bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–02–08
25 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Mitochondrial superoxide signals shield the nucleus to delay ageing.
  2. Mitochondrial SLC6A6 supports taurine transport.
  3. Plastic microglia.
  4. Peeing your immune troubles away.
  5. Targeting immune cells in the aged brain reveals that engineered cytokine IL-10 enhances neurogenesis and improves cognition.
  6. Zebrafish macrophages convert physical wound signals into rapid vascular permeabilization.
  7. Acute peritonitis-induced adipose CD127+ ILC1s express PD-L1 and ameliorate inflammation in mice.
  8. Improving Cardiovascular Risk Factors in Survivors of Cancer.
  9. Mitochondria at the membrane provide a route to inflammatory cell death.
  10. Feeding-regulated glycogen metabolism drives rhythmic liver protein secretion.
  11. Vaccinations Dip Among Older Adults.
  12. Who does academic consulting serve?
  13. Integrative functional genomics analysis identifies pleiotropic genes for vascular diseases.
  14. Sclerostin deficiency sensitizes white adipocytes to thermogenic signals that induce beiging in mice.
  15. Immune cells from the gut drive development of Parkinson's disease in the brain.
  16. Pregnancy quenches inflammation through neuroimmune crosstalk.
  17. PtdIns(3,5)P2 is an endogenous ligand of STING in innate immune signalling.
  18. Splice isoform-perturbation coupled to single cell transcriptome profiling reveals functions of microexons in neurogenesis and autism-linked pathways.
  19. Inhibition of stress resilience and adult hippocampal neurogenesis by platelet-derived LPA16:0 in anxiety.
  20. B cell-intrinsic IL-2 signaling regulates inflammation by promoting IL-10 expression in CD25+ age-associated B cells.
  21. MerTK-triggered TGFβ1 autocrine signal regulates microglial response to neurodegeneration.
  22. Gut microbiota-dependent 24-hydroxycholesterol metabolism contributes to capsaicin-induced amelioration of Alzheimer's disease-like pathology in mice.
  23. A vascularized liver microphysiological system captures key features of hepatic insulin resistance and monocyte infiltration.
  24. TGFBI promotes liver fibrosis through remodeling the profibrotic microenvironment by a positive feedback regulatory loop.
  25. ER remodelling is a feature of ageing and depends on ER-phagy.
  1. Nat Metab. 2026 Feb 03.
    Mitochondrial superoxide signals shield the nucleus to delay ageing.
      
    DOI:  https://doi.org/10.1038/s42255-026-01461-8
  2. Nat Metab. 2026 Feb 06.
    Mitochondrial SLC6A6 supports taurine transport.
    Katsuhisa Inoue.
      
    DOI:  https://doi.org/10.1038/s42255-026-01471-6
  3. Nat Immunol. 2026 Feb;27(2): 169
    Plastic microglia.
    Ioana Staicu.
      
    DOI:  https://doi.org/10.1038/s41590-026-02424-7
  4. Cell Metab. 2026 Feb 03. pii: S1550-4131(25)00587-X. [Epub ahead of print]38(2): 252-253
    Peeing your immune troubles away.
    David S Schneider.
      The tradeoff of activating an immune response is that it can hurt the host as well as the pathogen. The work by Troha et al.1 shows that mice suffering from systemic inflammation can reduce the harm circulating cytokines cause by excreting them in urine.
    DOI:  https://doi.org/10.1016/j.cmet.2025.12.023
  5. Immunity. 2026 Jan 30. pii: S1074-7613(26)00038-5. [Epub ahead of print]
    Targeting immune cells in the aged brain reveals that engineered cytokine IL-10 enhances neurogenesis and improves cognition.
