Potency and efficacy of pharmacological PIP4K2 inhibitors in acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL), a complex malignancy, displays varying expression profiles of PIP4K2-related genes in adult patients. While PIP4K2A expression is elevated in ALL bone marrow cells compared to healthy bone marrow cells, PIP4K2B is downregulated, and PIP4K2C remains relatively unchanged. Despite the correlation between increased PIP4K2A expression and increased percentage of peripheral blood blasts, clinical outcomes do not strongly correlate with the expression of these genes. Here we investigated the therapeutic potential of three PIP4K2 inhibitors (THZ-P1-2, a131, and CC260) in ALL cell models. THZ-P1-2 emerges as the most effective inhibitor, inducing cell death and mitochondrial damage while reducing cell viability and metabolism significantly. Comparative analyses highlight the superior efficacy of THZ-P1-2 over a131 and CC260. Notably, THZ-P1-2 uniquely disrupts autophagic flux and inhibits the PI3K/AKT/mTOR pathway, indicating a distinct molecular mechanism. In summary, our findings elucidate the differential expression of PIP4K2-related genes in ALL and underscore the potential role of PIP4K2A in disease pathogenesis. The therapeutic promise of THZ-P1-2 in ALL treatment, along with its distinct effects on cell death mechanisms and signaling pathways, enriches our understanding of PIP4K2's involvement in ALL development and offers targeted therapy prospects.

Cisplatin Toxicity Causes Neutrophil-Mediated Inflammation in Zebrafish Larvae.

Cisplatin is an antineoplastic agent used to treat various tumors. In mammals, it can cause nephrotoxicity, tissue damage, and inflammation. The release of inflammatory mediators leads to the recruitment and infiltration of immune cells, particularly neutrophils, at the site of inflammation. Cisplatin is often used as an inducer of acute kidney injury (AKI) in experimental models, including zebrafish (Danio rerio), due to its accumulation in kidney cells. Current protocols in larval zebrafish focus on studying its effect as an AKI inducer but ignore other systematic outcomes. In this study, cisplatin was added directly to the embryonic medium to assess its toxicity and impact on systemic inflammation using locomotor activity analysis, qPCR, microscopy, and flow cytometry. Our data showed that larvae exposed to cisplatin at 7 days post-fertilization (dpf) displayed dose-dependent mortality and morphological changes, leading to a decrease in locomotion speed at 9 dpf. The expression of pro-inflammatory cytokines such as interleukin (il)-12, il6, and il8 increased after 48 h of cisplatin exposure. Furthermore, while a decrease in the number of neutrophils was observed in the glomerular region of the pronephros, there was an increase in neutrophils throughout the entire animal after 48 h of cisplatin exposure. We demonstrate that cisplatin can have systemic effects in zebrafish larvae, including morphological and locomotory defects, increased inflammatory cytokines, and migration of neutrophils from the hematopoietic niche to other parts of the body. Therefore, this protocol can be used to induce systemic inflammation in zebrafish larvae for studying new therapies or mechanisms of action involving neutrophils.

Evaluation of glomerular sirtuin-1 and claudin-1 in the pathophysiology of nondiabetic focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is the leading cause of nephrotic syndrome, which is characterized by podocyte injury. Given that the pathophysiology of nondiabetic glomerulosclerosis is poorly understood and targeted therapies to prevent glomerular disease are lacking, we decided to investigate the tight junction protein claudin-1 and the histone deacetylase sirtuin-1 (SIRT1), which are known to be involved in podocyte injury. For this purpose, we first examined SIRT1, claudin-1 and podocin expression in kidney biopsies from patients diagnosed with nondiabetic FSGS and found that upregulation of glomerular claudin-1 accompanies a significant reduction in glomerular SIRT1 and podocin levels. From this, we investigated whether a small molecule activator of SIRT1, SRT1720, could delay the onset of FSGS in an animal model of adriamycin (ADR)-induced nephropathy; 14 days of treatment with SRT1720 attenuated glomerulosclerosis progression and albuminuria, prevented transcription factor Wilms tumor 1 (WT1) downregulation and increased glomerular claudin-1 in the ADR + SRT1720 group. Thus, we evaluated the effect of ADR and/or SRT1720 in cultured mouse podocytes. The results showed that ADR [1 µM] triggered an increase in claudin-1 expression after 30 min, and this effect was attenuated by pretreatment of podocytes with SRT1720 [5 µM]. ADR [1 µM] also led to changes in the localization of SIRT1 and claudin-1 in these cells, which could be associated with podocyte injury. Although the use of specific agonists such as SRT1720 presents some benefits in glomerular function, their underlying mechanisms still need to be further explored for therapeutic use. Taken together, our data indicate that SIRT1 and claudin-1 are relevant for the pathophysiology of nondiabetic FSGS.

