Abstract
The mitochondrial network plays a critical role in the regulation of innate immune signaling and subsequent production of proinflammatory cytokines such as IFN-β and IL-1β. Dynamin-related protein 1 (DRP1) promotes mitochondrial fission and quality control to maintain cellular homeostasis during infection. However, mechanisms by which DRP1 and mitochondrial dynamics control innate immune signaling and the proinflammatory response are incompletely understood. Here we show that macrophage DRP1 is a positive regulator of TNF-α production during sterile inflammation or bacterial infection. Silencing macrophage DRP1 decreased mitochondrial fragmentation and TNF-α production upon stimulation with lipopolysaccharide (LPS) or methicillin-resistant Staphylococcus aureus (MRSA) infection. The defect in TNF-α induction could not be attributed to changes in gene expression. Instead, DRP1 was required for post-transcriptional control of TNF-α. In contrast, silencing DRP1 enhanced IL-6 and IL-1β production, indicating a distinct mechanism for DRP1-dependent TNF-α regulation. Our results highlight DRP1 as a key player in the macrophage pro-inflammatory response and point to its involvement in post-transcriptional control of TNF-α production.
Highlights
Tumor necrosis factor-a (TNF-a) is a potent pro-inflammatory mediator produced by macrophages upon infection to enhance host defense
Dynamin-related protein 1 (DRP1) protein levels were evaluated by immunoblot and were depleted in DRP1 KD macrophages compared to NT-Control macrophages (Figure 1A)
DRP1 was lowered at the protein level in primary differentiation macrophages compared to immortalized macrophages (Figure S1A), which is observed in other senescent cells relative to dividing cells (Mai et al, 2010)
Summary
Tumor necrosis factor-a (TNF-a) is a potent pro-inflammatory mediator produced by macrophages upon infection to enhance host defense. The 3′ untranslated region of Tnfa mRNA contains cis adenine and uridine-rich elements (ARE) where trans-acting factors such as the zinc-finger protein tristetraprolin (TTP) and TIA-1 bind to promote its degradation and translational arrest respectively (Anderson, 2000). Loss of these cis- or trans-acting elements in animal models of disease leads to TNF-a overproduction and chronic inflammation (Taylor et al, 1996; Kontoyiannis et al, 1999), demonstrating the importance of these regulatory mechanisms
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