    Paloma Navarro Negredo, Justin You, Max Hauptschein, Adam B Schroer, Daniel J Richard, Gita C Abhiraman, Andy P Tsai, Eric D Sun, Giulia Notarangelo, Julliana Ramirez-Matias, Olivia Y Zhou, Matthew T Buckley, Karen E Malacon, Lucy Xu, Juliana Sucharov, Eduardo Ramirez Lopez, Lora Picton, Tony Wyss-Coray, Robert A Saxton, Ricardo A Fernandes, Saul A Villeda, K Christopher Garcia, Anne Brunet.
      The immune system could play an important role in the age-related decline in brain function, yet specific immune-based strategies to enhance brain resilience in older individuals are lacking. Here, we combined engineered proteins and direct brain delivery to target immune cell populations within the old brain. We detected T cells with an exhaustion signature in the old brain and targeted them with a potent engineered checkpoint inhibitor (RIPR-PD1). This led to T cell expansion and strong pro-inflammatory responses in many brain cell types, notably microglia. To rescue age-related inflammatory imbalances in microglia, we used the anti-inflammatory cytokine interleukin (IL)-10. IL-10 boosted anti-inflammatory responses in old microglia, but it also triggered pro-inflammatory signaling. An engineered IL-10 variant that uncouples pro- and anti-inflammatory responses positively impacted the transcriptome of multiple cell types, enhanced neurogenesis, and improved cognition in aged mice. Our findings pave the way for immunotherapies for the aged brain.
    Keywords:  T cells; brain aging; checkpoint inhibitors; engineered proteins; inflammation; interleukin-10; microglia; neuro-immune interactions; neurogenesis; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.immuni.2026.01.016
  6. Nat Commun. 2026 Feb 06.
    Zebrafish macrophages convert physical wound signals into rapid vascular permeabilization.
    Zaza Gelashvili, Zhouyang Shen, Yanan Ma, Mark Jelcic, Philipp Niethammer.
      Blood vessels near injury sites rapidly dilate, become permeable, and release serum and leukocytes into the wounded tissue to support healing and regeneration. How the vasculature senses distant homeostatic tissue perturbations within seconds-to-minutes remains incompletely understood. Using high-speed imaging of live zebrafish larvae, we monitor two hallmark vascular responses to injury: vessel dilation and serum exudation. By genetic, pharmacologic, and osmotic perturbation along with leukocyte depletion, we show that the cPla2 nuclear membrane mechanotransduction pathway converts a ~ 50 μm/s osmotic wound signal into rapid vessel-permeabilization via perivascular macrophages, 5-lipoxygenase (Alox5a), and leukotriene A4 hydrolase (Lta4h). By revealing a previously undescribed physiological function of nuclear membrane mechanotransduction, we provide real-time insights into the long-range communication of wounds and blood vessels in intact tissue.
    DOI:  https://doi.org/10.1038/s41467-026-68520-2
  7. Nat Commun. 2026 Feb 05.
    Acute peritonitis-induced adipose CD127+ ILC1s express PD-L1 and ameliorate inflammation in mice.
    Ritsu Nagata, Yuichi Akama, Pedro Goncalves, Nicolas Serafini, Tomoko Kageyama, Masami Kawasumi, Manami Satoh, Motomu Shimaoka, Hiroshi Ohno, Naoko Satoh-Takayama.
      Peritonitis is an inflammation of the peritoneum primarily caused by gut perforation and consequent bacterial leakage, a known cause of sepsis. Although adipose tissue is recognized as an immunologically active organ, the involvement of adipose tissue innate lymphoid cells (ILC) in regulating peritonitis remains poorly understood. Here, we employ a cecal ligation and puncture mouse model and demonstrate that circulating CD127- group 1 ILC (ILC1) migrate into the mesenteric adipose tissue (MAT) during the inflammatory period of peritonitis. CD127- ILC1s undergo phenotypic changes to become CD127+ ILC1s, resulting in an increased number of CD127+ ILC1s in the MAT. We also show that this population of CD127+ ILC1s expresses PD-L1, exhibits low IFN-γ production, and potentially acts as a negative regulator of TNF production by γδ T cells, thereby controlling acute peritonitis. Our findings suggest that MAT-CD127+ ILC1s play an important regulatory role in acute peritonitis and may represent a potential therapeutic target for sepsis.
