bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2025–11–23
sixteen papers selected by
Kateryna Shkarina, Universität Bonn
  1. The NLRP6 inflammasome is activated by sterile or pathogen-induced endolysosomal damage.
  2. NEDD4L-mediated Gasdermin D and E ubiquitination regulates cell death and tissue injury.
  3. NINJ1.
  4. RIOK2 kinase regulates the translocation of the FADD-RIPK1-Caspase-8 complex to the ER and the cleavage of Gasdermin D to drive pyroptosis.
  5. NINJ1 blocks HSV-1 entry into macrophages to impact viral replication and immunity.
  6. LRRK2-mediated NLRC4 phosphorylation differentially regulates IL-1β/IL-18 secretion.
  7. Mitochondrial dysfunction acts as a modulator of the immunometabolic route for activating the cytosolic DNA sensor pathway in triggering innate immunosurveillance.
  8. Modulation function of sphingomyelin molecular species in TLR4 signaling and cell death.
  9. Proteoglycofili are glycosaminoglycan-containing fibrillar components released by neutrophils to neutralize bacteria.
  10. Induction, Isolation, and Characterization of Human Neutrophil Extracellular Traps (NETs) to Be Used in Functional Assays.
  11. Human M-MDSCs Impair Neutrophil Migration in the Infectious Microenvironment.
  12. Candida albicans activates Staphylococcus aureus virulence regulatory systems to drive toxin-mediated human cell death.
  13. Palmitoylation of TBK1 enhances the type I interferon signaling and strengthens anti-malarial immunity in mice.
  14. NLRP3 inhibition by VTX3232 tempers inflammation resulting in reduced body weight, hyperglycemia, and hepatic steatosis in obese male mice.
  15. Phosphoproteomic profiling of lipopolysaccharide stimulated toll-like receptor pathways in macrophages.
  16. Host immunometabolic regulation through viral sensing pathways.
  1. EMBO J. 2025 Nov 20.
    The NLRP6 inflammasome is activated by sterile or pathogen-induced endolysosomal damage.
    Alexandra Boegli, Elliott M Bernard, Louise Lacante, Gaël Majeux, Ella Hartenian, Vanessa Mack, Petr Broz.
      The cytosolic innate immune sensor NLRP6 controls host defense against bacteria and viruses in the gastrointestinal tract, but the underlying mechanism is poorly understood. Here, we report that NLRP6 forms an inflammasome following endolysosomal damage caused by sterile triggers or bacterial pathogens such as Listeria monocytogenes in human intestinal epithelial cells (IECs). NLRP6 activation requires Listeriolysin O-dependent cytosolic invasion of L. monocytogenes and triggers IEC pyroptosis and IL-1β release via ASC/caspase-1-mediated GSDMD cleavage. NLRP6 activation requires its NACHT domain and ATP binding, whereas inflammasome formation is independent of bacterial pathogen-associated molecular patterns (PAMPs), such as lipoteichoic acid or dsRNA, which were previously reported to activate NLRP6. L. monocytogenes mutants deficient in cell-to-cell spread or escape from secondary vacuoles induce lower levels of cell death, linking bacteria-induced endolysosomal damage to NLRP6 activation. Finally, sterile endolysosomal damage recapitulates pathogen-induced NLRP6 activation and induces IEC pyroptosis. In summary, our study reveals that NLRP6 enables intestinal epithelial cells to detect endolysosomal damage, thereby mediating their response not only to pathogens but more generally to wide-ranging sources of pathological endolysosomal damage.
    Keywords:  Endolysosomal Damage; Inflammasome; Listeria; NLRP6; Pyroptosis
    DOI:  https://doi.org/10.1038/s44318-025-00637-4
  2. Cell Death Differ. 2025 Nov 19.
    NEDD4L-mediated Gasdermin D and E ubiquitination regulates cell death and tissue injury.
    Sonia S Shah, Jantina A Manning, Yoon Lim, Diva Sinha, Ambika Mosale Venkatesh Murthy, Raja Ganesan, Nirmal Robinson, Emad S Alnemri, Seth L Masters, James E Vince, Sharad Kumar.