Physical exercise as a friend not a foe in acute kidney diseases through immune system modulation.

Regular and moderate exercise is being used for therapeutic purposes in treating several diseases, including cancer, cardiovascular diseases, arthritis, and even chronic kidney diseases (CKDs). Conversely, extenuating physical exercise has long been pointed out as one of the sources of acute kidney injury (AKI) due to its severe impact on the body's physiology. AKI development is associated with increased tubular necrosis, which initiates a cascade of inflammatory responses. The latter involves cytokine production, immune cell (macrophages, lymphocytes, and neutrophils, among others) activation, and increased oxidative stress. AKI can induce prolonged fibrosis stimulation, leading to CKD development. The need for therapeutic alternative treatments for AKI is still a relevant issue. In this context arises the question as to whether moderate, not extenuating, exercise could, on some level, prevent AKI. Several studies have shown that moderate exercise can help reduce tissue damage and increase the functional recovery of the kidneys after an acute injury. In particular, the immune system can be modulated by exercise, leading to a better recovery from different pathologies. In this review, we aimed to explore the role of exercise not as a trigger of AKI, but as a modulator of the inflammatory/immune system in the prevention or recovery from AKI in different scenarios. In AKI induced by ischemia and reperfusion, sepsis, diabetes, antibiotics, or chemotherapy, regular and/or moderate exercise could modulate the immune system toward a more regulatory immune response, presenting, in general, an anti-inflammatory profile. Exercise was shown to diminish oxidative stress, inflammatory markers (caspase-3, lactate dehydrogenase, and nitric oxide), inflammatory cytokines (interleukin (IL)-1b, IL-6, IL-8, and tumor necrosis factor-α (TNF-α)), modulate lymphocytes to an immune suppressive phenotype, and decrease tumor necrosis factor-ß (TGF-ß), a cytokine associated with fibrosis development. Thus, it creates an AKI recovery environment with less tissue damage, hypoxia, apoptosis, or fibrosis. In conclusion, the practice of regular moderate physical exercise has an impact on the immune system, favoring a regulatory and anti-inflammatory profile that prevents the occurrence of AKI and/or assists in the recovery from AKI. Moderate exercise should be considered for patients with AKI as a complementary therapy.

Cell lipid biology in infections: an overview.

Lipids are a big family of molecules with a vast number of functions in the cell membranes, within the cytoplasm, and extracellularly. Lipid droplets (LDs) are the most common storage organelles and are present in almost every tissue type in the body. They also have structural functions serving as building blocks of cellular membranes and may be precursors of other molecules such as hormones, and lipoproteins, and as messengers in signal transduction. Fatty acids (FAs), such as sterol esters and triacylglycerols, are stored in LDs and are used in ß-oxidation as fuel for tricarboxylic acid cycle (TCA) and adenosine triphosphate (ATP) generation. FA uptake and entrance in the cytoplasm are mediated by membrane receptors. After a cytoplasmic round of α- and ß-oxidation, FAs are guided into the mitochondrial matrix by the L-carnitine shuttle system, where they are fully metabolized, and enter the TCA cycle. Pathogen infections may lead to impaired lipid metabolism, usage of membrane phospholipids, and LD accumulation in the cytoplasm of infected cells. Otherwise, bacterial pathogens may use lipid metabolism as a carbon source, thus altering the reactions and leading to cellular and organelles malfunctioning. This review aims to describe cellular lipid metabolism and alterations that occur upon infections.