    DOI:  https://doi.org/10.1038/s41467-026-69100-0
  8. JAMA Netw Open. 2026 Feb 02. 9(2): e2555772
    Improving Cardiovascular Risk Factors in Survivors of Cancer.
    Stephanie B Dixon, Bonnie Ky.
      
    DOI:  https://doi.org/10.1001/jamanetworkopen.2025.55772
  9. Cell Metab. 2026 Feb 03. pii: S1550-4131(25)00550-9. [Epub ahead of print]38(2): 260-262
    Mitochondria at the membrane provide a route to inflammatory cell death.
    Zezhao Chen, Daichao Xu.
      In a recent issue of Cell, Wang et al. identify "mitoxyperilysis," a previously unknown lytic cell death pathway where combined innate immune and metabolic stress triggers prolonged mitochondria-plasma membrane contact, causing local oxidative damage and membrane rupture. This mTORC2-regulated process identifies a therapeutic axis for inflammatory diseases and cancer.
    DOI:  https://doi.org/10.1016/j.cmet.2025.12.019
  10. Nat Metab. 2026 Feb 05.
    Feeding-regulated glycogen metabolism drives rhythmic liver protein secretion.
    Meltem Weger, Daniel Mauvoisin, Dominic Hoyle, Jingkui Wang, Eva Martin, James Rae, Charles Ferguson, Glynis Klinke, Michelle Cielesh, Kyle L Macauslane, Mark Larance, Manfredo Quadroni, Iain Templeman, Jean-Philippe Walhin, Leonidas G Karagounis, James A Betts, Jonathan D Johnston, Fanny Durussel, Dmitri Firsov, Stephane Fournier, Olivier Müller, Benjamin L Schulz, Robert G Parton, Benjamin D Weger, Frédéric Gachon.
      The liver has a key role in inter-organ communication by secreting most circulating plasma proteins. However, the mechanisms governing hepatic protein secretion remain unclear. Here we show that hepatic protein secretion follows a diurnal rhythm regulated by food intake in humans and mice. Using liver microsomal proteomics, we find that proteins implicated in the early secretory pathway, such as protein glycosylation and folding in the endoplasmic reticulum (ER) and Golgi apparatus, exhibit a rhythmic expression profile, which is abolished in Bmal1-knockout mice. Mechanistically, we show that hepatic glycogenolysis provides substrates for protein N-glycosylation. In mice, perturbing hepatic glycogenolysis with pharmacological or nutritional interventions leads to ER stress and attenuates diurnal protein secretion. We confirm these results in humans, as genetic variants associated with glycogen storage disease and congenital disorders of glycosylation also alter hepatic protein secretion. Overall, our work uncovers hepatic glycogen metabolism as a circadian regulator of protein secretion.
    DOI:  https://doi.org/10.1038/s42255-026-01453-8
  11. JAMA. 2026 Feb 06.
    Vaccinations Dip Among Older Adults.
    Samantha Anderer.
      
    DOI:  https://doi.org/10.1001/jama.2025.26382
  12. Nature. 2026 Feb;650(8100): 266
    Who does academic consulting serve?
    Nicolás C Zanetta-Colombo.
      
    Keywords:  Funding; Research management; Scientific community
    DOI:  https://doi.org/10.1038/d41586-026-00343-z
  13. Nat Commun. 2026 Feb 05.
    Integrative functional genomics analysis identifies pleiotropic genes for vascular diseases.
    Charles U Solomon, David G McVey, Catherine Andreadi, Peng Gong, Lenka Turner, Dedrick S S Song, Heming Zhang, Dominic P Lee, Elisavet Karamanavi, Wei Yang, Jiapeng Chu, Runji Chen, Kim E Haworth, Chukwuemeka George Anene-Nzelu, Hui Li, Matthew J Denniff, Peter Y Li, Yanhong Zhang, Xiaoxin Huang, Gavin E Morris, Peter A Greer, Emma J Stringer, Haojie Yu, Roger S Y Foo, Gillian Douglas, Nilesh J Samani, Tom R Webb, Shu Ye.
