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Published on: May 21, 2018
17β-Estradiol Attenuates LPS-Induced Macrophage Inflammation In Vitro and Sepsis-Induced Vascular Inflammation In
Man-Li Zhang1, Hui Chen1, Zhan Yang2,3
1Department of Critical Care Medicine, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, Hebei 050000, China.
Abstract:
Excessive release of cytokines such as IL-1β and other inflammatory mediators synthesized and secreted by macrophages is the fundamental link of uncontrolled inflammatory response in sepsis. 17β-Estradiol (E2) plays anti-inflammatory and vascular protective effects by regulating leukocyte infiltration and the expression of chemokines or cytokines induced by injury. However, the role of E2 in the inflammatory response of macrophages in sepsis and its mechanism are still not fully understood. In the present study, we show that E2 alleviates vascular inflammation in sepsis mice induced by cecal ligation puncture (CLP). E2 significantly decreases RAW 264.7 cell inflammation response by downregulating the expression of NLRP3. Furthermore, we found that miR-29a-5p was significantly downregulated in LPS-treated macrophages. Treating RAW 264.7 cells with E2 markedly upregulated the miR-29a-5p expression level. More importantly, we demonstrated that miR-29a-5p repressed NLRP3 expression by directly targeting its 3'-UTR. Loss- and gain-of-function experiments revealed that transfection of the miR-29a-5p mimic abrogates LPS-induced macrophage inflammation. Moreover, depletion of miR-29a-5p by its inhibitor largely promotes LPS-induced macrophage inflammation. In summary, miR-29a-5p upregulation induced by E2 alleviated RAW 264.7 cell inflammation response by aggravating miR-29a-5p repression of NLRP3 expression. E2 exerts significant anti-inflammatory efficacy in macrophages by regulating the miR-29a-5p/NLRP3 axis. Targeting miR-29a-5p may be a novel therapeutic strategy to suppress sepsis-induced vascular inflammation.
Insights
17β-Estradiol (E2) reduces sepsis-induced inflammation in macrophages by upregulating miR-29a-5p. This microRNA targets and downregulates NLRP3, offering a potential therapeutic strategy for sepsis.
Area of Science:
- Immunology
- Molecular Biology
- Endocrinology
Background:
- Sepsis involves excessive cytokine release from macrophages, driving uncontrolled inflammation.
- 17β-Estradiol (E2) has known anti-inflammatory and vascular protective effects.
- The precise role and mechanism of E2 in macrophage inflammatory responses during sepsis remain unclear.
Purpose of the Study:
- To investigate the role of 17β-Estradiol (E2) in modulating macrophage inflammation in sepsis.
- To elucidate the underlying molecular mechanism involving microRNA and NLRP3.
- To explore potential therapeutic targets for sepsis-induced vascular inflammation.
Main Methods:
- Cecal ligation puncture (CLP) model in mice to induce sepsis.
- In vitro studies using RAW 264.7 macrophages treated with lipopolysaccharide (LPS) and E2.
- Quantitative real-time PCR, Western blotting, and luciferase reporter assays to assess gene and microRNA expression.
- Loss- and gain-of-function experiments using miR-29a-5p mimics and inhibitors.
Main Results:
- E2 alleviated vascular inflammation in CLP-induced sepsis mice and reduced inflammation in LPS-treated RAW 264.7 cells.
- E2 treatment downregulated NLRP3 expression and upregulated miR-29a-5p in macrophages.
- miR-29a-5p directly targeted the 3'-UTR of NLRP3, repressing its expression.
- Overexpression of miR-29a-5p inhibited LPS-induced macrophage inflammation, while its depletion exacerbated it.
Conclusions:
- E2 exerts anti-inflammatory effects in macrophages during sepsis by upregulating miR-29a-5p, which suppresses NLRP3 expression.
- The miR-29a-5p/NLRP3 axis is a key pathway mediating E2's anti-inflammatory action in sepsis.
- Targeting miR-29a-5p represents a promising therapeutic strategy for sepsis-induced vascular inflammation.