Sirtuins: Key pieces in the host response to pathogens' puzzle.

Global warming is changing the distribution of different pathogens around the globe, and humans are more susceptible to new or re-emerging infections. The human response to microbes is complex and involves different mechanisms of the immune system. Regulation of gene expression of immunity genes and of metabolism of immune cells are essential in this process. Both mechanisms could be regulated by protein lysine acetylation that will control chromatin structure affecting gene expression or key enzyme activity involved in cellular processes. Protein acetylation is crucial for the immunity and involves two families of enzymes: lysine acetyltransferases (KATs), which will promote protein acetylation, and lysine deacetylases (KDACs) that will reduce this modification. Lysine deacetylases are divided into Zinc-dependent or HDACs and NAD+ -dependent, or Sirtuins. These enzymes are in the nucleus, cytosol, and mitochondria of mammalian cells affecting different cellular pathways, such as metabolism, gene expression, DNA repair, cell proliferation, and apoptosis, opening the opportunity to explore these proteins as drug targets in different diseases, including cancer and neurodegenerative illness. Although widely explored in chronic diseases, very little is known about the role of Sirtuins during host response against microbes' infection. In this review we aim to explore the most recent literature evidencing a role for these enzymes during host responses to viruses, bacterial and protozoan infections, pointing out how these proteins can be manipulated by these pathogens to progress in the infection. Moreover, we will uncover the potential of host KDACs as therapeutic targets to prevent infections by activating effector immune functions.

P2RX7 signaling drives the differentiation of Th1 cells through metabolic reprogramming for aerobic glycolysis.

Introduction: This study provides evidence of how Th1 cell metabolism is modulated by the purinergic receptor P2X7 (P2RX7), a cation cannel activated by high extracellular concentrations of adenosine triphosphate (ATP). Methods: In vivo analysis was performed in the Plasmodium chabaudi model of malaria in view of the great relevance of this infectious disease for human health, as well as the availability of data concerning Th1/Tfh differentiation. Results: We show that P2RX7 induces T-bet expression and aerobic glycolysis in splenic CD4+ T cells that respond to malaria, at a time prior to Th1/Tfh polarization. Cell-intrinsic P2RX7 signaling sustains the glycolytic pathway and causes bioenergetic mitochondrial stress in activated CD4+ T cells. We also show in vitro the phenotypic similarities of Th1-conditioned CD4+ T cells that do not express P2RX7 and those in which the glycolytic pathway is pharmacologically inhibited. In addition, in vitro ATP synthase blockade and the consequent inhibition of oxidative phosphorylation, which drives cellular metabolism for aerobic glycolysis, is sufficient to promote rapid CD4+ T cell proliferation and polarization to the Th1 profile in the absence of P2RX7. Conclusion: These data demonstrate that P2RX7-mediated metabolic reprograming for aerobic glycolysis is a key event for Th1 differentiation and suggest that ATP synthase inhibition is a downstream effect of P2RX7 signaling that potentiates the Th1 response.

Tear Film Immunological Profile in Patients with Ocular Graft versus Host Disease.

PURPOSE: To analyze and compare the tear immunological profile in ocular GVHD (oGVHD) patients with that in non-oGVHD patients and to correlate them with ocular surface parameters based on the International Chronic Ocular GVHD Consensus Group (ICCGVHD) diagnostic criteria. METHODS: Tear samples from 20 individuals who underwent allo-hematopoietic stem cell transplantation and were grouped according the presence or absence of oGVHD were analyzed using Bio-Plex assay. RESULTS: IL-8 and MIP-1α levels were significantly higher in tears from oGVHD patients compared with those in tears from non-oGVHD patients (p<0.001 and p=0.001, respectively). Tear IL-8 levels correlated significantly with OSDI criteria (ρ=0.5159, p=0.001), ocular hyperemia (ρ=0.469, p=0.002), and corneal staining (ρ=0.339, p=0.032), whereas tear Mip-1α levels correlated with OSDI score (ρ=0.358, p=0.023). CONCLUSION: We demonstrated higher tear levels of IL-8 and MIP-1α in oGVHD patients and significant correlations between theses cytokines and ocular surface parameters based on the ICCGVHDCG criteria.

