bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–03–08
twenty-two papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Identification and characterization of dietary antigens in oral tolerance.
  2. Checkpoint blockade amplifies pro-regenerative type 2 immunity in tissue repair.
  3. Weighing in on the incretin revolution.
  4. Is glucagon action altered in steatotic liver disease?
  5. Lipid droplets meet mitochondria at the MIM protein insertase.
  6. Stress suppresses TRM cells.
  7. Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle.
  8. Somatic loss of the Y chromosome complements polygenic risk scores for type 2 diabetes risk prediction.
  9. Androgens help monocytes deliver pain relief.
  10. Magnetic gel injected into the heart could stop strokes.
  11. Multi-tissue transcriptomic aging atlas reveals predictive aging biomarkers in the killifish.
  12. Branched-chain α-keto acids impair glucose-stimulated insulin secretion in pancreatic β-cells under diabetes by reactivating the LDHA-lactate axis.
  13. Dual deconvolution in multiphoton structured illumination microscopy for deep-tissue super-resolution imaging.
  14. Function and regulation of the mitochondrial stress response.
  15. Gas-sensing neurons prime mitochondrial fitness to offset metabolic stress.
  16. Neutrophil-mediated anti-tumoral effects of caloric restriction.
  17. OMICmAge is a multiomic biological aging clock using electronic medical records.
  18. Lysine-11 ubiquitination drives type-I/III interferon induction by cGAS-STING and Toll-like receptors 3 and 4.
  19. Stress-hormone signalling protects spreading cancer cells from immune system.
  20. GPR146 in adipose tissue drives adipose-liver crosstalk and promotes hepatic steatosis in mice.
  21. Astrocytes engineered to fight Alzheimer's plaques.
  22. The glycolytic metabolite phosphoenolpyruvate restricts cGAS-driven inflammation to promote healthy aging.
  1. Sci Immunol. 2026 Mar 06. 11(117): eaeb4684
    Identification and characterization of dietary antigens in oral tolerance.
    Jamie E Blum, Ryan Kong, E A Schulman, Francis M Chen, Rabi Upadhyay, Gabriela Romero-Meza, Dan R Littman, Michael A Fischbach, Kazuki Nagashima, Elizabeth S Sattely.
      Food antigens elicit immune tolerance through the action of intestinal regulatory T (Treg) cells. Unlike food allergens, the proteins that mediate tolerance are mostly undescribed. Here, we found that epitopes derived from seed storage proteins are targets of murine intestinal Treg cells, with the most frequent response targeting the C terminus of the maize protein alpha-zein. A major histocompatibility complex (MHC) tetramer loaded with this antigen revealed that zein-specific T cells are predominantly intestinal Treg cells, develop concurrently with weaning, and constitute up to 2% of the peripheral Treg cell pool. Zein-responsive Treg cells repressed naïve T cell proliferation ex vivo, and prior dietary exposure resulted in a constrained response upon diverse inflammatory challenges in vivo, supporting a specific role for gut-resident Treg cells in suppressing systemic immune responses. Our work reveals the development, immune-suppressive characteristics, and function of naturally occurring Treg cells that recognize dietary seed storage proteins, a previously undescribed class of antigens in oral tolerance.
    DOI:  https://doi.org/10.1126/sciimmunol.aeb4684
  2. Nat Rev Immunol. 2026 Mar 05.
    Checkpoint blockade amplifies pro-regenerative type 2 immunity in tissue repair.
    Sinibaldo Romero Arocha, Alexander Clarke.
      
    DOI:  https://doi.org/10.1038/s41577-026-01285-3
  3. Nat Metab. 2026 Mar 04.
    Weighing in on the incretin revolution.
      
    DOI:  https://doi.org/10.1038/s42255-026-01490-3
  4. J Clin Invest. 2026 Mar 02. pii: e202425. [Epub ahead of print]136(5):
    Is glucagon action altered in steatotic liver disease?
    Raghavendra G Mirmira.
      
