bims-kimdis 2024-01-28 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024‒01‒28
fifteen papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

A ketogenic diet lowers myocardial fatty acid oxidation but does not affect oxygen consumption: a study in overweight humans.
Methodological Challenges and Confounders in Research on the Effects of Ketogenic Diets: A Literature Review of Meta-Analyses.
Emerging pathophysiological roles of ketone bodies.
Low-carbohydrate diet as a nutritional intervention in a major depression disorder: focus on relapse prevention.
Arachidonic acid inhibition of the NLRP3 inflammasome is a mechanism to explain the anti-inflammatory effects of fasting.
Dietary β-hydroxybutyric acid improves the growth performance of young ruminants based on rumen microbiota and volatile fatty acid biosynthesis.
Very low-carbohydrate diet with higher protein ratio improves lipid metabolism and inflammation in rats with diet-induced nonalcoholic fatty liver disease.
A Novel Acetone Sensor for Body Fluids.
Molecular crosstalk between circadian clock and NLRP3 inflammasome signaling in Parkinson's disease.
INVITED REVIEW: Ketone biology: the shifting paradigm of ketones and ketosis in the dairy cow.
Fasting diets: what are the impacts on eating behaviors, sleep, mood, and well-being?
Mitochondrial translocation of TFEB regulates complex I and inflammation.
Effect of Calorie Restriction and Intermittent Fasting Regimens on Brain-Derived Neurotrophic Factor Levels and Cognitive Function in Humans: A Systematic Review.
NLRP12 interacts with NLRP3 to block the activation of the human NLRP3 inflammasome.
The potential role of Hippo pathway regulates cellular metabolism via signaling crosstalk in disease-induced macrophage polarization.

Obesity (Silver Spring). 2024 Jan 23.

A ketogenic diet lowers myocardial fatty acid oxidation but does not affect oxygen consumption: a study in overweight humans.

Thien Vinh Luong, Mette Glavind Bülow Pedersen, Caroline Bruun Abild, Stephen C Cunnane, Etienne Croteau, Katrine Meyer Lauritsen, Mette Louise Gram Kjaerulff, Lars Poulsen Tolbod, Niels Møller, Esben Søndergaard, Lars Christian Gormsen.

OBJECTIVE: A ketogenic diet (KD) characterized by very low carbohydrate intake and high fat consumption may simultaneously induce weight loss and be cardioprotective. The "thrifty substrate hypothesis" posits that ketone bodies are more energy efficient compared with other cardiac oxidative substrates such as fatty acids. This work aimed to study whether a KD with presumed increased myocardial ketone body utilization reduces cardiac fatty acid uptake and oxidation, resulting in decreased myocardial oxygen consumption (MVO2 ).METHODS: This randomized controlled crossover trial examined 11 individuals with overweight or obesity on two occasions: (1) after a KD and (2) after a standard diet. Myocardial free fatty acid (FFA) oxidation, uptake, and esterification rate were measured using dynamic [11 C]palmitate positron emission tomography (PET)/computed tomography, whereas MVO2 and myocardial external efficiency (MEE) were measured using dynamic [11 C]acetate PET.
RESULTS: The KD increased plasma β-hydroxybutyrate, reduced myocardial FFA oxidation (p < 0.01) and uptake (p = 0.03), and increased FFA esterification (p = 0.03). No changes were observed in MVO2 (p = 0.2) or MEE (p = 0.87).
CONCLUSIONS: A KD significantly reduced myocardial FFA uptake and oxidation, presumably by increasing ketone body oxidation. However, this change in cardiac substrate utilization did not improve MVO2 , speaking against the thrifty substrate hypothesis.

DOI: https://doi.org/10.1002/oby.23967
Foods. 2024 Jan 12. pii: 248. [Epub ahead of print]13(2):

Methodological Challenges and Confounders in Research on the Effects of Ketogenic Diets: A Literature Review of Meta-Analyses.

Katalin Szendi, Edit Murányi, Nicole Hunter, Balázs Németh.

