Abstract
Tissue-resident macrophages play critical roles in controlling homeostasis, tissue repair, and immunity. Inflammatory macrophages can sustain tissue damage and promote the development of fibrosis during infections and sterile tissue injury. The NLRP3 inflammasome and its effector cytokine IL-1β have been identified as important mediators of fibrosis. Epirubicin, an anthracycline topoisomerase II inhibitor, has been reported to inhibit myeloid inflammatory cytokine production and to promote tissue tolerance following bacterial infection. We investigated the anti-inflammatory properties of epirubicin on the NLRP3 inflammasome and TLR4-mediated inflammation in PMA-primed THP-1 and in primary human peritoneal macrophages (PM). Low-dose epirubicin at non-cytotoxic doses downregulated NLRP3 inflammasome components and reduced the release of cleaved caspase-1, bioactive IL-1β, and TNF-α following NLRP3 activation in a dose-dependent fashion. In addition, epirubicin attenuated inflammatory macrophage responses after TLR4 and TLR2 ligation. These anti-inflammatory effects were not mediated by the induction of autophagy or altered MAPK signaling, but as the result of a global transcriptional suppression of LPS-dependent genes. Epirubicin-treated macrophages displayed reduced acetylation of histone 3 lysine 9 (H3K9ac), suggesting anti-inflammatory epigenetic imprinting as one underlying mechanism.
Highlights
Inflammation is a host response towards destructive stimuli that aims at limiting tissue damage and restoring homeostasis [1]
IL-1β release was reduced by prophylactic treatment with low-dose epirubicin at 0.1 μg/mL when administered 24 h before stimulation, but not when administered at the same time as LPS (Figure 1A)
In dose-finding studies, treatment with epirubicin in concentrations starting from 0.1 μg/mL was effective in reducing the release of IL-1β from peritoneal macrophages (PM) and THP-1 (Figure 1B) and the release of cleaved caspase-1 from PM into cell culture supernatants (Figure 1C)
Summary
Inflammation is a host response towards destructive stimuli that aims at limiting tissue damage and restoring homeostasis [1]. The inflammatory host response needs to be tightly regulated, as the unrestricted release of inflammatory mediators can lead to pathological fibrosis, impairing normal tissue function and promoting organ failure and death [2]. In addition to their role in promoting wound healing responses and tissue repair [3], organ-resident macrophages have been shown to contribute to the development of organ fibrosis by promoting tissue injury, maintaining pro-fibrotic responses, or blocking resolution pathways [4,5]. IL-1β is well known to drive pro-fibrotic responses in the liver, lung, and kidneys in experimental models [12,13,14], these data suggest a role of the inflammasome beyond the mere IL-1β release, implying tumor necrosis factor (TNF) [8]
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