    DOI:  https://doi.org/10.1172/JCI202425
  5. Nat Cell Biol. 2026 Mar 05.
    Lipid droplets meet mitochondria at the MIM protein insertase.
      
    DOI:  https://doi.org/10.1038/s41556-026-01901-3
  6. Nat Immunol. 2026 Mar;27(3): 385
    Stress suppresses TRM cells.
    Stephanie Houston.
      
    DOI:  https://doi.org/10.1038/s41590-026-02465-y
  7. Cell. 2026 Feb 27. pii: S0092-8674(26)00115-7. [Epub ahead of print]
    Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle.
    Abigail Xie, Julia S Brunner, Sangita Chakraborty, Angela M Montero, Anna E Bridgeman, Katrina I Paras, Ruobing Cui, Maider Fagoaga-Eugui, Monika Komza, Paige K Arnold, Benjamin T Jackson, Santiago Noriega Madrazo, Mohamed I Atmane, Sebastian E Carrasco, Lydia W S Finley.
      The tricarboxylic acid (TCA) cycle couples nutrient oxidation with the generation of reducing equivalents that power oxidative phosphorylation. Nevertheless, the requirement for components of the TCA cycle is context-specific, raising the question of which TCA cycle outputs support cell fitness. Here, we demonstrate that citrate clearance is an essential function of the TCA cycle. As citrate production increases, so do TCA cycle activity and dependence upon aconitase 2 (ACO2), the enzyme that initiates citrate catabolism in the TCA cycle. Disrupting citrate catabolism activates the integrated stress response and impairs cell fitness, and these effects are reversed by preventing citrate production or promoting mitochondrial citrate efflux. In vivo, ACO2 deficiency induces citrate accumulation and triggers tubular degeneration in the kidney, a tissue that physiologically takes up circulating citrate. Thus, intracellular citrate accumulation can be a metabolic liability, and citrate clearance is a major function of ACO2 in the TCA cycle.
    Keywords:  ACO2; TCA cycle; cell metabolism; citrate; integrated stress response
    DOI:  https://doi.org/10.1016/j.cell.2026.01.028
  8. Nat Med. 2026 Mar 02.
    Somatic loss of the Y chromosome complements polygenic risk scores for type 2 diabetes risk prediction.
      
    DOI:  https://doi.org/10.1038/s41591-026-04214-y
  9. Nat Rev Immunol. 2026 Mar 05.
    Androgens help monocytes deliver pain relief.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-026-01287-1
  10. Nature. 2026 Mar 04.
    Magnetic gel injected into the heart could stop strokes.
    Nick Petrić Howe.
      