      Several vascular diseases including coronary artery disease, hypertension, stroke, and abdominal aortic aneurysm, have significant genetic underpinnings. Genome-wide association studies have unveiled many genetic loci associated with one or more of these diseases. However, the causative genes at most of these loci are yet to be determined, which hampers the translation of the genetic findings into a better understanding of the disease mechanisms and the identification of new therapeutic targets. Here, in an integrative functional genomics analysis of these loci, we identify a panel of likely causal genes, some of which are pleiotropic for more than one of these vascular diseases. Pooled CRISPR knockout screen analyses of these likely causal genes indicate that many of them influence vascular smooth muscle cell behaviour, and validation experiments of selected genes confirm that FES, BCAR1, CARF and SMARCA4 exert such effects. Further functional experiments focusing on FES, a pleiotropic gene for both coronary artery disease and hypertension, show that it modulates the expression of genes involved in vascular remodeling and that Fes knockout in mice promotes atherosclerosis as well as raises blood pressure. These findings provide an insight into the genetic basis of vascular diseases and inform targets for therapeutic development.
    DOI:  https://doi.org/10.1038/s41467-026-69273-8
  14. Nat Commun. 2026 Feb 05.
    Sclerostin deficiency sensitizes white adipocytes to thermogenic signals that induce beiging in mice.
    Gillian M Choquette, Soohyun P Kim, Kevin J Wilkinson, Belen C Avelar, Sushrut Pathy, Zhu Li, Jasmine Wu, Susan Aja, Daniel L J Thorek, Michael J Wolfgang, Ryan C Riddle.
      Maintenance of bone mass is coordinated with adipose tissue function through the secretion of hormones and endocrine factors that act on the opposing tissue. Sclerostin, a small glycoprotein produced by osteocytes embedded within the bone matrix, potently suppresses bone formation by antagonizing Wnt/β-catenin signaling while stimulating adipose tissue accumulation via the same mechanism of action. Since sclerostin-deficient mice develop pockets of multilocular adipocytes in subcutaneous adipose, we investigate the influence of sclerostin on thermogenic and β3-adrenergic stimuli-induced white adipose tissue beiging. Here, we report that Sost gene expression in bone and serum sclerostin levels are induced by β3-adrenergic agonists via an adipose-to-bone relay. Gene knockout studies suggest sclerostin acts to inhibit adipose tissue beiging by modulating β-catenin, as male Sost-/- mice display a greater abundance of beige adipocytes after chronic treatment with CL316,243 or cold exposure. Likewise, housing at thermoneutrality is sufficient to eliminate the decrease in fat mass and increased insulin sensitivity evident in sclerostin mutants under standard conditions. We also demonstrate that co-administration of a β3-adrenergic agonist and a sclerostin neutralizing antibody synergistically influences metabolic parameters in a mouse obesity model. These data suggest utility in interrogating this interaction in the treatment of metabolic disorders.
    DOI:  https://doi.org/10.1038/s41467-026-69227-0
  15. Nature. 2026 Feb 04.
    Immune cells from the gut drive development of Parkinson's disease in the brain.
    Veerle Baekelandt.
      
    Keywords:  Neurodegeneration; Neuroscience; Parkinson's disease; Physiology
    DOI:  https://doi.org/10.1038/d41586-026-00284-7
  16. Nat Immunol. 2026 Feb 04.
    Pregnancy quenches inflammation through neuroimmune crosstalk.
    Thomas Korn.
      
    DOI:  https://doi.org/10.1038/s41590-026-02418-5
  17. Nature. 2026 Feb 04.
    PtdIns(3,5)P2 is an endogenous ligand of STING in innate immune signalling.