      The membrane pore-forming gasdermin (GSDM) proteins are essential executors of pyroptosis. The GSDM family members GSDMD and GSDME can also target mitochondrial membranes, driving apoptosis. Here, we identify the ubiquitin ligase NEDD4L as a key regulator of GSDMD and GSDME, two GSDMs involved in cell death. NEDD4L ubiquitinates both these proteins to control their stability and intracellular expression levels. Knockout of mouse Nedd4l (also called Nedd4-2) results in lung and kidney damage with perinatal lethality within three weeks of birth. These mice demonstrated elevated GSDMD in alveolar epithelia and increased GSDME in kidney tubular epithelia, suggesting tissue-specific regulation by NEDD4L. Renal tubule-specific Nedd4l knockout mice showed GSDM activation, tubular cell death and reduced kidney function after high sodium diet. NEDD4L-deficient cells showed increased GSDM activation, IL-1β release and were significantly more susceptible to cell death induced by NLRP3 agonists, cytotoxic agents, and bacterial infection. These results demonstrate that NEDD4L regulates GSDMD and GSDME functions by preventing their accumulation and reveals an unexplored link between GSDM stability and cell death.
    DOI:  https://doi.org/10.1038/s41418-025-01598-1
  3. Curr Biol. 2025 Nov 17. pii: S0960-9822(25)01338-7. [Epub ahead of print]35(22): R1072-R1073
    NINJ1.
    Elliott M Bernard, Ella Hartenian, Petr Broz.
      Bernard, Hartenian, and Broz introduce NINJ1, a transmembrane protein that mediates plasma membrane rupture during lytic cell death.
    DOI:  https://doi.org/10.1016/j.cub.2025.10.030
  4. Nat Commun. 2025 Nov 17. 16(1): 10060
    RIOK2 kinase regulates the translocation of the FADD-RIPK1-Caspase-8 complex to the ER and the cleavage of Gasdermin D to drive pyroptosis.
    Mingtong Ma, Fei Wang, Pengfei Cui, Yingying Zhang, Hanyu Ma, Yifan He, Yuanna Cheng, Jingping Huang, Jingxiang Wang, Xiangyang Wu, Hua Yang, Ruijuan Zheng, Haowen Ma, Qian Cai, Lin Wang, Baoxue Ge.
      Macrophage infection by the pathogenic bacteria Yersinia or mimic stimulation of lipopolysaccharide (LPS) and transforming growth factor-β-activated kinase 1 (TAK1) inhibitor or tumor necrosis factor (TNF) and TAK1 inhibitor induces caspase-8-mediated gasdermin D (GSDMD) cleavage and pyroptosis. However, the upstream regulator of caspase-8-dependent cleavage of GSDMD remains elusive. Here we show that Serine/threonine-protein kinase RIO2 (RIOK2) interacts with the Fas-associated protein with death domain (FADD) and is essential for caspase-8-driven GSDMD cleavage. RIOK2's kinase activity drives the transport of lysosome to ER through activating myosin II and thereby translocate FADD-RIPK1-caspase-8 complex from lysosome to ER. Importantly, RIOK2's ATPase activity enhances its binding to this complex and directly triggers caspase-8 and gasdermin D cleavage both at ER and in vitro. Furthermore, RIOK2-mediated pyroptosis enhances host defense against Yersinia infection. Thus, our findings define an upstream regulator of caspase-8-dependent pyroptosis, implying a role of organelle crosstalk in spatial cleavage of gasdermins.
    DOI:  https://doi.org/10.1038/s41467-025-65012-7
  5. EMBO Rep. 2025 Nov 19.
    NINJ1 blocks HSV-1 entry into macrophages to impact viral replication and immunity.
    Ella Hartenian, Magalie Agustoni, Petr Broz.