Cytokines and Immune Cells Profile in Different Tissues of Rodents Induced by Environmental Enrichment: Systematic Review.

Environmental Enrichment (EE) is based on the promotion of socio-environmental stimuli, which mimic favorable environmental conditions for the practice of physical activity and health. The objective of the present systematic review was to evaluate the influence of EE on pro-and anti-inflammatory immune parameters, but also in cell activation related to the innate and acquired immune responses in the brain and peripheral tissues in rodents. Three databases [PubMed (2209 articles), Scopus (1154 articles), and Science Direct (1040 articles)] were researched. After applying the eligibility criteria, articles were selected for peer review, independently, as they were identified by September 2021. The protocol for this systematic review was registered in the PROSPERO. Of the 4417 articles found, 16 were selected for this systematic review. In the brain, EE promoted a reduction in proinflammatory cytokines and chemokines. In the blood, EE promoted a higher percentage of leukocytes, an increase in CD19+ B lymphocytes, and the proliferation of Natura Killer (NK cells). In the bone marrow, there was an increase in the number of CD27- and CD11b+ mature NK cells and a reduction in CD27- and CD11b+ immature Natural Killer cells. In conclusion, EE can be an immune modulation approach and plays a key role in the prevention of numerous chronic diseases, including cancer, that have a pro-inflammatory response and immunosuppressive condition as part of their pathophysiology.

The dual effect of acetate on microglial TNF-α production.

INTRODUCTION: Short-Chain Fatty Acids (SCFA) are products of intestinal microbial metabolism that can reach the brain and alter microglia in health and disease contexts. However, data are conflicting on the effect of acetate, the most abundant SCFA in the blood, in these cells. OBJECTIVE: The authors aimed to investigate acetate as a modulator of the inflammatory response in microglia stimulated with LPS. METHOD: The authors used an immortalized cell line, C8-B4, and primary cells for in vitro treatments with acetate and LPS. Cell viability was analyzed by MTT, cytokine by RT-PCR, ELISA, and flow cytometry. The authors also performed in vivo and in silico analyses to study the role of acetate and the TNF-α contribution to the development of Experimental Autoimmune Encephalomyelitis (EAE). RESULTS: Acetate co-administered with LPS was able to exacerbate the production of pro-inflammatory cytokines at gene and protein levels in cell lines and primary culture of microglia. However, the same effects were not observed when acetate was administered alone or as pretreatment, prior to the LPS stimulus. Additionally, pharmacological inhibition of histone deacetylase concomitantly with acetate and LPS led to decreased TNF-α production. In silico analysis showed a crucial role of the TNF-α pathway in EAE development. Moreover, acetate administration in vivo during the initial phase of EAE led to a better disease outcome and reduced TNF-α production. CONCLUSION: Treatment with acetate was able to promote the production of TNF-α in a concomitant LPS stimulus of microglia. However, the immune modulation of microglia by acetate pretreatment may be a component in the generation of future therapies for neurodegenerative diseases.

Melanopsin (Opn4) is an oncogene in cutaneous melanoma.