    Jay Xiaojun Tan, Bo Lv, Jie Li, Tuo Li, Fenghe Du, Xiang Chen, Xuewu Zhang, Xiao-Chen Bai, Zhijian J Chen.
      Exposure to cytosolic DNA triggers innate immune responses through cyclic GMP-AMP (cGAMP) synthase (cGAS)1,2,3. After binding to DNA, cGAS produces cGAMP as a second messenger that binds to stimulator of interferon genes (STING), a signalling adaptor protein anchored to the endoplasmic reticulum (ER)3-5. STING then traffics from the ER through the Golgi to perinuclear vesicle clusters, which leads to activation of the kinases TBK1 and IKK and subsequent induction of interferons and other cytokines6-9. Here we show that phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2; also known as PI(3,5)P2) is an endogenous ligand of STING that functions together with cGAMP to induce STING activation. Proteomic analyses identified a constitutive interaction between STING and PIKFYVE, an enzyme that produces PtdIns(3,5)P2 in mammalian cells. Deletion of PIKFYVE blocked STING trafficking from the ER and TBK1 activation. In vitro reconstitution uncovered a strong and selective effect of PtdIns(3,5)P2 on STING activation by cGAMP. PtdIns(3,5)P2 bound directly to STING in fluorescence resonance energy transfer assays. Consistently, cryo-electron microscopy revealed that PtdIns(3,5)P2 promotes cGAMP-induced STING oligomerization10, functioning as a molecular glue. Similar to PIKFYVE depletion, mutation of the PtdIns(3,5)P2-binding residues in STING largely blocked its trafficking and downstream signalling. These findings reveal that PtdIns(3,5)P2 is a lipid ligand of STING with essential roles in innate immunity.
    DOI:  https://doi.org/10.1038/s41586-025-10084-0
  18. Nat Commun. 2026 Feb 03. 17(1): 1217
    Splice isoform-perturbation coupled to single cell transcriptome profiling reveals functions of microexons in neurogenesis and autism-linked pathways.
    Steven J Dupas, Guillermo E Parada, Jack Daiyang Li, Kevin R Brown, Jason Moffat, Benjamin J Blencowe.
      A major goal of biomedical research is to assign functions to the myriad alternative RNA and protein isoforms. This challenge is particularly relevant to the mammalian nervous system, which produces complex repertoires of alternative splicing events. Here, we describe CHyMErA-seq, a platform that couples systematic deletion of exons to a single cell transcriptomics read-out, and apply this method to investigate a critical program of brain-specific microexons. Perturbation of microexons during neurogenesis reveals convergent roles in the temporal regulation of gene expression programs that direct signaling pathways and morphogenesis. We further observe microexons, including those in the Bin1, Clasp1, Gfra1, Med23, Ptprf and Ralgapb genes, that are required for the correct timing of autism-linked gene expression. Collectively, we describe a flexible system for isoform-resolution perturbation at a single cell level, together with insights into the roles of microexons in the developmental timing of neurogenesis transcriptomic signatures linked to brain disorders.
    DOI:  https://doi.org/10.1038/s41467-025-67931-x
  19. Nat Commun. 2026 Feb 06.
    Inhibition of stress resilience and adult hippocampal neurogenesis by platelet-derived LPA16:0 in anxiety.
    Thomas Larrieu, Fabio Grieco, Charline Carron, Marta Vilademunt, Crystal Weber, Kyllian Ginggen, Aurélie Delacrétaz, Hector Gallart-Ayala, Mumeko C Tsuda, Heather A Cameron, Chin B Eap, Julijana Ivanisevic, Pierre Magistretti, Evgenia Salta, Giorgia Tosoni, Dilara Ayyildiz, Ludovic Telley, Alexandre Dayer, Camille Piguet, Nicolas Toni.