      Restriction factors block multiple stages of viral infection. Here we describe how Ninjurin1 (NINJ1) controls HSV-1 infection of macrophages, a key cell type that protects mice against infection. We observe that Ninj1-/- mouse macrophages are more susceptible to HSV-1 infection than WT cells. Given the role of NINJ1 during cell death, we investigate whether its antiviral activity is linked to this function. Surprisingly, we do not observe differences in cell death at early timepoints post HSV-1 infection between genotypes. Instead, we attribute the higher infection rate of Ninj1-/- macrophages to enhanced entry, with more viral particles entering each cell and a greater fraction of infected cells. The increased viral loads in Ninj1-/- cells result in higher ISG and cytokine RNA expression, which we ascribe to both TLR signaling and STING-mediated recognition. Cytokine secretion, however, is severely dampened in infected Ninj1-/- cells, pointing to greater viral replication suppressing the induction of inflammation. In conclusion, NINJ1 acts as a gatekeeper for HSV-1 entry in macrophages, impacting the inflammatory phenotype associated with HSV-1 infection.
    Keywords:  Cell Death; HSV-1; NINJ1; Restriction Factors; Virology
    DOI:  https://doi.org/10.1038/s44319-025-00638-8
  6. Front Immunol. 2025 ;16 1675137
    LRRK2-mediated NLRC4 phosphorylation differentially regulates IL-1β/IL-18 secretion.
    Sharmina Deloer, Ivan Fuss, Portia Gough, Anketse Debebe, Mellissa Picker, Robert J Devita, Inga Peter, Warren Strober.
      In the present study, we explored the relation of LRRK2-kinase phosphorylation of the NLRC4 inflammasome to NLRC4 inflammasome function in normal humans and mice, as well as in patients with Crohn's disease (CD). We found that LRRK2-kinase was both necessary and sufficient for NLRC4 phosphorylation in human mononuclear cells and likely in murine mononuclear cells as well. In addition, such phosphorylation requires ASC association with the nascent NLRC4 inflammasome and is necessary for ASC function. Finally, we found that inhibition of LRRK2-kinase phosphorylation of NLRC4 impairs inflammasome IL-1β production but has little to no effect on its IL-18 production. The mechanism of this dichotomy was revealed in studies of NLRC4 inflammasome activity, showing that pro-IL-1β cleavage is partially dependent on LRRK2-mediated ASC binding and cleavage function, whereas pro-IL-18 is independent of such ASC function. In accompanying studies of circulating cells from patients with CD, a disease associated with LRRK2 polymorphisms that affect LRRK2 expression, we showed that patient cells exhibited increased NLRC4 inflammasome activation; in addition, inhibition of LRRK2-kinase impaired IL-1β secretion but had little or no effect on IL-18 secretion by patient cells. Finally, studies of WT mice or mice with epithelial cell-specific NLRC4 deletion revealed that NLRC4 inflammasome activation causes impairment of gut barrier function that is abrogated by inhibition of LRRK2-kinase activity. Thus, NLRC4 inflammasome function is increased in CD, and its regulation by an LRRK2-kinase inhibitor is calibrated to prevent NLRC4-mediated barrier dysfunction.
    Keywords:  Crohn’s disease; LRRK2; NLRC4; inflammasome; inflammation
    DOI:  https://doi.org/10.3389/fimmu.2025.1675137
  7. J Transl Med. 2025 Nov 19. 23(1): 1321
    Mitochondrial dysfunction acts as a modulator of the immunometabolic route for activating the cytosolic DNA sensor pathway in triggering innate immunosurveillance.
    Cristina Algieri, Salvatore Nesci, Francesca Oppedisano.
      Mitochondria, in addition to their classic role in energy production, have emerged as central hubs in the regulation of innate immunity. Under conditions of cellular stress, mitochondrial dysfunction triggers the release of mitochondrial DNA (mtDNA) into the cytosol or extracellular space, activating potent inflammatory pathways such as cGAS-STING, NLRP3 and TLR9. mtDNA release, driven by factors such as oxidative damage, membrane permeabilization, and various cell death pathways, is involved in immune surveillance and the pathogenesis of various diseases. At the same time, this downstream event leads to profound reorganization of immune cell metabolism, influencing functional polarization and inflammatory outcomes. This review presents the mitochondrion as an interface between metabolism, immunity, immunometabolites, and danger signalling. We explore the molecular mechanisms of mtDNA release, its conversion into immune signals, and its impact on metabolism in immune cells. Translational implications for pathologies such as neurodegenerative, autoimmune, and neoplastic diseases are also discussed. Deciphering the interconnection between mitochondrial stress, mtDNA release, and immunometabolic rewiring could open new avenues for the treatment of complex diseases and drive innovation in immunotherapy and regenerative medicine.
