bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–03–22
sixteen papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Python metabolomics uncovers a conserved postprandial metabolite and gut-brain feeding pathway.
  2. Seeing lipids where they live.
  3. Single-cell multi-omic analysis of mitochondrial mutational mosaicism and dynamics.
  4. Can weight-loss pills replace injectables? What the science says.
  5. Masked mitochondria slip into cells to treat disease in mice.
  6. Strength persists after a mid-life course of obesity drugs.
  7. Stress can cause eczema to flare up - now we know why.
  8. FGF1 orchestrates circadian hepatic triglyceride secretion.
  9. Faster ticking of 'biological clock' predicts shorter lifespan.
  10. Targeting lipid droplets in the management of MASLD.
  11. Cell type-specific enhancers regulate IL-22 expression in innate and adaptive type 3 lymphoid cells.
  12. Prasugrel inhibits TLR7-driven autoimmunity in systemic lupus erythematosus by acetylating cGAS.
  13. Distinct origins and niches determine the cellular responsiveness of CNS macrophages after repopulation.
  14. Mitochondrial control of glycerolipid synthesis by a PEP shuttle.
  15. Calcium-mediated calreticulin-IRE1α interaction drives dynamic fluctuation of IRE1α activity under chronic endoplasmic reticulum stress.
  16. A sympathetic-eosinophil axis orchestrates psychological stress to exacerbate skin inflammation.
  1. Nat Metab. 2026 Mar 19.
    Python metabolomics uncovers a conserved postprandial metabolite and gut-brain feeding pathway.
    Shuke Xiao, Mengjie Wang, Thomas G Martin, Barry Scott, Xing Fang, Xinming Liu, Yongjie Yang, Sipei Fu, Steven D Truong, Jack F Gugel, Gregory L Maas, Marcus P Mullen, Jennifer Hampton Hill, Veronica L Li, Andrew L Markhard, Mingming Zhao, Wei Qi, Saranya C Reghupaty, Meng Zhao, Jan Spaas, Wei Wei, Trine Moholdt, John A Hawley, Christian T Voldstedlund, Erik A Richter, Xiaoke Chen, Katrin J Svensson, Daniel Bernstein, Leslie A Leinwand, Yong Xu, Jonathan Z Long.
      Most mammals consume small and frequent meals. By contrast, pythons are ambush predators that exhibit extreme feeding and fasting patterns and provide a unique model for uncovering molecular mediators of the postprandial response1-3. Using untargeted metabolomics, we show that circulating levels of the metabolite para-tyramine-O-sulphate (pTOS) are increased more than 1,000-fold in pythons after a single meal. In pythons, pTOS production occurs in a microbiome-dependent manner via sequential decarboxylation and sulphation of dietary tyrosine. In both pythons and mice, pTOS administration activates a neural population in the ventromedial hypothalamus (VMH). In mice, these VMH neurons are required for the anorexigenic effects of pTOS. Chronic administration of pTOS to diet-induced obese male mice suppresses food intake and body weight. pTOS is also present in human blood, where its levels are increased after a meal. Together, these data uncover a conserved postprandial anorexigenic metabolite that links nutrient intake to energy balance.
    DOI:  https://doi.org/10.1038/s42255-026-01485-0
  2. Nat Cell Biol. 2026 Mar 20.
    Seeing lipids where they live.
    Aubrey Weigel.
      
    DOI:  https://doi.org/10.1038/s41556-026-01919-7
  3. Nat Commun. 2026 03 16. pii: 2532. [Epub ahead of print]17(1):
    Single-cell multi-omic analysis of mitochondrial mutational mosaicism and dynamics.
    Yu-Hsin Hsieh, Pauline Kautz, Lena Nitsch, Ambre M Giguelay, Janet Liebold, Veronika Dimitrova, Stephania Contreras Castillo, Freya Jungen, Gabor Zsurka, Genevieve Trombly, Markus Schuelke, Wolfram S Kunz, Caleb A Lareau, Leif S Ludwig.
      Mitochondrial DNA (mtDNA) mutations occur more frequently than nuclear mutations and are associated with various diseases. While single-cell sequencing enables mtDNA variant heteroplasmy analysis, a holistic view of mtDNA mutational landscapes in individual cells has remained limited. Here, we leverage mitochondrial single-cell ATAC-seq and mtDNA-hypermutated POLGD274A knock-in HEK293 cell lines to introduce two metrics-single-cell mtDNA mutations per million base pairs (scmtMPM) and heteroplasmy-weighted mitochondrial local constraint scores (scwMSS)-to capture cellular mutational loads and somatic mosaicism. We demonstrate that individual POLGD274A cells exhibit complex mutational landscapes, with pathogenic mutations and truncating variants only present at subthreshold levels, indicative of their negative selection. In human healthy donors and mitochondriopathy patients, we identify constrained mutations in complex I, highlighting previously unrecognized mtDNA mutational landscape heterogeneity present on the single-cell level. Overall, scmtMPM and scwMSS provide a framework to investigate fundamental properties of mitochondrial genetics, disease, and somatic mosaicism.
    DOI:  https://doi.org/10.1038/s41467-026-70399-y
  4. Nature. 2026 Mar 17.
    Can weight-loss pills replace injectables? What the science says.
    Mariana Lenharo.
      