  Several meta-analyses have found a positive association between a popular type of "fad diet", ketogenic diets, and their effect on anthropometric and blood parameters. However, the non-specific inclusion criteria for meta-analyses may lead to incorrect conclusions. The aim of this literature review is to highlight the main confounders and methodological pitfalls of meta-analyses on ketogenic diets by inspecting the presence of key inclusion criteria. The PubMed, Embase, and Web of Science databases and the Cochrane Database of Systematic Reviews were searched for meta-analyses. Most meta-analyses did not define the essential parameters of a ketogenic diet (i.e., calories, macronutrient ratio, types of fatty acids, ketone bodies, etc.) as inclusion criteria. Of the 28 included meta-analyses, few addressed collecting real, re-measured nutritional data from the ketogenic diet and control groups in parallel with the pre-designed nutritional data. Most meta-analyses reported positive results in favor of ketogenic diets, which can result in erroneous conclusions considering the numerous methodological pitfalls and confounders. Well-designed clinical trials with comparable results and their meta-analyses are needed. Until then, medical professionals should not recommend ketogenic diets as a form of weight loss when other well-known dietary options have been shown to be healthy and effective.

Keywords:  caloric intake; confounder; fad diet; ketogenic diet; ketone bodies; literature review; meta-analysis; types of fatty acids

DOI:  https://doi.org/10.3390/foods13020248
Physiology (Bethesda). 2024 Jan 23.

Emerging pathophysiological roles of ketone bodies.

Hiroaki Tsuruta, Kosuke Yamahara, Mako Yasuda-Yamahara, Shinji Kume.

  The discovery of insulin approximately a century ago greatly improved the management of diabetes, including many of its life-threatening acute complications like ketoacidosis. This breakthrough saved many lives and extended the healthy lifespan of many patients with diabetes. However, there is still a negative perception of ketone bodies stemming from ketoacidosis. Originally, ketone bodies were thought of as a vital source of energy during fasting and exercise. Furthermore, in recent years, research on calorie restriction and its potential impact on extending healthy lifespans, as well as studies on ketone bodies, have gradually led to a reevaluation of the significance of ketone bodies in promoting longevity. Thus, in this review we discuss the emerging and hidden roles of ketone bodies in various organs, including the heart, kidneys, skeletal muscles, and brain, as well as their potential impact on malignancies and lifespan.

Keywords:  Fuel metabolism; HMGCS2; Ketone bodies; Ketongenic diet; Longevity

DOI:  https://doi.org/10.1152/physiol.00031.2023
Nutr Neurosci. 2024 Jan 21. 1-14

Low-carbohydrate diet as a nutritional intervention in a major depression disorder: focus on relapse prevention.

Michał Walaszek, Zofia Kachlik, Wiesław Jerzy Cubała.

  Objectives: Mood disorders are trending to be among the leading causes of years lived with disability. Despite multiple treatment options, around 30% patients with major depressive disorder (MDD) develop treatment resistant depression (TRD) and fail to respond to current pharmacological therapies. This study aimed to explore the potential benefits of nutritional treatment strategies, along with their molecular mechanisms of action, focusing especially on low-carbohydrate diet (LCHD), ketogenic diet (KD) and other strategies based on carbohydrates intake reduction.Methods: A comprehensive literature review was conducted to determine the impact of LCHD on alleviating depressive symptoms in patients with MDD, along with an explanation of its mode of action.Results: The study revealed significant impact of nutritional interventions based on restriction in carbohydrate intake such as LCHD, KD or sugar-sweetened beverages (SSB) exclusion on anxiety or depression symptoms reduction, mood improvement and lower risk of cognitive impairment or depression. The efficacy of these approaches is further substantiated by their underlying molecular mechanisms, mainly brain-derived neurotrophic factor (BDNF) which is a potential key target of sugar restriction diets in terms of neuroplasticity.Discussion: Healthcare professionals may consider implementing LCHD strategies for MDD and TRD patients to modify the disease process, maintain euthymia, and prevent depressive episode relapses. Ranging from the exclusion of SSB to the adherence to rigorous LCHD regimens, these nutritional approaches are safe, straightforward to implement, and may confer benefits for well-being and relapse prevention in this specific patient population.