      Anxiety is an aggravating comorbidity of many psychiatric disorders that is often underdiagnosed and undertreated, and little is known on the mechanisms underlying its regulation. Here, we find that serum LPA16:0 abundance increases with trait anxiety in both humans and mice; while high LPA16:0 levels are sufficient to reduce the in vitro proliferation of adult hippocampal neural stem/progenitor cells. In humans, the main LPA receptor LPA1, bears single nucleotide polymorphism variants associated with anxiety. In mice, LPA16:0 decreases hippocampal neurogenesis and stress resilience, whereas LPA1 antagonism or the reduction of platelets, the main source of circulating LPA16:0, increases adult neurogenesis and resilience to acute stress. Conditional knockdown of LPA₁ receptor in neural stem cells is sufficient to enhance cell proliferation in the dentate gyrus. Finally, the inhibition of adult neurogenesis abolishes the beneficial effect of LPA1 antagonism on resilience against both acute and chronic stress. Together, these findings identify circulating LPA16:0 as a biomarker of trait anxiety and LPA16:0-LPA1 signaling as a regulation mechanism of mood-related behavior through the decrease of adult neurogenesis.
    DOI:  https://doi.org/10.1038/s41467-026-69240-3
  20. Immunity. 2026 Jan 30. pii: S1074-7613(26)00037-3. [Epub ahead of print]
    B cell-intrinsic IL-2 signaling regulates inflammation by promoting IL-10 expression in CD25+ age-associated B cells.
    Juliette Gauthier, Maxime Maugendre, Simon Léonard, Yoni Desvois, Maïwenn Pineau, Romain Pinon, Nicolas Hipp, Karin Tarte, Patricia Amé, Sophie Hillion, Laure Michel, Céline Delaloy.
      Interleukin (IL)-2 can impact both plasma cell (PC) differentiation and the generation of IL-10pos B cells. We generated mice bearing a B cell-specific deletion of Il2rb (Il2rbΔB) to define the B cell-intrinsic role of IL-2. Il2rbΔB mice displayed normal B cell development and homeostasis but increased extrafollicular PC responses upon immunization. In vitro, IL-2 sustained both PC differentiation and expression of a regulatory program. In vivo, IL-2 signaling defined a PDCA-1pos splenic B cell subset exhibiting age-associated B cell (ABC) features. Mechanistically, synergistic IL-2 and IFN-γ signaling induced expression of the transcription factor Maf in these ABC progenitors. MAF promoted IL-10 expression and repression of pro-inflammatory programs. In a preclinical multiple sclerosis model, CD25pos ABCs contributed to the pool of protective regulatory B cells, and loss of IL-2 signaling reduced IL-10pos B cells in the central nervous system and exacerbated neuroinflammation. Thus, IL-2 signaling promotes the generation of IL-10pos ABCs, with implications for autoimmunity and inflammation.
    Keywords:  EAE; IL-10; IL-2; MAF; PDCA-1 B cells; age-associated B cell; inflammation; mice model; plasma cell differentiation; regulatory B cell
    DOI:  https://doi.org/10.1016/j.immuni.2026.01.015
  21. Nat Commun. 2026 Feb 03.
    MerTK-triggered TGFβ1 autocrine signal regulates microglial response to neurodegeneration.
    Yingying Huang, Zhangyuzi Deng, Zhijie Zhou, Koukou Fu, Fuhai Liu, Haoyue Zhang, Jian Chen, Jing Yang, Ying Cao.
      Microglial phagocytosis exerts essential roles in neurodegeneration, but how phagocytic processes may reciprocally regulate microglia remains incompletely understood. Here, we report that microglial response in the mouse model of pathological axonal degeneration depends on the phagocytic receptor MerTK. The MerTK-triggered downstream phospholipase C signal is sufficient to induce the up-regulation of PU.1 and IRF8, the two central transcription factors governing microglial functions. Chromatin immunoprecipitation-sequencing analyses identify that PU.1 and IRF8 directly target the gene locus of TGFβ1, and disruption of this PU.1-IRF8 targeting site abolishes the induction of microglial TGFβ1 during neurodegeneration. Of importance, neurodegeneration-induced TGFβ1 acts in an autocrine manner, and the microglia-specific deletion of TGFβ1 or its receptors TGFβR1 or TGFβR2 blocks microglial response. Moreover, microglial TGFβ1 autocrine signaling similarly occurs in the 5×FAD mouse model of Alzheimer's disease and in human patients. These results have delineated an important mechanism underlying microglial response to neurodegeneration.
