Abstract
BackgroundThe liver is a vital target for sepsis-related injury, leading to inflammatory pathogenesis, multiple organ dysfunction and high mortality rates. Monocyte-derived macrophage transformations are key events in hepatic inflammation. N1-[(4-methoxy)methyl]-4-methyl-1,2-benzenediamine (FC-99) previously displayed therapeutic potential on experimental sepsis. However, the underlying mechanism of this protective effect is still not clear.ResultsFC-99 treatment attenuated the liver dysfunction in septic mice that was accompanied with reduced numbers of pro-inflammatory Ly6Chi monocytes in the peripheral blood and CD11b+F4/80lo monocyte-derived macrophages in the liver. These effects were attributed to the FC-99-induced apoptosis of CD11b+ cells. In PMA-differentiated THP-1 cells, FC-99 repressed the expression of CD11b, CD14 and caspase3 and resulted in a high proportion of Annexin V+ cells. Moreover, let-7a-5p expression was abrogated upon CLP stimulation in vivo, whereas it was restored by FC-99 treatment. TargetScan analysis and luciferase assays indicated that the anti-apoptotic protein BCL-XL was targeted by let-7a-5p. BCL-XL was inhibited by FC-99 in order to induce monocyte apoptosis, leading to the impaired monocyte-to-macrophage differentiation.Materials and MethodsMurine acute liver failure was generated by caecal ligation puncture surgery after FC-99 administration; Blood samples and liver tissues were collected to determine the monocyte/macrophage subsets and the induction of apoptosis. Human acute monocytic leukemia cell line (THP-1) cells were pretreated with FC-99 followed by phorbol-12-myristate-13-acetate (PMA) stimulation, in order to induce monocyte-to-macrophage differentiation. The target of FC-99 and the mechanistic analyses were conducted by microarrays, qRT-PCR validation, TargetScan algorithms and a luciferase report assay.ConclusionsFC-99 exhibits potential therapeutic effects on CLP-induced liver dysfunction by restoring let-7a-5p levels.
Highlights
Sepsis is characterized by life-threatening organ dysfunction that is caused by a dysregulated host response to infection
FC-99 treatment attenuated the liver dysfunction in septic mice that was accompanied with reduced numbers of pro-inflammatory Ly6Chi monocytes in the peripheral blood and CD11b+F4/80lo monocyte-derived macrophages in the liver
Let-7a-5p expression was abrogated upon cecal ligation and puncture (CLP) stimulation in vivo, whereas it was restored by FC-99 treatment
Summary
Sepsis is characterized by life-threatening organ dysfunction that is caused by a dysregulated host response to infection. The hepatocytes are primed to recruit additional cells to the liver in order to protect the body from the invading microorganisms [4]. The liver triggers the inflammatory response of the body in order to eliminate microorganisms efficiently, which represents a double-edged sword that results in liver damage due to an overwhelming systemic inflammatory response [5]. Liver dysfunction occurs during early sepsis that has been demonstrated at 1.5 h post CLP following mouse surgery [6, 7]. This process is an independent factor for multiple organ disorders and sepsis-induced death [5]. The underlying mechanism of this protective effect is still not clear
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