Keywords:  BDNF; Depression; MDD; ketogenic diet; low-carbohydrate diet; neuroplasticity; nutritional psychiatry; relapse prevention

DOI:  https://doi.org/10.1080/1028415X.2024.2303218
Cell Rep. 2024 Jan 23. pii: S2211-1247(24)00028-7. [Epub ahead of print]43(2): 113700

Arachidonic acid inhibition of the NLRP3 inflammasome is a mechanism to explain the anti-inflammatory effects of fasting.

Milton Pereira, Jonathan Liang, Joy Edwards-Hicks, Allison M Meadows, Christine Hinz, Sonia Liggi, Matthias Hepprich, Jonathan Mudry, Kim Han, Julian L Griffin, Iain Fraser, Michael N Sack, Christoph Hess, Clare E Bryant.

  Elevated interleukin (IL)-1β levels, NLRP3 inflammasome activity, and systemic inflammation are hallmarks of chronic metabolic inflammatory syndromes, but the mechanistic basis for this is unclear. Here, we show that levels of plasma IL-1β are lower in fasting compared to fed subjects, while the lipid arachidonic acid (AA) is elevated. Lipid profiling of NLRP3-stimulated mouse macrophages shows enhanced AA production and an NLRP3-dependent eicosanoid signature. Inhibition of cyclooxygenase by nonsteroidal anti-inflammatory drugs decreases eicosanoid, but not AA, production. It also reduces both IL-1β and IL-18 production in response to NLRP3 activation. AA inhibits NLRP3 inflammasome activity in human and mouse macrophages. Mechanistically, AA inhibits phospholipase C activity to reduce JNK1 stimulation and hence NLRP3 activity. These data show that AA is an important physiological regulator of the NLRP3 inflammasome and explains why fasting reduces systemic inflammation and also suggests a mechanism to explain how nonsteroidal anti-inflammatory drugs work.

Keywords:  CP: Immunology; CP: Metabolism; NLRP3; eicosanoids; inflammasome; inflammation; lipidomics; metaflammation; prostaglandins

DOI:  https://doi.org/10.1016/j.celrep.2024.113700
Front Microbiol. 2023 ;14 1296116

Dietary β-hydroxybutyric acid improves the growth performance of young ruminants based on rumen microbiota and volatile fatty acid biosynthesis.

Jianmin Chai, Zeyue Liu, Jun Wu, Yuan Kang, Mahmoud M Abdelsattar, Wei Zhao, Shiqin Wang, Shuli Yang, Feilong Deng, Ying Li, Yimin Zhuang, Naifeng Zhang.

  Introduction: The ketone body β-hydroxybutyric acid (BHB) plays critical roles in cellular proliferation and metabolic fuel utilization; however, its effects on the rumen microbiota remain unknown.Methods: Here, three doses of BHB (low, medium, and high) were supplemented to early-weaned goat kids.
Results: Compared with controls, the beneficial effects of BHB on growth and rumen development were observed in goats at 90 days of age (d). The low dose of dietary BHB increased the concentration of rumen acetate, propionate, and butyrate on d90. The sequencing results of the rumen microbiota revealed marked shifts in rumen microbial community structure after early-weaned goat kids consumed BHB for 2 months. The signature bacterial ASVs for each treatment were identified and were the main drivers contributing to microbial interactions in the rumen. The bacteria associated with rumen weight were also correlated with body weight. Some classified bacterial signatures, including Prevotella, Olsenella umbonate, and Roseburia faecis, were related to rumen volatile fatty acids and host development.
Conclusion: Overall, dietary BHB altered rumen microbiota and environments in young goats, which contributed to rumen development and growth.

