Cold Stress Induced Liver Injury of Mice through Activated NLRP3/Caspase-1/GSDMD Pyroptosis Signaling Pathway

Abstract

The body needs to generate heat to ensure basic life activities when exposed to cold temperatures. The liver, as the largest glycogen storage organ in the body and main heat-producing organ at rest, may play a role in chronic cold exposure. Recent studies suggested that pyroptosis plays a crucial role in liver diseases. However, the role of pyroptosis in cold stress-induced liver injury is not clear. Hence, in this study, we attempted to investigate the effects of chronic cold exposure on liver function, apoptosis, oxidative stress and inflammation in mice by establishing a mouse model of chronic cold exposure, and to investigate whether pyroptosis pathways are involved in the process of chronic cold exposure. In vivo, our results show that inflammatory cell infiltration and other pathological changes in liver cells and the activity of liver enzyme evidently increased in the serum and liver of cold-exposed mice, suggesting cold stress may result in liver injury. Remarkably, increased expression of heat shock protein 70 (HSP70) and HSP90 proteins proved the cold stress model is successfully constructed. Then, elevated levels of apoptosis, inflammation, oxidative stress and pyroptosis related proteins and mRNAs, such as cysteinyl aspartate specific proteinase-3 (Caspase-3), inducible nitric oxide synthase (iNOS), nuclear factor erythroid2-related factor 2 (Nrf2) and gasdermins D (GSDMD), confirmed that cold exposure activated apoptosis, oxidative stress and pyroptosis, and released inflammation cytokines. Meanwhile, in vitro, we got similar results as in vivo. Further, adding an NLR family pyrin domain containing 3 (NLRP3) inhibitors found that suppression expression of NLRP3 results in the essential proteins of pyroptosis and antioxidant evidently reduced, and adding GSDMD inhibitor found that suppression expression of GSDMD accompanies with the level of Nrf2 and heme oxygenase-1 (HO-1) obviously reduced. In summary, these findings provide a new understanding of the underlying mechanisms of the cold stress response, which can inform the development of new strategies to combat the effects of hypothermia.

A Preliminary Study of Mild Heat Stress on Inflammasome Activation in Murine Macrophages

“…Our findings fit in with previous observations that inflammasome function is sensitive to temperature, both hypothermic and hyperthermic [ 19 , 25 , 28 , 29 , 30 , 31 , 32 , 33 ]. Notably, mutations in NLRP3 (first discovered as cryopyrin) are responsible for a group of disorders known as cryopyrin-associated autoinflammatory syndromes (CAPS) [ 19 ].…”

“…Karasawa et al recently discovered that mutant NLRP3 aggregates in the cold to nucleate inflammasome assembly and activation, explaining some of the characteristic cold-induced inflammation in a subtype of CAPS [ 19 ]. Consistently, severe hypothermia (4 °C) was associated with increased inflammasome activation in a model of cold-stress-induced liver injury in mice [ 30 ]. However, as opposed to severe hypothermia (4 °C), several studies have shown that mild hypothermia (32–34 °C) inhibits inflammasome function in WT cells and rats [ 29 , 31 , 33 ].…”

Glucose supplementation improves intestinal amino acid transport and muscle amino acid pool in pigs during chronic cold exposure

“…Early data have certainly established that cold stress in livestock is common in winter ( Young, 1983 ). Recent studies have shown that long-term exposure of animals to low temperatures inhibits growth, along with adverse effects such as inflammation ( Liu et al., 2019 , 2022 ; Luo et al., 2019 ). As the building blocks of peptides and proteins, AA are necessary for all life-sustaining processes.…”

“…Extensive data have confirmed that cold limits animal growth and increases feed intake ( Bayril et al., 2020 ; Toghiani et al., 2020 ). More worryingly, long-term cold exposure induces oxidative stress and inflammation in organs, even causing death in animals ( Liu et al., 2019 , 2022 ; Luo et al., 2019 ). Adaptation to low ambient temperature is one of the mechanisms vital to the survival of mammals.…”

Whole genome sequencing identified genomic diversity and candidated genes associated with economic traits in Northeasern Merino in China

“…Additionally, GO enriched to “heat shock protein binding, GO:0031072”, which is associated with heat shock protein binding activity ( Yue et al, 2020 ). It has been reported that the expression of heat shock proteins is increased in mice exposed to cold stimuli ( Liu et al, 2022b ). This phenomenon has also been observed in goats and the expression of the heat shock protein 70 gene is breeds specific ( Banerjee et al, 2014 ).…”