    Keywords:  Cardiovascular biology; Health care; Materials science
    DOI:  https://doi.org/10.1038/d41586-026-00740-4
  11. Nat Aging. 2026 Mar 03.
    Multi-tissue transcriptomic aging atlas reveals predictive aging biomarkers in the killifish.
    Emma K Costa, Jingxun Chen, Ian H Guldner, Lajoyce Mboning, Natalie Schmahl, Aleksandra Tsenter, Rahul Nagvekar, Man-Ru Wu, Patricia Moran-Losada, Louis-S Bouchard, Sui Wang, Param Priya Singh, Matteo Pellegrini, Anne Brunet, Tony Wyss-Coray.
      Aging is associated with progressive tissue dysfunction, leading to frailty and mortality. Characterizing aging features, such as changes in gene expression and dynamics, shared across tissues or specific to each tissue, is crucial for understanding systemic and local factors contributing to the aging process. We performed RNA sequencing on 13 tissues at six different ages in male and female African turquoise killifish, the shortest-lived vertebrate that can be raised in captivity. This comprehensive, sex-balanced 'atlas' dataset revealed varying strength of sex-age interactions across killifish tissues and age-altered genes and biological pathways that are evolutionarily conserved in mice and humans. We discovered a female-biased myeloid shift with age in the killifish hematopoietic organ, developed tissue-specific 'transcriptomic clocks' and identified biomarkers predictive of chronological age. We showed the importance of sex-specific clocks for selected tissues, validated the tissue clocks with an independent transcriptomic dataset and used them to evaluate different lifespan interventions in the killifish. Our work provides a comprehensive resource for studying aging dynamics across tissues in the killifish, a powerful vertebrate aging model.
    DOI:  https://doi.org/10.1038/s43587-026-01074-6
  12. Nat Commun. 2026 Mar 02.
    Branched-chain α-keto acids impair glucose-stimulated insulin secretion in pancreatic β-cells under diabetes by reactivating the LDHA-lactate axis.
    Huige Lin, Melody Yuen Man Ho, Baomin Wang, Shama Mansoori, Yumei Yang, Wen Wang, Pui Kin So, Aimin Xu, Shilun Yang, Junlei Chang, Ada Man Hau Man, Hailong Piao, Chen Gao, Parco Ming Fai Siu, Xiaomu Li, Kenneth King Yip Cheng.
      Dysmetabolism of branched-chain amino acid (BCAA) causes insulin resistance in type 2 diabetes, yet its effect on insulin-producing β-cells remains unclear. Here, we demonstrate that branched-chain α-ketoacids (BCKAs), derived from BCAAs, inhibited glucose-stimulated insulin secretion (GSIS) and glucose fluxes across human islets, mouse islets, and mouse β-cells. In diabetic humans, elevated circulating BCKAs negatively correlated with insulin secretory ability. Treatment with BCKA or its impaired catabolism suppressed GSIS in human islets and male mice, while reducing BCKA improved glucose tolerance and GSIS in male and female diabetic mice. Mechanistically, BCKA redirected glucose metabolism from the TCA cycle to the "β-cell disallowed" lactate dehydrogenase A (LDHA)-lactate axis. BCKA directly bound to LDHA, promoting its dimerization and enhancing enzymatic activity. β-cell-specific LDHA ablation restored GSIS and glucose tolerance in BCKA-fed male mice. Our findings demonstrate that BCKA disrupts insulin secretion through LDHA reactivation, linking aberrant BCAA metabolism to β-cell dysfunction in diabetes.
    DOI:  https://doi.org/10.1038/s41467-026-70004-2
  13. Nat Commun. 2026 Mar 04. pii: 2123. [Epub ahead of print]17(1):
    Dual deconvolution in multiphoton structured illumination microscopy for deep-tissue super-resolution imaging.
    Sumin Lim, Sungsam Kang, Jin Hee Hong, Young-Ho Jin, Kalpak Gupta, Moonseok Kim, Suhyun Kim, Wonshik Choi, Seokchan Yoon.
      Imaging in thick biological tissues is often degraded by sample-induced aberrations, which reduce resolution and contrast, particularly in super-resolution techniques. While hardware-based adaptive optics (AO) using wavefront shaping can correct these aberrations, their complexity and cost hinder widespread adoption. Here, we present a computational AO framework for multiphoton structured illumination microscopy, enabling deep-tissue super-resolution imaging with minimal hardware modifications. By replacing the photodetector with a camera from the conventional laser-scanning multiphoton microscope, we capture a sequence of scanned images. Using virtual structured illumination, we develop a dual deconvolution algorithm that independently corrects excitation and emission aberrations, recovering an aberration-free object spectrum with an extended spatial frequency bandwidth. We experimentally validate this framework through two-photon super-resolution imaging, achieving a lateral resolution of 130 nm-one-fourth of the emission wavelength-at a depth of 180 μm in thick mouse brain tissue, where conventional deconvolution fails to maintain super-resolution capability. This approach provides a cost-effective and accessible alternative to hardware-based AO, expanding the potential for high-resolution deep-tissue imaging in biological research.
    DOI:  https://doi.org/10.1038/s41467-026-69798-y
  14. Nat Struct Mol Biol. 2026 Mar 05.
    Function and regulation of the mitochondrial stress response.
    Joshua B Sheetz, Srividya Chandrasekhar, Michael Rapé.
      As mitochondria have crucial roles in metabolism and signaling, their structure and function must be continuously monitored and rapidly adjusted to meet cellular demands. Critical to this regulation is a conserved stress response that detects and alleviates challenges to mitochondrial integrity. Recent work has shown that mitochondrial stress often elicits simultaneous protective reactions that act in a coordinated and tightly regulated fashion to preserve this essential organelle. Here we review components, coordination and control within this comprehensive stress response and discuss how increased understanding of mitochondrial stress signaling is beginning to inform therapeutic approaches directed against diseases of high unmet need.
    DOI:  https://doi.org/10.1038/s41594-026-01769-9
  15. Proc Natl Acad Sci U S A. 2026 Mar 10. 123(10): e2525619123
    Gas-sensing neurons prime mitochondrial fitness to offset metabolic stress.
    Rebecca Cornell, Ava Handley, Roger Pocock.
      The mitochondrial unfolded protein response (UPRmt) is triggered by cells to alleviate proteotoxicity in response to metabolic stress. The ability to anticipate and prime cells against mitochondrial stress, by sensing potentially toxic changes in the external or internal environment, would provide a survival advantage. Yet, whether and how animals anticipate mitochondrial stress remains unclear. Here, we show that the Caenorhabditis elegans receptor guanylyl cyclase GCY-9 regulates neuropeptide signaling from carbon dioxide-sensing neurons to govern a noncanonical mitochondrial stress response in the intestine. This noncell autonomous stress response induces atypical mitochondrial chaperone transcription, confers mitochondrial stress resistance, and increases mitochondrial membrane potential and respiration. We show that starvation decreases GCY-9 expression and propose that the resultant cytoprotective program is launched to offset metabolic and proteotoxic risks. Thus, environmental sensing by peripheral neurons can preemptively enhance systemic mitochondrial function in response to metabolic uncertainty.
    Keywords:  Caenorhabditis elegans; gas-sensing; mitochondrial stress; neuropeptide
    DOI:  https://doi.org/10.1073/pnas.2525619123
  16. Cell Metab. 2026 Mar 03. pii: S1550-4131(26)00047-1. [Epub ahead of print]38(3): 443-444
    Neutrophil-mediated anti-tumoral effects of caloric restriction.
    Chin Sern Yiong, Melissa Shu Feng Ng.
      Caloric restriction confers several benefits in cancer, but the underlying mechanisms are not understood. In this issue of Cell Metabolism, Gao et al. highlight a newly identified neutrophil-dependent pathway modulated by caloric restriction.1.
    DOI:  https://doi.org/10.1016/j.cmet.2026.02.004
  17. Nat Aging. 2026 Mar 02.
    OMICmAge is a multiomic biological aging clock using electronic medical records.
      