Keywords:  goats; growth; rumen microbiota; volatile fatty acids; β-hydroxybutyric acid

DOI:  https://doi.org/10.3389/fmicb.2023.1296116
J Nutr Biochem. 2024 Jan 18. pii: S0955-2863(24)00016-0. [Epub ahead of print] 109583

Very low-carbohydrate diet with higher protein ratio improves lipid metabolism and inflammation in rats with diet-induced nonalcoholic fatty liver disease.

I-Ting Wu, Wan-Ju Yeh, Wen-Chih Huang, Hsin-Yi Yang.

  Non-alcoholic fatty liver disease (NAFLD) is commonly associated with obesity, and it is mainly treated through lifestyle modifications. The very low-carbohydrate diet (VLCD) can help lose weight rapidly but the possible effects of extreme dietary patterns on lipid metabolism and inflammatory responses in individuals with NAFLD remain debatable. Moreover, VLCD protein content may affect its effectiveness in weight loss, steatosis, and inflammatory responses. Therefore, we investigated the effects of VLCDs with different protein contents in NAFLD rats and the mechanisms underlying these effects. After a 16-week inducing period, the rats received an isocaloric normal diet (NC group) or a VLCD with high or low protein content (NVLH vs. NVLL group, energy ratio: protein/carbohydrate/lipid = 20/1/79 vs. 6/1/93) protein content for the next 8 weeks experimental period. We noted that the body weight decreased in both the NVLH and NVLL groups; nevertheless, the NVLH group demonstrated improvements in ketosis. The NVLL group led to hepatic lipid accumulation, possibly by increasing very-low-density lipoprotein receptor (VLDLR) expression and elevating liver oxidative stress, subsequently activating the expression of Nrf2, and inflammation through the TLR4/TRIF/NLRP3 and TLR4/MyD88/NF-κB pathway. The NVLH was noted to prevent the changes in VLDLR and the TLR4-inflammasome pathway partially. The VLCD also reduced the diversity of gut microbiota and changed their composition. In conclusion, although low-protein VLCD consumption reduces BW, it may also lead to metabolic disorders and changes in microbiota composition; nevertheless, a VLCD with high protein content may partially alleviate these limitations.

Keywords:  Gut microbiota; Inflammation; Nonalcoholic fatty liver disease; Protein; Steatosis; Very low-carbohydrate diet

DOI:  https://doi.org/10.1016/j.jnutbio.2024.109583
Biosensors (Basel). 2023 Dec 22. pii: 4. [Epub ahead of print]14(1):

A Novel Acetone Sensor for Body Fluids.

Oscar Osorio Perez, Ngan Anh Nguyen, Asher Hendricks, Shaun Victor, Sabrina Jimena Mora, Nanxi Yu, Xiaojun Xian, Shaopeng Wang, Doina Kulick, Erica Forzani.

  Ketones are well-known biomarkers of fat oxidation produced in the liver as a result of lipolysis. These biomarkers include acetoacetic acid and β-hydroxybutyric acid in the blood/urine and acetone in our breath and skin. Monitoring ketone production in the body is essential for people who use caloric intake deficit to reduce body weight or use ketogenic diets for wellness or therapeutic treatments. Current methods to monitor ketones include urine dipsticks, capillary blood monitors, and breath analyzers. However, these existing methods have certain disadvantages that preclude them from being used more widely. In this work, we introduce a novel acetone sensor device that can detect acetone levels in breath and overcome the drawbacks of existing sensing approaches. The critical element of the device is a robust sensor with the capability to measure acetone using a complementary metal oxide semiconductor (CMOS) chip and convenient data analysis from a red, green, and blue deconvolution imaging approach. The acetone sensor device demonstrated sensitivity of detection in the micromolar-concentration range, selectivity for detection of acetone in breath, and a lifetime stability of at least one month. The sensor device utility was probed with real tests on breath samples using an established blood ketone reference method.

Keywords:  breath sensor; digital medicine; fat burning; fat oxidation; ketones; metabolic rate; point of care; wearable sensor

DOI:  https://doi.org/10.3390/bios14010004
Heliyon. 2024 Jan 30. 10(2): e24752

Molecular crosstalk between circadian clock and NLRP3 inflammasome signaling in Parkinson's disease.

