Abstract
Sterile stimuli can trigger inflammatory responses, and in some cases can lead to a variety of acute or chronic diseases. In this study, we hypothesize that a benzimidazole inhibitor may be used as a therapeutic in the treatment of sterile inflammation. In vitro, this inhibitor blocks TLR signalling and inflammatory responses. The benzimidazole inhibitor does not prevent mouse macrophage activation after stimulation with 2,6,10,14-tetramethylpentadecane (TMPD, also known as pristane), a hydrocarbon oil that mimics features of sterile inflammation when injected in vivo. However, C57BL/6J female mice treated with the benzimidazole inhibitor exhibited a significant reduction of pristane-dependent induction of splenocyte number and weight. Conversely, no significant difference was observed in males. Using mass spectrometry, we found that the urine of pristane-injected mice contained increased levels of putative markers for several inflammatory diseases, which were reduced by the benzimidazole inhibitor. To study the mechanism, we showed that pristane-injected mice had increased cell free DNA in serum, which was not impacted by inhibitor treatment. However, chemokine release (e.g. MCP-1, RANTES and TARC) was significantly reduced in inhibitor-treated mice. Thus, the benzimidazole inhibitor might be used as a new drug to block the recruitment of immune cells during sterile inflammatory diseases in humans.
Highlights
Sterile stimuli can trigger inflammatory responses, and in some cases can lead to a variety of acute or chronic diseases
We found that the benzimidazole inhibitor reduced RANTES and IL-6 release in bone marrowderived macrophages (BMDMs) stimulated with the TLR3 agonist Poly I:C (Fig. 1, right panel)
BMDMs pre-treated with the benzimidazole inhibitor or vehicle, followed by stimulation with CpG for different time points showed a significant reduction of ERK-MAP kinase phosphorylation compared to control cells after 0.5 and 2 h (Fig. 2A,B and Supplementary Fig. S1A)
Summary
Sterile stimuli can trigger inflammatory responses, and in some cases can lead to a variety of acute or chronic diseases. We hypothesize that a benzimidazole inhibitor may be used as a therapeutic in the treatment of sterile inflammation. In vitro, this inhibitor blocks TLR signalling and inflammatory responses. The benzimidazole inhibitor does not prevent mouse macrophage activation after stimulation with 2,6,10,14-tetramethylpentadecane (TMPD, known as pristane), a hydrocarbon oil that mimics features of sterile inflammation when injected in vivo. We found that the urine of pristane-injected mice contained increased levels of putative markers for several inflammatory diseases, which were reduced by the benzimidazole inhibitor. Interestingly pristane induces an increase in serum DNA even after inhibitor treatment, whereas serum proinflammatory chemokines were significantly reduced in inhibitor-treated mice. Our results suggest that the use of the benzimidazole inhibitor as a therapeutic should allow amelioration of innate immune responses to sterile inflammatory diseases, mainly targeting IRAK1 and IRAK4
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