    DOI:  https://doi.org/10.1038/s43587-026-01072-8
  18. Nat Cell Biol. 2026 Mar 06.
    Lysine-11 ubiquitination drives type-I/III interferon induction by cGAS-STING and Toll-like receptors 3 and 4.
    Alexis Betrancourt, M Talha Cinko, Ana Beatriz Varanda, Maykel Arias, Iratxe Uranga-Murillo, Natacha Peña, Lucia-Maria Kaps, Long Fung Chau, Bianca Buratti, Johannes Brägelmann, Diego de Miguel, Kerstin Becker, Ramona Casper, Rocio Martin, Antonio Alcami, Brian J Ferguson, Julian Pardo, Eva Rieser, Henning Walczak.
      Pattern recognition receptor (PRR)-induced interferon (IFN) is critical for effective immunity. The PRRs Toll-like receptor (TLR) 3, TLR4 and cyclic GMP-AMP synthase (cGAS), together with the stimulator of IFN genes (STING), signal through TANK-binding kinase 1 (TBK1), which activates the type-I/III IFN-inducing transcription factor interferon-response factor 3 (IRF3). The mechanism by which these PRRs activate TBK1 remains unresolved. Here we show that lysine-11 (K11)-linked ubiquitination drives TBK1 activation by these PRRs. The E3 ligase ANKIB1 attaches K11-linked ubiquitin chains to components of the TLR3- and cGAS-STING-induced signalosomes. This facilitates Optineurin recruitment to these complexes, in turn enabling recruitment and activation of TBK1 and IRF3, defining an uncharacterized signalling axis. In mice, ANKIB1 deficiency dampens IFN induction via TLR3 and cGAS-STING, reducing interferonopathy and compromising protection against HSV-1, respectively. Together, our results demonstrate an unanticipated and critical role for ANKIB1-generated K11-linked ubiquitination in the immune response activated by cGAS-STING, TLR3 and TLR4.
    DOI:  https://doi.org/10.1038/s41556-026-01886-z
  19. Nature. 2026 Mar 04.
    Stress-hormone signalling protects spreading cancer cells from immune system.
      
