Endoplasmic reticulum stress may activate NLRP3 inflammasomes via TXNIP in preeclampsia

Abstract

Preeclampsia (PE) development is often associated with placental immune and inflammatory dysregulation, as well as endoplasmic reticulum (ER) stress. However, the mechanisms linking ER stress and inflammatory dysregulation to PE have not been clarified. It has been reported that thioredoxin-interacting protein (TXNIP), which can bind with and activate the NLR family pyrin domain containing 3 (NLRP3) inflammasome, plays a critical role in immune regulation. Recent experimental evidence suggests that activated NLRP3 inflammasomes can activate interleukin-1β (IL-1β) production in the placenta of patients with PE. The objective of the current study was to explore if TXNIP plays a critical signaling role linking ER stress with NLRP3 inflammasome activation in PE. We hypothesised that ER stress would induce TXNIP production, which would bind with NLRP3 inflammasomes to activate IL-1β production. HTR8/SVneo cells were subjected to six hours hypoxia followed by six hours reoxygenation (H/R). These cells showed a higher protein level of NLRP3 and IL-1β, as well as a higher enzymatic activity of caspase-1, indicating enhanced inflammatory dysregulation and ER stress. Cells transfected with TXNIP siRNA showed reduced NLRP3 inflammasome activation. Cells treated with 4-phenylbutyric acid, an inhibitor of ER stress, showed a similar result. In addition, the outgrowth of explant with TXNIP lentivirus in H/R or Tunicamycin (inducers of ER stress) was also measured to verify our hypothesis. These findings demonstrated that TXNIP could influence inflammatory dysregulation by mediating ER stress and NLRP3 inflammasome activation in PE. This novel mechanism may further explain the inflammation observed at the maternal-fetal interface, which leads to placental dysfunction in a patient with PE.

Thioredoxin interacting protein protects mice from fasting induced liver steatosis by activating ER stress and its downstream signaling pathways

“…In addition, gene expression of ATF6 and protein expression of cATF6 were significantly lower in TXNIP-KO mice in fasted state and this is also important, because there is a report indicating autophagy is activated by the signal downstream of AFT6 46 . Although TXNIP has been suggested as a downstream protein of ER stress 47 – 49 , our results strongly suggest TXNIP to be one of the proteins regulating ER stress signaling in the mouse liver under fasted conditions.…”

Relevance of NLRP3 Inflammasome-Related Pathways in the Pathology of Diabetic Wound Healing and Possible Therapeutic Targets

“…In addition, since they act as K+ efflux channels, tandem pore domains in the weak inward rectifying K+ channel 2 (TWIK2) and P2X7 receptor (P2X7R) are necessary for this process [ 18 , 19 ]. Similarly, an increase in intracellular Ca2+ concentration induced by endoplasmic reticulum (ER) Ca2+ release can also activate the assembly of the NLRP3 inflammasome through thioredoxin-interacting protein (TXNIP) [ 20 , 21 ]. Furthermore, the exogenous and endogenous stimuli could induce the generation of mitochondrial reactive oxygen species (mtROS) by activating oxidative systems and thereby promote assembly and activation of NLRP3 inflammasome.…”

The Inflammasome in Reproductive Biology: A Promising Target for Novel Therapies

“…Future research should take a deeper look into the potential mechanisms of inflammasome activation such as extracellular potassium levels (22); the role of oxidative stress on inflammasome activation (49,50); or whether the inflammasome-mediated process of pyroptosis, or the non-canonical inflammasome pathways, involving caspase-11 in rodents (caspase-4/5 in humans), or caspase-8 are involved in conditions associated with reproduction. To this extent, a recent article has been published showing that hypoxia and endoplasmic reticulum stress activate the NLRP3 inflammasome in primary human trophoblasts, resulting in increased expression of Thioredoxin-interacting protein (TXNIP), a key regulator of inflammasome activation (51). Moreover, these findings were consistent with increased cleavage of caspase-1 and GSDM-D, thus indicating that placental pyroptosis contributes to the systemic release of factors involved in preeclampsia (52).…”