    Keywords:  Diabetes; Medical research; Metabolism; Obesity
    DOI:  https://doi.org/10.1038/d41586-026-00856-7
  5. Nature. 2026 Mar 19.
    Masked mitochondria slip into cells to treat disease in mice.
    Edward Chen.
      
    Keywords:  Cell biology; Gene therapy; Medical research; Metabolism
    DOI:  https://doi.org/10.1038/d41586-026-00869-2
  6. Nature. 2026 Mar 19.
    Strength persists after a mid-life course of obesity drugs.
      
    Keywords:  Metabolism
    DOI:  https://doi.org/10.1038/d41586-026-00852-x
  7. Nature. 2026 Mar 19.
    Stress can cause eczema to flare up - now we know why.
    Miryam Naddaf.
      
    Keywords:  Immunology; Neuroscience; Sensory systems
    DOI:  https://doi.org/10.1038/d41586-026-00876-3
  8. Nat Commun. 2026 Mar 19.
    FGF1 orchestrates circadian hepatic triglyceride secretion.
    Benan Pelin Sermikli, Sihao Liu, Kyeongkyu Kim, Linnea Hases, Tim van Zutphen, Ashley Untereiner, Jocelyn Torres, Mingxiao He, Lillian Crossley, Yang Dai, Jonathan Zhu, Chandra Lekha Koopari, Weiwei Fan, Morgan L Truitt, Johan W Jonker, Annette R Atkins, Michael Downes, Ronald M Evans.
      Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) represents a global health crisis associated with dysregulated hepatic triglyceride (TG) synthesis, oxidation and secretion. Despite progress in targeting hepatic lipid synthesis/oxidation for MASLD treatment and a well-documented relationship between circadian rhythms and lipid metabolism, the adaptive mechanisms coordinating TG secretion with circadian timing remain incompletely understood. Here we identify an autocrine regulatory pathway where circadian hepatic Fibroblast Growth Factor 1 (Fgf1) expression synchronizes diurnal TG secretion with the active phase. FGF1 activation of FGFR4 induces an mTORC1-IRE1-XBP1 signaling cascade involving atypical IRE1 activation that promotes TG secretion. Consistently, dietary-driven MASLD is exacerbated in liver-specific FGF1 knockout mice, while exogenous FGF1 halts disease progression in a Metabolic dysfunction-Associated Steatohepatitis (MASH) mouse model. This study causally associates FGF1 circadian rhythmicity with TG secretion to establish FGF1 as a crucial pacemaker in hepatic lipid homeostasis.
    DOI:  https://doi.org/10.1038/s41467-026-70849-7
  9. Nature. 2026 Mar 19.
    Faster ticking of 'biological clock' predicts shorter lifespan.
      
    DOI:  https://doi.org/10.1038/d41586-026-00866-5
  10. Gut. 2026 Mar 18. pii: gutjnl-2026-338145. [Epub ahead of print]
    Targeting lipid droplets in the management of MASLD.
    Sepideh Mikaeeli, David E Cohen.
      
