17β-Estradiol Attenuates LPS-Induced Macrophage Inflammation In Vitro and Sepsis-Induced Vascular Inflammation In Vivo by Upregulating miR-29a-5p Expression

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.

aveExpression of mir-29a-5p, sclerostin and fetuin-A in patients with chronic kidney disease and their correlation with vascular calcification

“…As shown in Table 1, miR-29a-5p and sclerostin showed higher expression, but the fetuin-A expression was lower in the study group than in the control group, indicating seases, as reported in several studies (11). In this study, miR-29a-5p was further found to be highly expressed in CKD patients and positively correlated with vascular calcification (r=0.695, p=0.001) as its expression increased when patients developed vascular calcification.…”

Estrogen receptor subtype mediated anti-inflammation and vasorelaxation via genomic and nongenomic actions in septic mice

“…It was found that E 2 can modulate the expression of the inflammatory factors in immune cells to exert beneficial effects. ( 9 , 15 ) Although inflammatory factors can impair vascular functions to prompt the development of pathophysiological progression,( 16 ) it remains a mystery for E 2 to modulate inflammatory factors in vascular endothelial cells.…”

Estrogen-sensitive activation of SGK1 induces M2 macrophages with anti-inflammatory properties and a Th2 response at the maternal–fetal interface

“…Moreover, in studies on the critical roles of trophoblasts in the pathogenesis of RPL, LPS-induced M1 macrophage polarization suppressed trophoblast migration and invasion [ 13 , 22 ]. Interestingly, 17ß-estradiol (E 2 ) has been reported to attenuate LPS-induced elevation of TLR4 and macrophage inflammation [ 23 , 24 ]. Recently, E 2 was demonstrated to facilitate the resolution of pro-inflammation conditions by enhancing the polarization of M1 to M2 macrophages, thereby conferring cardioprotection [ 25 ].…”