Estrogen plays an important role by influencing the NLRP3 inflammasome

Dong, Wanglin; Peng, Qianwen; Liu, Zhuoxin; Xie, Zhenxing; Guo, Xiajun; Li, Yuanyuan; Chen, Chaoran

doi:10.1016/j.biopha.2023.115554

Cited by 11 publications

(3 citation statements)

References 224 publications

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“…In particular, our analysis of the Human Atlas database reveals that increased transcriptional levels of inflammasome-related genes, altered by sorafenib treatment, are associated with an unfavorable prognosis in HCC patients, specifically in men. This observation suggests a potential sex-dependent role for inflammasome activation in HCC therapy, in line with reports pointing to an estrogenic control of inflammasome activity [35]. Therefore, genderspecific considerations in inflammasome-based therapeutic strategies are required when searching for a specific inflammasome signature and its association with treatment efficacy.…”

Section: Discussionsupporting

confidence: 76%

Induction of the Inflammasome Pathway by Tyrosine Kinase Inhibitors Provides an Actionable Therapeutic Target for Hepatocellular Carcinoma

Tutusaus,

Sanduzzi-Zamparelli,

Boix

et al. 2024

Cancers

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During the last decade, tyrosine kinase inhibitors (TKIs) sorafenib and regorafenib have been standard systemic treatments for advanced hepatocellular carcinoma (HCC). Previous data associated sorafenib with inflammasome activation. However, the role of the inflammasome in sorafenib and regorafenib signaling has not been described in liver cancer patients. For this purpose, we analyzed inflammasome-related transcriptomic changes in a murine HCC model. Our data confirmed inflammasome activation after both TKI treatments, sharing a similar pattern of increased gene expression. According to human database results, transcriptional increase of inflammasome genes is associated with poorer prognosis for male liver cancer patients, suggesting a sex-dependent role for inflammasome activation in HCC therapy. In biopsies of HCC and its surrounding tissue, we detected durable increases in the inflammasome activation pattern after sorafenib or regorafenib treatment in male patients. Further supporting its involvement in sorafenib action, inflammasome inhibition (MCC950) enhanced sorafenib anticancer activity in experimental HCC models, while no direct in vitro effect was observed in HCC cell lines. Moreover, activated human THP-1 macrophages released IL-1β after sorafenib administration, while 3D Hep3B spheres displayed increased tumor growth after IL-1β addition, pointing to the liver microenvironment as a key player in inflammasome action. In summary, our results unveil the inflammasome pathway as an actionable target in sorafenib or regorafenib therapy and associate an inflammasome signature in HCC and surrounding tissue with TKI administration. Therefore, targeting inflammasome activation, principally in male patients, could help to overcome sorafenib or regorafenib resistance and enhance the efficacy of TKI treatments in HCC.

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Section: Discussionsupporting

confidence: 76%

Induction of the Inflammasome Pathway by Tyrosine Kinase Inhibitors Provides an Actionable Therapeutic Target for Hepatocellular Carcinoma

Tutusaus,

Sanduzzi-Zamparelli,

Boix

et al. 2024

Cancers

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“…In contrast, Chen et al found that the NLRP3 inflammasome exerts a more significant influence on high fat diet-induced atherosclerosis in female than male mice [ 94 ]. This suggests sex-dependent variations in the inflammasome’s response to diverse inflammatory stimuli, largely due to the regulatory effects of sex hormones [ 95 – 98 ]. Considering that inflammasome signaling proteins caspase-1, ASC, and IL-1β are increased in the cortex of aged female mice compared to aged male mice [ 99 ], further studies would benefit from a longer timeline or the use of ovariectomized female mice to test whether our phenotype is estrogen-dependent.…”

Section: Discussionmentioning

confidence: 99%

Sex-dependent effects of carbohydrate source and quantity on caspase-1 activity in the mouse central nervous system

