abrogated this response. LPS triggered acute Drp1 phosphorylation at serine 635 (S635), followed by sustained Drp1 dephosphorylation at serine 656 (S656), in BMMs. LPS‐induced S656 dephosphorylation was abrogated in MyD88‐deficient BMMs, suggesting that this post‐translational modification is particularly important for Tlr4‐inducible fission. Pharmacological or genetic targeting of Tlr4‐inducible fission had selective effects on inflammatory mediator production, with LPS‐inducible mitochondrial fission promoting the expression and/or secretion of a subset of inflammatory mediators in BMMs and mouse embryonic fibroblasts. Thus, triggering of Tlr4 results in MyD88‐dependent activation of Drp1, leading to inducible mitochondrial fission and subsequent inflammatory responses in macrophages. Here, we demonstrate that lipopolysaccharide (LPS) acts via a Tlr4–MyD88–Drp1 axis to initiate mitochondrial fission and selective inflammatory responses in macrophages. We also show that LPS promotes sequential dynamin‐related protein 1 (Drp1) serine phosphorylation (S635) and dephosphorylation (S656), with the latter modification requiring the adaptor molecule myeloid differentiation primary response 88 (MyD88). We did not observe LPS‐inducible mitochondrial DNA replication in the same cells, suggesting that LPS‐inducible mitochondrial fission can occur independently of mitochondrial DNA replication. |
| Databáze: | OpenAIRE |
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