Jiahua Huang, Wenwei Li.

  Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Research has recently found that both animal models and patients with PD have circadian dysfunction, accompanied by abnormal expression of circadian genes and proteins, which implies that the circadian clock plays a crucial role in PD etiopathogenesis. In addition, a strong relationship between NLRP3 inflammasome signaling and PD has been observed. Meanwhile, the activation of the NLRP3 inflammasome is highly relevant to dysfunctions of the molecular clock. Therefore, alleviating the neuroinflammation caused by NLRP3 inflammasome signaling by adjusting the abnormal molecular clock may be a potential strategy for preventing and treating PD. In this article, we have reviewed the potential or direct relationship between abnormalities of the circadian clock and NLRP3 inflammasome signaling in PD.

Keywords:  Circadian rhythm; NLRP3 inflammasome; Parkinson's disease

DOI:  https://doi.org/10.1016/j.heliyon.2024.e24752
J Dairy Sci. 2024 Jan 19. pii: S0022-0302(24)00020-1. [Epub ahead of print]

INVITED REVIEW: Ketone biology: the shifting paradigm of ketones and ketosis in the dairy cow.

J Eduardo Rico, Mario A Barrientos-Blanco.

  Ketosis is currently regarded as a major metabolic disorder of dairy cows, reflective of the animal's efforts to adapt to energy deficit while transitioning into lactation. Currently viewed as a pathology by some, ketosis is associatively implicated in milk production losses and peripartal health complications that increase the risk of early removal of cows from the herd, thus carrying economic losses for dairy farmers, and jeopardizing the sustainability of the dairy industry. Despite decades of intense research in the mitigation of ketosis and its sequelae, our ability to lessen its purported impacts remains limited. Moreover, the association of ketosis to reduced milk production and peripartal disease is often erratic and likely mired by concurrent potential confounders. In this review we discuss the potential reasons for these apparent paradoxes in the light of currently available evidence, with a focus on the limitations of observational research, and the necessary steps to unambiguously identify the impacts of ketosis on cow health and performance via controlled randomized experimentation. A nuanced perspective is proposed that considers the dissociation of ketosis -as a disease- from healthy hyperketonemia. Furthermore, in consideration of a growing body of evidence that highlights positives roles of ketones in the mitigation of metabolic dysfunction and chronic diseases, we consider the hypothetical functions of ketones as health-promoting metabolites and ponder on their potential usefulness to enhance dairy cow health and productivity.

Keywords:  Ketosis; dairy cow; hyperketonemia; paradigm shift

DOI:  https://doi.org/10.3168/jds.2023-23904
Front Nutr. 2023 ;10 1256101

Fasting diets: what are the impacts on eating behaviors, sleep, mood, and well-being?

Elham Hosseini, Achraf Ammar, Jessica K Josephson, Deanna L Gibson, Gholamreza Askari, Nicola L Bragazzi, Khaled Trabelsi, Wolfgang I Schöllhorn, Zeinab Mokhtari.

  Fasting diets (FDs) have drawn great attention concerning their contribution to health and disease over the last decade. Despite considerable interest in FDs, the effect of fasting diets on eating behaviors, sleep, and mood-essential components of diet satisfaction and mental health- has not been addressed comprehensively. Understanding the critical role that fasting plays in these elements will open up potential treatment avenues that have not yet been explored. The aim of the present paper was to conduct a comprehensive critical review exploring the effects of fasting on eating behaviors, sleep, and mood. There is currently a lack of clarity regarding which fasting option yields the most advantageous effects, and there is also a scarcity of consistent trials that assess the effects of FDs in a comparable manner. Similarly, the effects and/or treatment options for utilizing FDs to modify eating and sleep behaviors and enhance mood are still poorly understood. Further researches aiming at understanding the impacts of various fasting regimes, providing new insights into the gut-brain axis and offering new treatment avenues for those with resistant anxiety and depression, are warranted. Alteration of eating behaviors can have lasting effects on various physiological parameters. The use of fasting cures can underpin ancient knowledge with scientific evidence to form a new approach to the prevention and treatment of problems associated with co-morbidities or challenges pertaining to eating behaviors. Therefore, a thorough examination of the various fasting regimens and how they impact disease patterns is also warranted.