The search for new therapeutical targets for cutaneous melanoma and other cancers is an ongoing task. We expanded this knowledge by evaluating whether opsins, light- and thermo-sensing proteins, could display tumor-modulatory effects on melanoma cancer. Using different experimental approaches, we show that melanoma cell proliferation is slower in the absence of Opn4, compared to Opn4WT due to an impaired cell cycle progression and reduced melanocyte inducing transcription factor (Mitf) expression. In vivo tumor progression of Opn4KO cells is remarkably reduced due to slower proliferation, and higher immune system response in Opn4KO tumors. Using pharmacological assays, we demonstrate that guanylyl cyclase activity is impaired in Opn4KO cells. Evaluation of Tumor Cancer Genome Atlas (TCGA) database confirms our experimental data as reduced MITF and OPN4 expression in human melanoma correlates with slower cell cycle progression and presence of immune cells in the tumor microenvironment (TME). Proteomic analyses of tumor bulk show that the reduced growth of Opn4KO tumors is associated with reduced Mitf signaling, higher translation of G2/M proteins, and impaired guanylyl cyclase activity. Conversely, in Opn4WT tumors increased small GTPase and an immune-suppressive TME are found. Such evidence points to OPN4 as an oncogene in melanoma, which could be pharmacologically targeted.

Leptin Signaling Suppression in Macrophages Improves Immunometabolic Outcomes in Obesity.

Obesity is a major concern for global health care systems. Systemic low-grade inflammation in obesity is a major risk factor for insulin resistance. Leptin is an adipokine secreted by the adipose tissue that functions by controlling food intake, leading to satiety. Leptin levels are increased in obesity. Here, we show that leptin enhances the effects of LPS in macrophages, intensifying the production of cytokines, glycolytic rates, and morphological and functional changes in the mitochondria through an mTORC2-dependent, mTORC1-independent mechanism. Leptin also boosts the effects of IL-4 in macrophages, leading to increased oxygen consumption, expression of macrophage markers associated with a tissue repair phenotype, and wound healing. In vivo, hyperleptinemia caused by diet-induced obesity increases the inflammatory response by macrophages. Deletion of leptin receptor and subsequently of leptin signaling in myeloid cells (ObR-/-) is sufficient to improve insulin resistance in obese mice and decrease systemic inflammation. Our results indicate that leptin acts as a systemic nutritional checkpoint to regulate macrophage fitness and contributes to obesity-induced inflammation and insulin resistance. Thus, specific interventions aimed at downstream modulators of leptin signaling may represent new therapeutic targets to treat obesity-induced systemic inflammation.

Severe COVID-19 Shares a Common Neutrophil Activation Signature with Other Acute Inflammatory States.

Severe COVID-19 patients present a clinical and laboratory overlap with other hyperinflammatory conditions such as hemophagocytic lymphohistiocytosis (HLH). However, the underlying mechanisms of these conditions remain to be explored. Here, we investigated the transcriptome of 1596 individuals, including patients with COVID-19 in comparison to healthy controls, other acute inflammatory states (HLH, multisystem inflammatory syndrome in children [MIS-C], Kawasaki disease [KD]), and different respiratory infections (seasonal coronavirus, influenza, bacterial pneumonia). We observed that COVID-19 and HLH share immunological pathways (cytokine/chemokine signaling and neutrophil-mediated immune responses), including gene signatures that stratify COVID-19 patients admitted to the intensive care unit (ICU) and COVID-19_nonICU patients. Of note, among the common differentially expressed genes (DEG), there is a cluster of neutrophil-associated genes that reflects a generalized hyperinflammatory state since it is also dysregulated in patients with KD and bacterial pneumonia. These genes are dysregulated at the protein level across several COVID-19 studies and form an interconnected network with differentially expressed plasma proteins that point to neutrophil hyperactivation in COVID-19 patients admitted to the intensive care unit. scRNAseq analysis indicated that these genes are specifically upregulated across different leukocyte populations, including lymphocyte subsets and immature neutrophils. Artificial intelligence modeling confirmed the strong association of these genes with COVID-19 severity. Thus, our work indicates putative therapeutic pathways for intervention.