    Keywords:  FATTY LIVER; LIPIDS; LIVER; METABOLIC DYSFUNCTION-ASSOCIATED STEATOHEPATITIS
    DOI:  https://doi.org/10.1136/gutjnl-2026-338145
  11. Nat Commun. 2026 Mar 14.
    Cell type-specific enhancers regulate IL-22 expression in innate and adaptive type 3 lymphoid cells.
    Ankita Saini, Leone S Hopkins, Vanida A Serna, Matthew V D McCullen, Nicholas G Selner, Bishan Bhattarai, José L Fachi, Rebecca A Glynn, Katharina E Hayer, Craig H Bassing, Marco Colonna, Eugene M Oltz.
      IL-22, a signature cytokine for type 3 lymphoid cells, including T helper 17/22 (Th17/22) and type 3 innate lymphoid cells (ILC3), mediates epithelial homeostasis and protective pathogen responses in barrier tissues. Upon dysregulation, IL-22 can drive chronic inflammatory diseases, yet little is known about transcriptional elements modulating its expression. Here, we identify two enhancers, E22-1 and E22-2, with distinct capacities for regulating Il22 expression in type 3 lymphoid cells. Both enhancers are necessary for protection from Citrobacter rodentium infection and for the onset of IL-22-mediated psoriasis. E22-2 is specifically required for IL-22 expression in ILC3s, while E22-1 functions in both Th17/22 and ILC3. The ILC3 specificity of E22-2 is attributed to the presence of multiple Runx3 sites and the lack of a functional RORγt motif. We conclude that Th17/22 and ILC3 cells use distinct cis-elements to differentially regulate IL-22 expression, while orchestrating homeostatic protection and pathogen defense in barrier tissues.
    DOI:  https://doi.org/10.1038/s41467-026-70636-4
  12. Nat Commun. 2026 Mar 18.
    Prasugrel inhibits TLR7-driven autoimmunity in systemic lupus erythematosus by acetylating cGAS.
    Zeng-Lin Guo, Li-Ming Sun, Shuai Jiang, Ming Zhao, Yuhui Li, Jinjing Qian, Yakai Fu, Chunmei Wu, Ying Yuan, Wen Xue, Shao-Zhen Jiang, Sen-Chao Yuan, Xucheng Lv, Xingxing Yang, Lehua Yin, Peng-Peng Zhu, Yu Yu, Xin Xu, Kai Wang, Qiu-Ying Han, Zhuoxin Li, Zhi-Hui Su, Xi-Ping Yu, Jiaqi Wu, Hong Cai, Tian Xia, Yuan Chen, Xue-Min Zhang, Wei-Hua Li, Ai-Ling Li, Tao Zhou, Zhanguo Li, Qiong Fu, Xinhua He, Tao Li.
      Systemic lupus erythematosus (SLE) has a complex, multifactorial etiology, which contributes to a lack of definitive cure and limited treatment efficacy. Here, we report that cyclic GMP-AMP synthase (cGAS) is significantly activated in SLE patients. We further demonstrate that cGAS deletion protects mice from lupus-like symptoms induced by the TLR7 agonist imiquimod (IMQ). In a screen of 3,159 FDA-approved drugs, we identify the antiplatelet agent prasugrel as a potent cGAS inhibitor. Mechanistically, prasugrel disrupts the DNA-triggered liquid phase condensation and activation of cGAS via direct acetylation. Strikingly, we find that prasugrel exhibits remarkable efficacy in treating SLE in both mouse models and patient cells. Importantly, we report elevated plasma cyclic GMP-AMP (cGAMP) in SLE patients and identify it as a potential biomarker for predicting prasugrel response. Thus, our work elucidates the essential role of cGAS in SLE pathogenesis and presents prasugrel as a promising therapeutic option with immediate translational potential.
    DOI:  https://doi.org/10.1038/s41467-026-70794-5
  13. Nat Immunol. 2026 Mar 18.
    Distinct origins and niches determine the cellular responsiveness of CNS macrophages after repopulation.
    Maximilian Fliegauf, Damien Levard, Francesco Cardamone, Maximilian Frosch, Siegmar Kuhn, Roman Sankowski, Martino Provinciali, Anaelle Aurelie Dumas, Adrià Dalmau Gasull, Philipp Aktories, Alexander Oschwald, Marius Schwabenland, Rebekka Scholz, Marc D Beyer, Jonas J Neher, Michael Kollefrath, Dimos Baltas, Wilfried Reichardt, Dominik von Elverfeldt, Denis Vivien, Jovana Cupovic, Nicola Iovino, Marina Rubio, Lukas Amann, Marco Prinz.
      Nonparenchymal central nervous system (CNS)-associated macrophages (CAMs) mediate immune responses at brain boundaries. Perivascular and leptomeningeal CAMs are collectively termed subdural CAMs (sdCAMs). Both sdCAMs and juxtaneuronal microglia are derived from embryonic yolk sac precursors, long-living and maintain their populations through self-renewal. Following depletion, microglia autonomously repopulate from single surviving cells. In contrast, the course of sdCAM repopulation remains poorly understood. Here, by combining multilineage fate mapping, multiomic profiling and high-resolution imaging, we demonstrate divergent repopulation dynamics between sdCAMs and microglia. Unlike microglia, sdCAMs do not renew cell-autonomously, but become transiently accessible to CCR2+Ly6C+ monocyte engraftment after niche induction in an integrin-dependent manner. Moreover, replenished monocyte-derived sdCAMs remain transcriptomically, epigenetically and functionally distinct from their embryo-derived counterparts. Finally, we present a protocol enabling selective exchange of sdCAMs, modulating disease response without functionally affecting microglia. These new insights into CNS immune biology suggest new therapeutic avenues for neuroinflammatory and neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s41590-026-02457-y