    Keywords:  Complex diseases; Immunity; Inflammation; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1186/s12967-025-07392-4
  8. Cell Rep. 2025 Nov 18. pii: S2211-1247(25)01340-3. [Epub ahead of print]44(12): 116568
    Modulation function of sphingomyelin molecular species in TLR4 signaling and cell death.
    Xuhao Huang, Hirotaka Kanoh, Jumpei Ueno, Ushio Ishikawa, Takahiro Nitta, Masayuki Takamatsu, Atsushi Shimoyama, Makoto Taniguchi, Shinya Hanashima, Kei-Ichiro Inamori, Jin-Ichi Inokuchi, Koichi Fukase, Kazuya Kabayama.
      The innate immune system provides the first line of defense against pathogens. However, the mechanisms underlying its endogenous regulation remain unclear. We identified sphingomyelin (SM) as a novel immunomodulatory ligand. SM in serum consists of various fatty acid species. Our findings reveal that SM species regulate inflammatory cell death and cytokine release in an acyl-chain-dependent manner via Toll-like receptor 4 (TLR4)-myeloid differentiation factor-2 (MD-2) signaling. Specifically, N-lauroyl-D-erythro-sphingosylphosphorylcholine (SM C12) and N-myristoyl-D-erythro-sphingosylphosphorylcholine (SM C14) induce inflammatory cell death and pyroptosis in mouse macrophages. The activation of human caspase-4, mouse caspase-11, and gasdermin D underlies this pyroptotic response, and we have identified SM C12 as a ligand for caspase-4. Our results suggest a dual role for SM in mediating inflammation or suppressing LPS-stimulated inflammation through both cell surface TLR4/MD-2 interaction and intracellular caspase signaling pathways. This newfound understanding of SM's immunomodulatory properties opens avenues for exploring its therapeutic potential in modulating innate immune responses.
    Keywords:  CP: immunology; TLR4; cell death; inflammation; innate immunity; sphingomyelin
    DOI:  https://doi.org/10.1016/j.celrep.2025.116568
  9. Cell Rep. 2025 Nov 13. pii: S2211-1247(25)01312-9. [Epub ahead of print]44(11): 116541
    Proteoglycofili are glycosaminoglycan-containing fibrillar components released by neutrophils to neutralize bacteria.
    Antonin C André, Marina V Barroso, Jurate Skerniskyte, Lorine Debande, Vanessa Paul, Nathan Broussaudier, Ahmad Sabbah, Jules Tritschler, Mélina Siegwald, Caroline Ridley, Isabelle Svahn, Amber D Bowler, Valérie Demais, Katia Boniface, Stéphane Rigaud, Jean-Yves Tinevez, Philippe J Sansonetti, Freddy Radtke, Romain R Vivès, David J Thornton, Benoit S Marteyn.
      Here, we uncover that neutrophils release a fibrillar complex, named proteoglycofili (PGF), under hypoxic conditions or upon bacterial infection, using Shigella as a model. PGF are preferentially released by neutrophils over neutrophil extracellular traps upon bacterial infection. PGF are released by living neutrophils, do not contain DNA, are mainly composed of granule proteins, and contain cytokines. We reveal that the fibrillar structure of PGF is sustained by two glycosaminoglycans (GAGs), hyaluronic acid, and chondroitin sulfate, released by neutrophils. We demonstrate that PGF are potent antimicrobials, which degrade virulence factors of Shigella and block its growth, similar to E. coli or Salmonella. GAGs are essential for PGF antimicrobial activity both in vitro and in vivo. Beyond bacterial infections, and reported in a mouse model of colon cancer, our results strongly suggest that GAGs may be released by neutrophils in a broad range of inflammatory diseases.
    Keywords:  CP: Immunology; CP: Microbiology; GAG; Shigella; anoxia; antimicrobial; bacteria; chondroitin sulfate; glycosaminoglycan; hyaluronic acid; neutrophils; proteoglycofili
    DOI:  https://doi.org/10.1016/j.celrep.2025.116541
  10. Methods Mol Biol. 2026 ;2990 105-118
    Induction, Isolation, and Characterization of Human Neutrophil Extracellular Traps (NETs) to Be Used in Functional Assays.