Keywords:  diet; eating behavior; fasting; mental health; sleep

DOI:  https://doi.org/10.3389/fnut.2023.1256101
EMBO Rep. 2024 Jan 23.

Mitochondrial translocation of TFEB regulates complex I and inflammation.

Chiara Calabrese, Hendrik Nolte, Melissa R Pitman, Raja Ganesan, Philipp Lampe, Raymond Laboy, Roberto Ripa, Julia Fischer, Ruhi Polara, Sameer Kumar Panda, Sandhya Chipurupalli, Saray Gutierrez, Daniel Thomas, Stuart M Pitson, Adam Antebi, Nirmal Robinson.

  TFEB is a master regulator of autophagy, lysosome biogenesis, mitochondrial metabolism, and immunity that works primarily through transcription controlled by cytosol-to-nuclear translocation. Emerging data indicate additional regulatory interactions at the surface of organelles such as lysosomes. Here we show that TFEB has a non-transcriptional role in mitochondria, regulating the electron transport chain complex I to down-modulate inflammation. Proteomics analysis reveals extensive TFEB co-immunoprecipitation with several mitochondrial proteins, whose interactions are disrupted upon infection with S. Typhimurium. High resolution confocal microscopy and biochemistry confirms TFEB localization in the mitochondrial matrix. TFEB translocation depends on a conserved N-terminal TOMM20-binding motif and is enhanced by mTOR inhibition. Within the mitochondria, TFEB and protease LONP1 antagonistically co-regulate complex I, reactive oxygen species and the inflammatory response. Consequently, during infection, lack of TFEB specifically in the mitochondria exacerbates the expression of pro-inflammatory cytokines, contributing to innate immune pathogenesis.

Keywords:  LONP1; Metabolism; Mitochondria; Salmonella; TFEB

DOI:  https://doi.org/10.1038/s44319-024-00058-0
Medicina (Kaunas). 2024 Jan 22. pii: 191. [Epub ahead of print]60(1):

Effect of Calorie Restriction and Intermittent Fasting Regimens on Brain-Derived Neurotrophic Factor Levels and Cognitive Function in Humans: A Systematic Review.

Refat Alkurd, Lana Mahrous, Falak Zeb, Moien Ab Khan, Hamid Alhaj, Husam M Khraiwesh, MoezAlIslam E Faris.

  Background: The potential positive interaction between intermittent fasting (IF) and brain-derived neurotrophic factor (BDNF) on cognitive function has been widely discussed. This systematic review tried to assess the efficacy of interventions with different IF regimens on BDNF levels and their association with cognitive functions in humans. Interventions with different forms of IF such as caloric restriction (CR), alternate-day fasting (ADF), time-restricted eating (TRE), and the Ramadan model of intermittent fasting (RIF) were targeted. Methods: A systematic review was conducted for experimental and observational studies on healthy people and patients with diseases published in EMBASE, Scopus, PubMed, and Google Scholar databases from January 2000 to December 2023. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statements (PRISMA) for writing this review. Results: Sixteen research works conducted on healthy people and patients with metabolic disorders met the inclusion criteria for this systematic review. Five studies showed a significant increase in BDNF after the intervention, while five studies reported a significant decrease in BDNF levels, and the other six studies showed no significant changes in BDNF levels due to IF regimens. Moreover, five studies examined the RIF protocol, of which, three studies showed a significant reduction, while two showed a significant increase in BDNF levels, along with an improvement in cognitive function after RIF. Conclusions: The current findings suggest that IF has varying effects on BDNF levels and cognitive functions in healthy, overweight/obese individuals and patients with metabolic conditions. However, few human studies have shown that IF increases BDNF levels, with controversial results. In humans, IF has yet to be fully investigated in terms of its long-term effect on BDNF and cognitive functions. Large-scale, well-controlled studies with high-quality data are warranted to elucidate the impact of the IF regimens on BDNF levels and cognitive functions.

