Abstract
Sepsis is a heterogeneous syndrome caused by a dysregulated host response during the process of infection. Neutrophils are involved in the development of sepsis due to their essential role in host defense. COVID-19 is a viral sepsis. Disfunction of neutrophils in sepsis has been described in previous studies, however, little is known about the role of microRNA-let-7b (miR-let-7b), toll-like receptor 4 (TLR4), and nuclear factor kappa B (NF-κB) activity in neutrophils and how they participate in the development of sepsis. In this study, we investigated the regulatory pathway of miR-let-7b/TLR4/NF-κB in neutrophils. We also explored the downstream cytokines released by neutrophils following miR-let-7b treatment and its therapeutic effects in cecal ligation and puncture (CLP)-induced septic mice. Six-to-eight-week-old male C57BL/6 mice underwent CLP following treatment with miR-let-7b agomir. Survival (n=10), changes in liver and lungs histopathology (n=4), circulating neutrophil counts (n=4), the liver-body weight ratio (n=4–7), and the lung wet-to-dry ratio (n=5–6) were recorded. We found that overexpression of miR-let-7b could significantly down-regulate the expression of human-derived neutrophilic TLR4 at a post-transcriptional level, a decreased level of proinflammatory factors including interleukin-6 (IL-6), IL-8, tumor necrosis factor α (TNF-α), and an upregulation of anti-inflammatory factor IL-10 in vitro. After miR-let-7b agomir treatment in vivo, neutrophil recruitment was inhibited and thus the injuries of liver and lungs in CLP-induced septic mice were alleviated (p=0.01 and p=0.04, respectively), less weight loss was reduced, and survival in septic mice was also significantly improved (p=0.013). Our study suggested that miR-let-7b could be a potential target of sepsis.
Highlights
In 2020, the world was challenged by the COVID-19 pandemic
Using the data provided in the Human Protein Atlas, a genome-wide transcriptomic depository of protein-coding genes in human blood cells [37], we first evaluated the presence of toll-like receptor 4 (TLR4) expression (Figure 1) and the associated functional data of human neutrophils
The analysis showed that human miR-let-7b targets 15 and 14 genes within the Toll-like receptors (TLRs) and nuclear factor kappa B (NF-kB) pathways, respectively
Summary
In 2020, the world was challenged by the COVID-19 pandemic. The novel coronavirus has remained a crude contributor to the mortality rate and has severely endangered public health worldwide [1]. Sepsis is defined as a heterogeneous syndrome associated with organ dysfunction [2]. The pathogenesis and mechanisms involved in COVID-19 and sepsis both converge on a pivotal role played by the host inflammatory response. Findings concerning sepsis may be useful for anti-inflammatory therapy for patients with COVID-19. Current therapeutic choices are limited and fail to reduce the mortality rate associated with sepsis [3]; a better understanding of the mechanisms of sepsis and providing new targets are critical to improve public health
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