    Quang Khai Doan, Cindy Qiu, Patrice Decker.
      Polymorphonuclear neutrophils (PMNs) represent ~60% of circulating leukocytes in humans. Once activated, PMNs can release neutrophil extracellular traps (NETs), molecular complexes composed of DNA and proteins from granules. Although NETs play a protective role in fighting microbes, they may become harmful under certain circumstances, especially in some inflammatory autoimmune diseases.Because NETs can be either beneficial or deleterious depending on the microenvironment, a deeper characterization of NETs and NET-inducing stimuli as well as a better understanding of the different properties and activities of NETs is required, in both physiological and pathological contexts.In the present chapter, we describe tools not only to induce and isolate NETs, but also required methods to characterize NETs via biochemical approaches and imaging, in order to prove that obtained structures conform to the definition of NETs exhibiting typical extracellular fibers. NETs produced with our protocol are suitable for detailed assessment of their biological properties in functional studies.
    Keywords:  Autoimmunity; Biochemical characterization; Immunofluorescence; Inflammation; NET induction and isolation; Neutrophil extracellular traps (NETs); Neutrophil isolation; Neutrophils
    DOI:  https://doi.org/10.1007/978-1-0716-4997-8_9
  11. J Leukoc Biol. 2025 Nov 17. pii: qiaf165. [Epub ahead of print]
    Human M-MDSCs Impair Neutrophil Migration in the Infectious Microenvironment.
    Hannah K Weppner, Maya A Singh, Elizabeth N Katsnelson, David J Douin, Martin D McCarter, Richard P Tobin, Laurel E Hind.
      Patients who survive sepsis experience a prolonged period of immunosuppression. This period is accompanied by the expansion of monocytic myeloid-derived suppressor cells (M-MDSCs), a subset of suppressive myeloid cells; however, the impact of M-MDSCs on the innate immune response to infection is not well understood. Here we investigate the effect of MDSCs on neutrophils, a critical component of the innate immune response, during bacterial infection. We found that M-MDSCs, differentiated from monocytes in vitro, impaired neutrophil chemotaxis to IL-8 in a simple microfluidic chemotactic device. We then integrated M-MDSCs and neutrophils into our 3D infection-on-a-chip device that incorporates key features of an infectious environment including an endothelial lumen, a collagen extracellular matrix, and a source of Pseudomonas aeruginosa. When M-MDSCs were present in the matrix during simulated infection with Pseudomonas aeruginosa, significantly fewer neutrophils extravasated from the lumen, and those that left traveled a shorter distance from the lumen edge. We found IL-10 secretion increased during infections in the presence of M-MDSCs and blocking IL-10 restored neutrophil extravasation, indicating IL-10 secretion reduces neutrophil extravasation in the presence of M-MDSCs. In summary, we demonstrated impaired neutrophil chemotaxis, extravasation, and migration in the presence of M-MDSCs during bacterial infection and found increased levels of IL-10 contribute to reduced extravasation, indicating that MDSCs play a role in regulating the immune environment, leading to a reduced neutrophil response to infection.
    Keywords:  M-MDSCs; bacterial infection; migration; neutrophils
    DOI:  https://doi.org/10.1093/jleuko/qiaf165
  12. bioRxiv. 2025 Oct 03. pii: 2025.10.03.680095. [Epub ahead of print]
    Candida albicans activates Staphylococcus aureus virulence regulatory systems to drive toxin-mediated human cell death.
    Kara R Eichelberger, Nicholas A Podar, Jia A Mei, Jacob M Curry, Ravishankar Chandrasekaran, Saikat Paul, Julie A Bastarache, Victor J Torres, Brian M Peters, James E Cassat.