Keywords:  BDNF; Ramadan fasting; cognitive function; intermittent fasting; metabolic condition

DOI:  https://doi.org/10.3390/medicina60010191
Sci Signal. 2024 Jan 23. 17(820): eabg8145

NLRP12 interacts with NLRP3 to block the activation of the human NLRP3 inflammasome.

Jared R Coombs, Alina Zamoshnikova, Caroline L Holley, Madhavi P Maddugoda, Daniel Eng Thiam Teo, Camille Chauvin, Lionel F Poulin, Nazarii Vitak, Connie M Ross, Manasa Mellacheruvu, Rebecca C Coll, Leonhard X Heinz, Sabrina S Burgener, Stefan Emming, Mathias Chamaillard, Dave Boucher, Kate Schroder.

Inflammasomes are multiprotein complexes that drive inflammation and contribute to protective immunity against pathogens and immune pathology in autoinflammatory diseases. Inflammasomes assemble when an inflammasome scaffold protein senses an activating signal and forms a signaling platform with the inflammasome adaptor protein ASC. The NLRP subfamily of NOD-like receptors (NLRs) includes inflammasome nucleators (such as NLRP3) and also NLRP12, which is genetically linked to familial autoinflammatory disorders that resemble diseases caused by gain-of-function NLRP3 mutants that generate a hyperactive NLRP3 inflammasome. We performed a screen to identify ASC inflammasome-nucleating proteins among NLRs that have the canonical pyrin-NACHT-LRR domain structure. Only NLRP3 and NLRP6 could initiate ASC polymerization to form "specks," and NLRP12 failed to nucleate ASC polymerization. However, wild-type NLRP12 inhibited ASC inflammasome assembly induced by wild-type and gain-of-function mutant NLRP3, an effect not seen with disease-associated NLRP12 mutants. The capacity of NLRP12 to suppress NLRP3 inflammasome assembly was limited to human NLRP3 and was not observed for wild-type murine NLRP3. Furthermore, peripheral blood mononuclear cells from patients with an NLRP12 mutant-associated inflammatory disorder produced increased amounts of the inflammatory cytokine IL-1β in response to NLRP3 stimulation. Thus, our findings provide insights into NLRP12 biology and suggest that NLRP3 inhibitors in clinical trials for NLRP3-driven diseases may also be effective in treating NLRP12-associated autoinflammatory diseases.

DOI: https://doi.org/10.1126/scisignal.abg8145
Front Immunol. 2023 ;14 1344697

The potential role of Hippo pathway regulates cellular metabolism via signaling crosstalk in disease-induced macrophage polarization.

Yina An, Shuyu Tan, Jingjing Yang, Ting Gao, Yanjun Dong.

  Macrophages polarized into distinct phenotypes play vital roles in inflammatory diseases by clearing pathogens, promoting tissue repair, and maintaining homeostasis. Metabolism serves as a fundamental driver in regulating macrophage polarization, and understanding the interplay between macrophage metabolism and polarization is crucial for unraveling the mechanisms underlying inflammatory diseases. The intricate network of cellular signaling pathway plays a pivotal role in modulating macrophage metabolism, and growing evidence indicates that the Hippo pathway emerges as a central player in network of cellular metabolism signaling. This review aims to explore the impact of macrophage metabolism on polarization and summarize the cell signaling pathways that regulate macrophage metabolism in diseases. Specifically, we highlight the pivotal role of the Hippo pathway as a key regulator of cellular metabolism and reveal its potential relationship with metabolism in macrophage polarization.

Keywords:  Hippo; inflammatory diseases; macrophage polarization; metabolism; regulatory network

DOI:  https://doi.org/10.3389/fimmu.2023.1344697