Valiauga,

Talley,

Khemmani

et al. 2024

J Neuroinflammation

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Background Mounting evidence links glucose intolerance and diabetes as aspects of metabolic dysregulation that are associated with an increased risk of developing dementia. Inflammation and inflammasome activation have emerged as a potential link between these disparate pathologies. As diet is a key factor in both the development of metabolic disorders and inflammation, we hypothesize that long term changes in dietary factors can influence nervous system function by regulating inflammasome activity and that this phenotype would be sex-dependent, as sex hormones are known to regulate metabolism and immune processes. Methods 5-week-old male and female transgenic mice expressing a caspase-1 bioluminescent reporter underwent cranial window surgeries and were fed control (65% complex carbohydrates, 15% fat), high glycemic index (65% carbohydrates from sucrose, 15% fat), or ketogenic (1% complex carbohydrates, 79% fat) diet from 6 to 26 weeks of age. Glucose regulation was assessed with a glucose tolerance test following a 4-h morning fast. Bioluminescence in the brain was quantified using IVIS in vivo imaging. Blood cytokine levels were measured using cytokine bead array. 16S ribosomal RNA gene amplicon sequencing of mouse feces was performed to assess alterations in the gut microbiome. Behavior associated with these dietary changes was also evaluated. Results The ketogenic diet caused weight gain and glucose intolerance in both male and female mice. In male mice, the high glycemic diet led to increased caspase-1 biosensor activation over the course of the study, while in females the ketogenic diet drove an increase in biosensor activation compared to their respective controls. These changes correlated with an increase in inflammatory cytokines present in the serum of test mice and the emergence of anxiety-like behavior. The microbiome composition differed significantly between diets; however no significant link between diet, glucose tolerance, or caspase-1 signal was established. Conclusions Our findings suggest that diet composition, specifically the source and quantity of carbohydrates, has sex-specific effects on inflammasome activation in the central nervous system and behavior. This phenotype manifested as increased anxiety in male mice, and future studies are needed to determine if this phenotype is linked to alterations in microbiome composition.

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“…Why only ~70% of female RA patients undergo remission is unknown, but certainly, pregnancy is known to lead to a downregulation of inflammatory responses, possibly to better carry an allogeneic fetus. Whatever the mechanism(s) that are involved, such findings do indicate that the regulation of inflammatory processes is different in males and females, and inflammatory processes developing in the post-menopausal state may be indirectly related to reproductive functions [75,76]. Thus, future considerations should investigate the potential efficacy of anti-inflammatory therapies in the onset and progression of several of the post-menopausal onset conditions and diseases.…”

Section: Variables and Factors Influencing Post-menopause Diseases An...mentioning

confidence: 99%

The Heterogeneity of Post-Menopausal Disease Risk: Could the Basis for Why Only Subsets of Females Are Affected Be Due to a Reversible Epigenetic Modification System Associated with Puberty, Menstrual Cycles, Pregnancy and Lactation, and, Ultimately, Menopause?

Hart

2024

IJMS

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For much of human evolution, the average lifespan was <40 years, due in part to disease, infant mortality, predators, food insecurity, and, for females, complications of childbirth. Thus, for much of evolution, many females did not reach the age of menopause (45–50 years of age) and it is mainly in the past several hundred years that the lifespan has been extended to >75 years, primarily due to public health advances, medical interventions, antibiotics, and nutrition. Therefore, the underlying biological mechanisms responsible for disease risk following menopause must have evolved during the complex processes leading to Homo sapiens to serve functions in the pre-menopausal state. Furthermore, as a primary function for the survival of the species is effective reproduction, it is likely that most of the advantages of having such post-menopausal risks relate to reproduction and the ability to address environmental stresses. This opinion/perspective will be discussed in the context of how such post-menopausal risks could enhance reproduction, with improved survival of offspring, and perhaps why such risks are preserved. Not all post-menopausal females exhibit risk for this set of diseases, and those who do develop such diseases do not have all of the conditions. The diseases of the post-menopausal state do not operate as a unified complex, but as independent variables, with the potential for some overlap. The how and why there would be such heterogeneity if the risk factors serve essential functions during the reproductive years is also discussed and the concept of sets of reversible epigenetic changes associated with puberty, pregnancy, and lactation is offered to explain the observations regarding the distribution of post-menopausal conditions and their potential roles in reproduction. While the involvement of an epigenetic system with a dynamic “modification-demodification-remodification” paradigm contributing to disease risk is a hypothesis at this point, validation of it could lead to a better understanding of post-menopausal disease risk in the context of reproduction with commonalities may also lead to future improved interventions to control such risk after menopause.

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Estrogen plays an important role by influencing the NLRP3 inflammasome

Cited by 11 publications

References 224 publications

Induction of the Inflammasome Pathway by Tyrosine Kinase Inhibitors Provides an Actionable Therapeutic Target for Hepatocellular Carcinoma

Induction of the Inflammasome Pathway by Tyrosine Kinase Inhibitors Provides an Actionable Therapeutic Target for Hepatocellular Carcinoma

Sex-dependent effects of carbohydrate source and quantity on caspase-1 activity in the mouse central nervous system

The Heterogeneity of Post-Menopausal Disease Risk: Could the Basis for Why Only Subsets of Females Are Affected Be Due to a Reversible Epigenetic Modification System Associated with Puberty, Menstrual Cycles, Pregnancy and Lactation, and, Ultimately, Menopause?

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