      Co-infection with Staphylococcus aureus and Candida albicans leads to worsened disease severity compared to mono-microbial infection. Because our understanding of the mechanisms driving enhanced disease severity during co-infection is limited, we sought to evaluate how interactions with C. albicans regulate S. aureus virulence towards host cells. We determined that C. albicans enhances S. aureus cytotoxicity towards murine monocytes via a mechanism requiring the Agr system. Agr is a major regulator of S. aureus virulence factors and was previously shown to be activated by C. albicans, but the Agr-regulated virulence factors driving immune cell death are unknown. We identified that enhanced murine monocyte cell death requires the α-type phenol soluble modulins and ψ-hemolysin. Because several S. aureus toxins have species-specific effects, we also tested how co-culture impacts cytotoxicity towards human monocytes. Unexpectedly, we discovered that C. albicans induces robust cytotoxicity of an S. aureus agr mutant (Δ agr ), which is completely non-toxic towards murine monocytes. Using reporter strains and combinatorial mutants, we identified that co-culture activates the SaeRS regulatory system in S. aureus, and SaeRS is required for human-specific cytotoxicity. We further discovered that the SaeRS-regulated toxin Panton-Valentine Leukocidin (PVL) drives S. aureus Δ agr cytotoxicity following co-culture. Finally, we observed similar cytotoxicity phenotypes using both S. aureus and C. albicans clinical isolates, demonstrating broad conservation of this interaction. Interestingly, the magnitude by which C. albicans isolates induce cytotoxicity of S. aureus Δ agr varies among strains tested. Overall, this study identifies that C. albicans activates a major S. aureus virulence regulatory system in a typically non-toxic strain, triggering S. aureus to induce potent human-selective cell death.
    DOI:  https://doi.org/10.1101/2025.10.03.680095
  13. Nat Commun. 2025 Nov 18. 16(1): 10109
    Palmitoylation of TBK1 enhances the type I interferon signaling and strengthens anti-malarial immunity in mice.
    Zhongxin Han, Siyi Xiong, Ke Zeng, Zilong Xiao, Liying Zhang, Yufen Zhang, Jiaying Guo, Wenqiang Peng, Yingchao Xie, Weiwei Liu, Xiao Yu.
      Precise regulation of type I interferon signaling is crucial for effective immune defense against infectious diseases. However, the molecular mechanisms governing this pathway are not fully understood. Here, we show a function for palmitoylation in enhancing anti-malarial immune responses. Our findings reveal that ZDHHC9 enhances the type I interferon signaling by palmitoylating TBK1 at cysteine 292. Following infection with Plasmodium yoelii N67, the delicate balance between palmitoylation and depalmitoylation of TBK1 is disrupted. Specifically, upregulation of APT2 promotes persistent depalmitoylation of TBK1 and triggers its selective autophagic degradation via K48-linked polyubiquitination at lysine 251/372 by E3 ligase TRIM27. This process acts as a recognition signal for the cargo receptor NDP52, resulting in inhibition of the type I interferon pathway. Notably, inhibition of APT2 using ML349 elevates type I interferon levels and improves survival rates against N67 infection. Here, we show that targeting APT2-mediated TBK1 depalmitoylation is a potential therapeutic strategy for malaria and may also be applicable to other diseases driven by dysregulated type I interferon signaling.
    DOI:  https://doi.org/10.1038/s41467-025-65081-8
  14. Mol Metab. 2025 Nov 14. pii: S2212-8778(25)00189-9. [Epub ahead of print] 102282
    NLRP3 inhibition by VTX3232 tempers inflammation resulting in reduced body weight, hyperglycemia, and hepatic steatosis in obese male mice.
    Jennyfer Bultinck, Shendong Yuan, Ludovico Cantuti-Castelvetri, Lander Brosens, Debby Bracke, James Collins, Jens Goethals, Christina Christianson, John Nuss, Kathleen Ogilvie.