  14. Cell. 2026 Mar 17. pii: S0092-8674(26)00224-2. [Epub ahead of print]
    Mitochondrial control of glycerolipid synthesis by a PEP shuttle.
    Tadashi Yamamuro, Daisuke Katoh, Guilherme Martins Silva, Hiroshi Nishida, Satoshi Oikawa, Yusuke Higuchi, Dandan Wang, Masanori Fujimoto, Naofumi Yoshida, Mark Li, Jihoon Shin, Zezhou Zhao, Jin-Seon Yook, Lijun Sun, Shingo Kajimura.
      Mitochondria provide a variety of metabolites, in addition to ATP, to meet cell-specific needs. One such metabolite is phosphoenolpyruvate (PEP), which contains a higher-energy phosphate bond than ATP and has diverse biological functions. However, how mitochondria-generated PEP is delivered to the cytosol and fulfills cell-specific requirements remains elusive. Here, we show that SLC25A35 regulates mitochondrial PEP efflux and glyceroneogenesis in lipogenic cells that utilize the pyruvate-to-PEP bypass. Reconstitution and structural studies demonstrated PEP transport by SLC25A35 in a pH gradient-dependent manner. Loss of SLC25A35 in adipocytes impaired the conversion of mitochondrial PEP into glycerol-3-phosphate, thereby reducing glycerolipid synthesis. Significantly, hepatic inhibition of SLC25A35 in obese mice alleviated steatosis and improved systemic glucose homeostasis. Together, these results suggest that mitochondria facilitate glycerolipid synthesis by providing PEP via SLC25A35, offering lipogenic mitochondria as a target to limit glycerolipid synthesis, a pivotal step in the pathogenesis of hepatic steatosis and type 2 diabetes.
    Keywords:  bioenergetics; diabetes; glyceroneogenesis; hepatic steatosis; mitochondria; obesity
    DOI:  https://doi.org/10.1016/j.cell.2026.02.017
  15. Nat Commun. 2026 Mar 17.
    Calcium-mediated calreticulin-IRE1α interaction drives dynamic fluctuation of IRE1α activity under chronic endoplasmic reticulum stress.
    Jianwei Cao, Xudong Zhao, Yunxin Xu, Chen Yang, Yazhen Huo, Ting Li, Wenjia Gu, Lei Wang, Youjun Wang, Likun Wang.
      The unfolded protein response (UPR) triggered by endoplasmic reticulum (ER) stress can be both pro-survival or pro-apoptotic, depending on the duration and intensity of the stress. ER stress under (patho)physiological conditions can last for long time, yet the dynamic regulation of the UPR under prolong ER stress is largely unknown. Here, we characterized the UPR dynamics during pharmacologically induced long-term ER stress and revealed an "up-down-up" fluctuation pattern of the IRE1α signal in various types of cells. A fluctuation of the calreticulin-IRE1α interaction intensity orchestrates dynamic regulation of IRE1α activity, which negatively correlates with the intensity of the interaction between IRE1α and BIP, a known suppressor of IRE1α. The calreticulin-IRE1α interaction is negatively affected by Ca2+ concentration, which showed "down-up-down" pattern in the ER lumen over time. Furthermore, a circadian rhythmic fluctuation of calreticulin-IRE1α interaction intensity is observed in mouse liver, accompanied by oscillation of IRE1α phosphorylation level at regular physiological conditions. Our study suggests a calcium-mediated, calreticulin-driven IRE1α activity fluctuation, representing an intermediate status that the cell adopts to cope with chronic ER stress that may exist under both pathophysiological and physiological conditions.
    DOI:  https://doi.org/10.1038/s41467-026-70679-7
  16. Science. 2026 Mar 19. 391(6791): 1269-1277
    A sympathetic-eosinophil axis orchestrates psychological stress to exacerbate skin inflammation.
    Jiahe Tian, Yudian Cao, Yilei Li, Junlong Sun, Cheng Zhan, Wei Ni, Yongjun Zheng, Yanqing Wang, Shenbin Liu.
      Psychological stress is believed to exacerbate dermatitis, yet the neurobiological mechanisms linking stress to immune processes remain elusive. We identified a subset of prodynorphin-positive (Pdyn+) noradrenergic sympathetic neurons in mice that specifically innervate hairy skin, mediating stress-induced exacerbation of skin inflammation in an eosinophil-dependent manner. Genetic ablation of Pdyn+ sympathetic neurons or eosinophils mitigated stress-evoked worsening of inflammation in atopic dermatitis-like mice, whereas optogenetic activation of these neurons precipitated inflammation through eosinophils. Pdyn+ sympathetic neurons recruited eosinophils through the CCL11-CCR3 axis and activated them through the adrenergic receptor beta2 (Adrb2) in inflamed skin. Our findings reveal a neuroimmunological mechanism underlying psychological stress-induced exacerbation of dermatitis, emphasizing the Pdyn+ sympathetic-eosinophil axis as a crucial interface between the brain and skin inflammation, with potential therapeutic implications.
    DOI:  https://doi.org/10.1126/science.adv5974
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