    DOI:  https://doi.org/10.1038/s41467-026-69189-3
  22. Nat Commun. 2026 Feb 03.
    Gut microbiota-dependent 24-hydroxycholesterol metabolism contributes to capsaicin-induced amelioration of Alzheimer's disease-like pathology in mice.
    Yawen Li, Hui Wang, Dongyuan Zhang, Shiqi Wang, Zheng Li, Jingjie Li, Shentao Tai, Dandan Tong, Bifeng Wang, Dingbing Lu, Shulu Yuan, Weiqi Sun, Biyu Yang, Chaobo Bai, Qi Wang, Jiuyang Ding, Zhihao Wang, Yang Gao, Haitao Yu, Kun Cui, Chang Liu, Jian Mao, Yun Yao, Fengyu Liu, You Wan, Junliang Yuan, Xuemei Liu, Jie Zheng.
      Dietary capsaicin intake appears to affect the pathogenesis of Alzheimer's disease (AD), while the underlying mechanisms remain unclear. Here, we found in human cohorts that moderate-to-high level of dietary capsaicin intake was associated with improved cognitive performance. Similarly, long-term oral capsaicin administration in male 5×FAD mice ameliorated AD-like pathologies and reshaped gut microbial composition. Gut microbiota transfer from capsaicin-treated mice produced similar effects of capsaicin intake. Moreover, capsaicin elevated the level of host 24(S)-hydroxycholesterol (24-HC), relating to the increase of gut Oscillibacter genus abundance. The 24-HC elevation enhanced microglial phagocytic activity in the brain, and inhibited proinflammatory factors production via liver x receptor β (LXRβ)-mediated transcriptional regulation. Finally, we observed elevation of 24-HC in plasma in AD patients with higher level of dietary capsaicin intake, which correlated with cognitive scores and plasma Aβ and p-tau biomarkers. These findings suggest the potential of capsaicin or capsaicin-rich diets in the prevention or treatment of AD and related diseases.
    DOI:  https://doi.org/10.1038/s41467-026-68937-9
  23. Nat Commun. 2026 Feb 03. 17(1): 950
    A vascularized liver microphysiological system captures key features of hepatic insulin resistance and monocyte infiltration.
    Erin N Tevonian, Ellen L Kan, Kairav K Maniar, Alex J Wang, Anisha Datta, Roger D Kamm, Douglas A Lauffenburger, Linda G Griffith.
      In vitro models can recapitulate aspects of human liver diseases, thereby aiding therapeutic development. Dynamic interactions with vascular and immune cells contribute to disease progression in ways that are challenging to capture in the hepatic spheroid models commonly used for assessing facets of metabolism and disease. To address this, we developed a microphysiological system (MPS) featuring multicellular human hepatic spheroids physically integrated with self-organized microvascular networks. We demonstrate this MPS's utility by modeling an insulin resistance state, where chronic exposure to disease-mimetic conditions yields altered hepatocyte metabolism, dysregulated vascular features, and increased inflammation state. We extend this system to capture disease-relevant changes in immune cell recruitment, showing that monocytes perfused through the vasculature will extravasate toward hepatic spheroids, with insulin-resistant samples exhibiting greater infiltration. Altogether, this vascularized liver MPS captures local hepatocyte-immune-microvascular interactions in an accessible microfluidic platform, enabling the study of clinically relevant immune-tissue interactions in complex metabolic disease.