      The NLRP3 inflammasome is a key innate immune sensor that orchestrates inflammatory responses to diverse stress signals, including metabolic danger cues. Dysregulated NLRP3 activation has been implicated in chronic diseases such as type 2 diabetes, atherosclerosis, and neurodegeneration, underscoring the broad pathophysiological role of the NLRP3 pathway. In the context of obesity and its associated conditions, NLRP3 inhibition by VTX3232, an oral, selective, and brain-penetrant NLRP3 inhibitor, potently suppressed the release of proinflammatory cytokines (IL-1β, IL-18, IL-1α, IL-6, and TNF) from macrophages and microglia stimulated with metabolic stressors including palmitic acid and cholesterol crystals. Moreover, NLRP3 inhibition by VTX3232 also blocked NLRP3-driven insulin resistance in primary human hepatocytes and adipocytes while normalizing the acute phase response and FGF-21 secretion in hepatocytes under palmitic acid-induced inflammation. In vivo, NLRP3 inhibition by VTX3232 reduced systemic and tissue-specific inflammation in a mouse model of diet-induced obesity, reflected by decreased circulating inflammatory mediators, reduced hepatic inflammation, fewer crown-like structures in adipose tissue, and diminished hypothalamic gliosis. These anti-inflammatory effects were accompanied by improvements in body weight, food intake, and obesity-associated comorbidities such as hyperglycemia, hepatic steatosis, and markers of cardiovascular and renal disease. Notably, these effects were confined to the context of obesity, as no impact was observed in lean mice. When combined with glucagon-like peptide-1 receptor agonism by semaglutide, NLRP3 inhibition by VTX3232 yielded additive metabolic benefits, highlighting complementary mechanisms of action. Together, these findings reinforce the biological rationale for targeting NLRP3 in inflammatory conditions such as obesity, expand on the role of NLRP3 in metabolic inflammation, and underscore the importance of continued investigation into the NLRP3 pathway as a central node in cardiometabolic disease.
    Keywords:  Drug Therapy; Inflammation; Insulin Resistance; Metabolism; Obesity; Steatosis
    DOI:  https://doi.org/10.1016/j.molmet.2025.102282
  15. Sci Data. 2025 Nov 21. 12(1): 1856
    Phosphoproteomic profiling of lipopolysaccharide stimulated toll-like receptor pathways in macrophages.
    Doeun Kim, Sung Hwan Yoon, Nathan P Manes, Aleksandra Nita-Lazar.
      Toll-like receptors (TLRs) are present on the surface of immune cells such as dendritic cells, macrophages, and natural killer cells. TLRs and other pattern recognition receptors (PRRs) are essential for the recognition of microbiological components. They trigger both innate and adaptive immune responses to defend against pathogenic microorganisms. Among the TLRs, TLR4 is one of the best-studied; it recognizes lipopolysaccharide (LPS) and initiates both TRIF- and MyD88-dependent signaling cascades. Regulators of TLR4 signaling, including numerous protein kinases, have a key role in innate and adaptive immune responses. Although TLR4 signaling pathways have been investigated using phosphoproteomics by mass spectrometry using data-dependent acquisition (DDA), the phosphoprotein landscape of the TLR4 signaling remains poorly incomplete, partly due to the technical limitations of DDA. To address this, we utilized data-independent acquisition (DIA) mass spectrometry to deeply explore phosphorylation dynamics within the LPS-stimulated TLR4 signaling pathway in macrophages.
    DOI:  https://doi.org/10.1038/s41597-025-06108-z
  16. Curr Opin Microbiol. 2025 Nov 18. pii: S1369-5274(25)00105-5. [Epub ahead of print]88 102683
    Host immunometabolic regulation through viral sensing pathways.
    Ana Julia Estumano Martins, Thaís Pirola Dos Santos, Wilias Greison Silva Santos, Enzo Triozzi, Pedro M Moraes-Vieira.
      Viruses are intracellular pathogens that have profoundly influenced biological evolution and continue to threaten global health through outbreaks such as influenza and COVID-19. Their ability to evade host immunity stems from evolutionary adaptations that manipulate cellular defense mechanisms. A critical aspect of virus-host interactions involves cellular receptors, which facilitate viral entry and trigger immune signaling. Among these, pattern recognition receptors (PRRs) and other proteins serve as key sensors of viral components, coordinating immune responses while reprogramming host metabolism to sustain antiviral defenses. However, many viruses hijack these metabolic changes to enhance replication, evade immune surveillance, or dysregulate cytokine production. This review explores how host cell virus-sensitive proteins, particularly PRRs and metabolically active proteins, modulate cellular metabolism during infection, shaping immune outcomes and revealing potential therapeutic targets for antiviral intervention.
    DOI:  https://doi.org/10.1016/j.mib.2025.102683
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