Thymic stromal lymphopoietin participates in the host response to intra-amniotic inflammation leading to preterm labor and birth

Kanninen, Tomi T.; Li, Tao; Romero, Roberto; Xu, Yi; Arenas‐Hernandez, Marcia; Galaz, José; Liu, Zhenjie; Miller, Derek; Levenson, Dustyn; Greenberg, Jonathan M.; Panzer, Jonathan; Padron, Justin; Theis, Kevin R.; Gomez‐Lopez, Nardhy

doi:10.1016/j.humimm.2023.06.005

Cited by 1 publication

(1 citation statement)

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“…RAGE can also bind PAMPs, such as LPS and bacterial/viral DNA [26,27,39,40], and DAMPs, such as HMGB1 and cffDNA [25,[41][42][43][44][45]. Thus, in the presence of cellular stressors, such as stretch, OS, and infection, hAECs have been shown to induce a proinflammatory stress response marked by NF-κB activation, secretion of proinflammatory cytokines, and secretion of HMGB1 and cffDNA in vitro [11,[46][47][48][49]. In addition to cffDNA, the receptors RAGE and TLR-9 have been shown to bind HMGB1 or HMGB1 complexes with cffDNA.…”

Section: Discussionmentioning

confidence: 99%

Stretch Causes cffDNA and HMGB1-Mediated Inflammation and Cellular Stress in Human Fetal Membranes

Padron,

Saito Reis,

et al. 2024

IJMS

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Danger-associated molecular patterns (DAMPs) are elevated within the amniotic cavity, and their increases correlate with advancing gestational age, chorioamnionitis, and labor. Although the specific triggers for their release in utero remain unclear, it is thought that they may contribute to the initiation of parturition by influencing cellular stress mechanisms that make the fetal membranes (FMs) more susceptible to rupture. DAMPs induce inflammation in many different tissue types. Indeed, they precipitate the subsequent release of several proinflammatory cytokines that are known to be key for the weakening of FMs. Previously, we have shown that in vitro stretch of human amnion epithelial cells (hAECs) induces a cellular stress response that increases high-mobility group box-1 (HMGB1) secretion. We have also shown that cell-free fetal DNA (cffDNA) induces a cytokine response in FM explants that is fetal sex-specific. Therefore, the aim of this work was to further investigate the link between stretch and the DAMPs HMGB1 and cffDNA in the FM. These data show that stretch increases the level of cffDNA released from hAECs. It also confirms the importance of the sex of the fetus by demonstrating that female cffDNA induced more cellular stress than male fetuses. Our data treating hAECs and human amnion mesenchymal cells with HMGB1 show that it has a differential effect on the ability of the cells of the amnion to upregulate the proinflammatory cytokines and propagate a proinflammatory signal through the FM that may weaken it. Finally, our data show that sulforaphane (SFN), a potent activator of Nrf2, is able to mitigate the proinflammatory effects of stretch by decreasing the levels of HMGB1 release and ROS generation after stretch and modulating the increase of key cytokines after cell stress. HMGB1 and cffDNA are two of the few DAMPs that are known to induce cytokine release and matrix metalloproteinase (MMP) activation in the FMs; thus, these data support the general thesis that they can function as potential central players in the normal mechanisms of FM weakening during the normal distension of this tissue at the end of a normal pregnancy.

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