    DOI:  https://doi.org/10.1038/s41467-025-68031-6
  24. Commun Biol. 2026 Feb 03.
    TGFBI promotes liver fibrosis through remodeling the profibrotic microenvironment by a positive feedback regulatory loop.
    Heming Wu, Xueqian Yan, Lijun Kuang, Yanfei Zhang, Shuting Ye, Rui Huang, Yuehua Zhang, Gaoliang Ouyang, Tiantian Wu, Fan Liu, Yingfu Liu.
      Liver fibrosis is a major global health burden with limited treatment options. Transforming growth factor-beta-induced protein (TGFBI) is crucial in fibrotic diseases and tumors, however, its precise mechanism in liver fibrosis remains unclear. Here we show that TGFBI promotes liver fibrosis in male C57BL/6 mice. TGFBI is upregulated in fibrotic livers and derived from non-parenchymal cells. Genetic TGFBI deficiency alleviates liver fibrosis in both CCl4 (carbon tetrachloride) injection and bile duct ligation (BDL) models. Mechanistically, PDGFRβ is identified via RNA sequencing as a key downstream molecule upregulated by TGFBI in hepatic stellate cells (HSCs) via the integrin αvβ3-FAK-STAT3 pathway, promoting HSC proliferation and activation. Meanwhile, TGFBI increases PDGF-B expression in macrophages through the integrin αvβ3-AKT-ERK pathway, driving their proliferation, migration and differentiation into the profibrotic TREM2+CD9+ subpopulation. Elevated PDGF-B reversely stimulates TGFBI production in macrophages, which creates a positive feedback loop. This TGFBI-mediated interaction between HSCs and macrophages remodels the profibrotic microenvironment to promote liver fibrosis, identifying a potential therapeutic target.
    DOI:  https://doi.org/10.1038/s42003-026-09601-2
  25. Nat Cell Biol. 2026 Feb 02.
    ER remodelling is a feature of ageing and depends on ER-phagy.
    Eric K F Donahue, Nathaniel L Hepowit, Elizabeth M Ruark, Alexandra G Mulligan, Brennen Keuchel, Nicholas D Urban, Li Peng, Stedman Stephens, Derek J Johnson, Natalie S Wallace, Lauren P Jackson, Mark H Ellisman, Rafael Arrojo E Drigo, Andrew W Folkmann, Matthias C Truttmann, Jason A MacGurn, Kristopher Burkewitz.
      The endoplasmic reticulum (ER) comprises an array of subdomains, each defined by a characteristic structure and function. Although altered ER processes are linked to age-onset pathogenesis, it is unclear whether shifts in ER structure or dynamics underlie these functional changes. Here we establish ER structural and functional remodelling as a conserved feature of ageing across yeast, Caenorhabditis elegans and mammals. Focusing on C. elegans as the exemplar of metazoan ageing, we reveal striking age-related reductions in ER volume across diverse tissues and a morphological shift from rough sheets to tubular ER. This morphological transition corresponds with large-scale shifts in ER proteome composition from protein synthesis to lipid metabolism, a phenomenon conserved in mammalian tissues. We show that Atg8 and ULK1-dependent ER-phagy drives age-associated ER remodelling through tissue-specific factors, including the previously uncharacterized ER-phagy regulator TMEM-131 and the IRE-1-XBP-1 branch of the unfolded protein response. Providing support for a model where ER remodelling is adaptive, diverse lifespan-extending paradigms downscale and remodel ER morphology throughout life. Furthermore, mTOR-dependent lifespan extension in yeast and worms requires ER-phagy, indicating that ER remodelling is a proactive and protective response during ageing. These results reveal ER-phagy and ER dynamics as pronounced, underappreciated mechanisms of both normal ageing and age-delaying interventions.
    DOI:  https://doi.org/10.1038/s41556-025-01860-1
This page is being maintained by Thomas Krichel. It was last updated on 2026‒02‒09 at 9:30.