The dual effect of acetate on microglial TNF-α production

Abstract Introduction: Short-Chain Fatty Acids (SCFA) are products of intestinal microbial metabolism that can reach the brain and alter microglia in health and disease contexts. However, data are conflicting on the effect of acetate, the most abundant SCFA in the blood, in these cells. Objective: The authors aimed to investigate acetate as a modulator of the inflammatory response in microglia stimulated with LPS. Method: The authors used an immortalized cell line, C8-B4, and primary cells for in vitro treatments with acetate and LPS. Cell viability was analyzed by MTT, cytokine by RT-PCR, ELISA, and flow cytometry. The authors also performed in vivo and in silico analyses to study the role of acetate and the TNF-α contribution to the development of Experimental Autoimmune Encephalomyelitis (EAE). Results: Acetate co-administered with LPS was able to exacerbate the production of pro-inflammatory cytokines at gene and protein levels in cell lines and primary culture of microglia. However, the same effects were not observed when acetate was administered alone or as pretreatment, prior to the LPS stimulus. Additionally, pharmacological inhibition of histone deacetylase concomitantly with acetate and LPS led to decreased TNF-α production. In silico analysis showed a crucial role of the TNF-α pathway in EAE development. Moreover, acetate administration in vivo during the initial phase of EAE led to a better disease outcome and reduced TNF-α production. Conclusion: Treatment with acetate was able to promote the production of TNF-α in a concomitant LPS stimulus of microglia. However, the immune modulation of microglia by acetate pretreatment may be a component in the generation of future therapies for neurodegenerative diseases. HIGHLIGHTS Acetate was able to exacerbate the production of TNF-α in microglia. Acetate administered as pre-treatment to LPS acts as an anti-inflammatory. Histone deacetylase decreased TNF-α production in Acetate- and LPS-treated cells. Depending on the time of administration, Acetate modulates microglia's activation. Acetate may threaten neurodegenerative and neuropsychiatric diseases.

In Vivo and In Vitro Models of Hepatocellular Carcinoma: Current Strategies for Translational Modeling.

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third leading cause of cancer-related death globally. HCC is a complex multistep disease and usually emerges in the setting of chronic liver diseases. The molecular pathogenesis of HCC varies according to the etiology, mainly caused by chronic hepatitis B and C virus infections, chronic alcohol consumption, aflatoxin-contaminated food, and non-alcoholic fatty liver disease associated with metabolic syndrome or diabetes mellitus. The establishment of HCC models has become essential for both basic and translational research to improve our understanding of the pathophysiology and unravel new molecular drivers of this disease. The ideal model should recapitulate key events observed during hepatocarcinogenesis and HCC progression in view of establishing effective diagnostic and therapeutic strategies to be translated into clinical practice. Despite considerable efforts currently devoted to liver cancer research, only a few anti-HCC drugs are available, and patient prognosis and survival are still poor. The present paper provides a state-of-the-art overview of in vivo and in vitro models used for translational modeling of HCC with a specific focus on their key molecular hallmarks.

Acute Kidney Injury Model Induced by Cisplatin in Adult Zebrafish.

Cisplatin is commonly used as chemotherapy. Although it has positive effects in cancer-treated individuals, cisplatin can easily accumulate in the kidney due to its low molecular weight. Such accumulation causes the death of tubular cells and can induce the development of Acute Kidney Injury (AKI), which is characterized by a quick decrease in kidney function, tissue damage, and immune cells infiltration. If administered in specific doses cisplatin can be a useful tool as an AKI inducer in animal models. The zebrafish has appeared as an interesting model to study renal function, kidney regeneration, and injury, as renal structures conserve functional similarities with mammals. Adult zebrafish injected with cisplatin shows decreased survival, kidney cell death, and increased inflammation markers after 24 h post-injection (hpi). In this model, immune cells infiltration and cell death can be assessed by flow cytometry and TUNEL assay. This protocol describes the procedures to induce AKI in adult zebrafish by intraperitoneal cisplatin injection and subsequently demonstrates how to collect the renal tissue for flow cytometry processing and cell death TUNEL assay. These techniques will be useful to understand the effects of cisplatin as a nephrotoxic agent and will contribute to the expansion of AKI models in adult zebrafish. This model can also be used to study kidney regeneration, in the search for compounds that treat or prevent kidney damage and to study inflammation in AKI. Moreover, the methods used in this protocol will improve the characterization of tissue damage and inflammation, which are therapeutic targets in kidney-associated comorbidities.

