Abstract
Endotoxin tolerance is an immunohomeostatic reaction to reiterant lipopolysaccharide (LPS) exposure that maintains a state of altered responsiveness in immune cells, resulting in the inhibition of the pro-inflammatory response and the resolution of inflammation. Microglia constitutes the first line of defense against endogenous and external challenges in the brain. MicroRNAs (miRs) serve a critical function in the regulation of inflammation. The aim of the present study was to investigate whether miR-155 regulates endotoxin tolerance. miR-155 and suppressor of cytokine signaling-1 (SOCS1) mRNA expression was measured using RT-qPCR. The expression of SOCS1 was measured by western blotting and immunofluorescence. TNF-α levels were detected by an enzyme-linked immunosorbent assay. The results indicated that miR-155 expression was significantly downregulated in the microglia and cortex tissue following the induction of endotoxin tolerance. This was consistent with an increase in the expression of SOCS1, a predicted target of miR-155 and key inhibitor of the inflammatory reaction. Transfection with miR-155 inhibitor significantly enhanced SOCS1 expression in the microglia following the induction of endotoxin tolerance. SOCS1 knockdown using short hairpin RNA partly inhibited the anti-inflammatory process and promoted the inflammatory response during endotoxin tolerance. The results of the current study indicate that miR-155 inhibition contributes to the development of endotoxin tolerance. Understanding how miRs regulate inflammatory mechanisms may facilitate the development of novel therapeutic strategies to treat CNS disorders.
Highlights
Sepsis‐induced central nervous system (CNS) dysfunction is a potentially irreversible acute brain dysfunction; as many as 71% of such patients go onto develop septic encephalopathy (SE) [1]
To investigate and compare miR‐155 expression in microglia during inflammation and endotoxin tolerance, BV2 cells and primary microglia were treated with lipopolysaccharide stimulation (LPS) to induce inflammation or repeated LPS to induce endotoxin tolerance. miR‐155
Endotoxin tolerance has been extensively investigated in peripheral macrophages [5,7,9,10]; little is known about the microglia and miRs that are involved in the development of endotoxin tolerance
Summary
Sepsis‐induced central nervous system (CNS) dysfunction is a potentially irreversible acute brain dysfunction; as many as 71% of such patients go onto develop septic encephalopathy (SE) [1]. The resident CNS macrophages, microglia, are the primary target cells of LPS and it has been demonstrated that sepsis induced by peripheral injection of LPS activates microglial cells [2,3]. Endotoxin tolerance has been observed in vitro and in vivo, in animal models and in humans [5] It is associated with changes in particular regulatory events, including deficiencies in the myeloid differentiation primary response 88 (MyD88) [7], reduced IL‐1 receptor‐associated kinase (IRAK)4‐MyD88 association [8], suppressed IRAK1 activation [9], as well as the upregulation of negative regulators, including IRAK‐M [10], suppressor of cytokine signaling 1 (SOCS1) and SH2 domain containing inositol‐5‐phosphatase (SHIP‐1) [11]. It has been demonstrated that SOCS1 affects a series of signaling pathways, including NF‐κB [14], c‐Jun N terminal kinase and p38 [15]
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