HMGB1 release from trophoblasts contributes to inflammation duringBrucella melitensisinfection

Abstract

Brucella melitensis infection causes acute necrotizing inflammation in pregnant animals; however, the pathophysiological mechanisms leading to placentitis are unknown. Here, we demonstrate that high-mobility group box 1 (HMGB1) acts as a mediator of placenta inflammation in B. melitensis-infected pregnant mice model. HMGB1 levels were increased in trophoblasts or placental explant during B. melitensis infection. Inhibition of HMGB1 activity with neutralising antibody significantly reduced the secretion of inflammatory cytokines in B. melitensis-infected trophoblasts or placenta, whereas administration of recombinant HMGB1 (rHMGB1) increased the inflammatory response. Mechanistically, this decreased inflammatory response results from inhibition of HMGB1 activity, which cause the suppression of both mitogen-activated protein kinases and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. Moreover, neutralising antibody to HMGB1 prevented B. melitensis infection-induced activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in trophoblasts. In contrast, in vitro stimulation of trophoblasts with rHMGB1 caused activation of NADPH oxidase and increased the production of ROS, which contributes to high bacterial burden within trophoblasts or placenta. In vivo, treatment with anti-HMGB1 antibody increases the number of Brucella survival within placenta in B. melitensis-infected pregnant mice but successfully reduced the severity of placentitis and abortion. KEYWORDS Brucella, HMGB1, inflammatory response, placentitis, trophoblast 1 | INTRODUCTION Brucellosis is a zoonotic disease of worldwide distribution caused by the facultative intracellular bacteria Brucella, which affects both human and animal and inflicts public health and economical burden in endemic areas (Celli, 2015). Although brucellosis in human is characterized by a chronic debilitating disease, brucellosis causes abortion and sterility in animal. However, the underlying mechanism by which Brucella infection induces animal abortion remains unknown. Better understanding of Brucella pathogenesis in placenta is essential for the development of effective treatments for prevention of abortion or infection within the herd. During pregnancy in natural hosts, Brucella strains can infect and replicate within placental trophoblasts, which are originated from the fetus, form the outer layer of the blastocyst within the placenta, and provide nutrients to the embryo (Wang et al., 2016). The highly Brucella-infected trophoblasts in placenta can lead to cell death, which might be helpful to recruit neutrophils, the cell type mediating the histopathology of Brucella-induced placentitis. Brucella abortus infection-induced acute necrotizing inflammation of the placenta

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“… 16 HMGB1 plays a positive role in a variety of malignant tumor behaviors. 10 , 17 It has been suggested that HMGB1 expression is abnormally high in various tumor tissues.…”

“…16 HMGB1 plays a positive role in a variety of malignant tumor behaviors. 10,17 It has been suggested that HMGB1 expression is abnormally high in various tumor tissues. This research initially confirmed that HMGB1 expression was upregulated in lung cancer tissues.…”

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