An Immunometabolic Shift Modulates Cytotoxic Lymphocyte Activation During Melanoma Progression in TRPA1 Channel Null Mice.

Melanoma skin cancer is extremely aggressive with increasing incidence and mortality. Among the emerging therapeutic targets in the treatment of cancer, the family of transient receptor potential channels (TRPs) has been reported as a possible pharmacological target. Specifically, the ankyrin subfamily, representing TRPA1 channels, can act as a pro-inflammatory hub. These channels have already been implicated in the control of intracellular metabolism in several cell models, but little is known about their role in immune cells, and how it could affect tumor progression in a process known as immune surveillance. Here, we investigated the participation of the TRPA1 channel in the immune response against melanoma tumor progression in a mouse model. Using Trpa1 +/+ and Trpa1 -/- animals, we evaluated tumor progression using murine B16-F10 cells and assessed isolated CD8+ T cells for respiratory and cytotoxic functions. Tumor growth was significantly reduced in Trpa1 -/- animals. We observed an increase in the frequency of circulating lymphocytes. Using a dataset of CD8+ T cells isolated from metastatic melanoma patients, we found that TRPA1 reduction correlates with several immunological pathways. Naïve CD8+ T cells from Trpa1 +/+ and Trpa1 -/- animals showed different mitochondrial respiration and glycolysis profiles. However, under CD3/CD28 costimulatory conditions, the absence of TRPA1 led to an even more extensive metabolic shift, probably linked to a greater in vitro killling ability of Trpa1 -/- CD8+ T cells. Therefore, these data demonstrate an unprecedented role of TRPA1 channel in the metabolism control of the immune system cells during carcinogenesis.

Targeting immune cell metabolism in kidney diseases.

Insights into the relationship between immunometabolism and inflammation have enabled the targeting of several immunity-mediated inflammatory processes that underlie infectious diseases and cancer or drive transplant rejection, but this field remains largely unexplored in kidney diseases. The kidneys comprise heterogeneous cell populations, contain distinct microenvironments such as areas of hypoxia and hypersalinity, and are responsible for a functional triad of filtration, reabsorption and secretion. These distinctive features create myriad potential metabolic therapeutic targets in the kidney. Immune cells have crucial roles in the maintenance of kidney homeostasis and in the response to kidney injury, and their function is intricately connected to their metabolic properties. Changes in nutrient availability and biomolecules, such as cytokines, growth factors and hormones, initiate cellular signalling events that involve energy-sensing molecules and other metabolism-related proteins to coordinate immune cell differentiation, activation and function. Disruption of homeostasis promptly triggers the metabolic reorganization of kidney immune and non-immune cells, which can promote inflammation and tissue damage. The metabolic differences between kidney and immune cells offer an opportunity to specifically target immunometabolism in the kidney.

Sensing soluble uric acid by Naip1-Nlrp3 platform.

Uric acid (UA), a product of purine nucleotide degradation able to initiate an immune response, represents a breakpoint in the evolutionary history of humans, when uricase, the enzyme required for UA cleavage, was lost. Despite being inert in human cells, UA in its soluble form (sUA) can increase the level of interleukin-1ß (IL-1ß) in murine macrophages. We, therefore, hypothesized that the recognition of sUA is achieved by the Naip1-Nlrp3 inflammasome platform. Through structural modelling predictions and transcriptome and functional analyses, we found that murine Naip1 expression in human macrophages induces IL-1ß expression, fatty acid production and an inflammation-related response upon sUA stimulation, a process reversed by the pharmacological and genetic inhibition of Nlrp3. Moreover, molecular interaction experiments showed that Naip1 directly recognizes sUA. Accordingly, Naip may be the sUA receptor lost through the human evolutionary process, and a better understanding of its recognition may lead to novel anti-hyperuricaemia therapies.