    Keywords:  Cancer; Immunology
    DOI:  https://doi.org/10.1038/d41586-026-00650-5
  20. Nat Commun. 2026 Mar 03.
    GPR146 in adipose tissue drives adipose-liver crosstalk and promotes hepatic steatosis in mice.
    Yu Shi, Kai Yan Cheng, Thi Tun Thi, Yifan Wang, Yang Yang, Xiaoyun Cao, Vanna Chhay, Yujia Shen, Yuchen He, Tianyun Zhao, Yan Ting Lim, Amy Deik, Courtney Dennis, Kerry Pierce, Kevin Bullock, Martin Wabitsch, Clary B Clish, Alexander S Banks, Radoslaw M Sobota, Chad A Cowan, Haojie Yu.
      The limited therapeutic options for metabolic dysfunction-associated steatotic liver disease (MASLD) underscore the need for deeper mechanistic insight and new treatment strategies. Here, we identify the orphan G protein-coupled receptor GPR146 as a regulator of hepatic steatosis through adipose-liver crosstalk. Human genetic analyses link the GPR146 locus to circulating markers of liver injury and inflammation. In mice, both constitutive and acute GPR146 depletion protect against diet-induced obesity and hepatic steatosis. Notably, adipose-specific, but not liver-specific, GPR146 deletion reduces hepatic lipid accumulation by limiting free fatty acid (FFA) influx. Mechanistically, GPR146 promotes adipogenesis in preadipocytes via Gαq-PKC-AKT signaling, increasing lipid storage capacity, and enhances lipolysis in mature adipocytes through ERK activation, elevating circulating FFA. Together, these coordinated actions increase FFA delivery to the liver, promoting triglyceride accumulation. Our findings establish GPR146 as a pleiotropic regulator of adipose tissue biology and a potential therapeutic target for MASLD.
    DOI:  https://doi.org/10.1038/s41467-026-70136-5
  21. Science. 2026 Mar 05. 391(6789): 990-991
    Astrocytes engineered to fight Alzheimer's plaques.
    Jake Boles, David Gate.
      Genetically altered astrocytes reduce a cardinal pathological feature of Alzheimer's disease.
    DOI:  https://doi.org/10.1126/science.aef8451
  22. Nat Aging. 2026 Mar 06.
    The glycolytic metabolite phosphoenolpyruvate restricts cGAS-driven inflammation to promote healthy aging.
    Zengqing Song, Huaibin Hu, Wanpeng Zhang, Xincheng Zheng, Liyun Liang, Bing Zhao, Guangping Song, Jianing Li, Sen Li, Yuqi Wen, Biyu Zhang, Wen Wang, Guozhen Deng, Cunjin Zhang, Hua Jiang, Supei Hu, Haiqing Tu, Min Wu, Huiyan Li.
      Aging involves multiple detrimental changes in the systemic milieu, leading to functional deterioration and age-related diseases. However, the potential self-protective adaptive alterations during aging remain underexplored. Here we show that phosphoenolpyruvate (PEP), a glycolytic metabolite, acts as a protective factor against age-related chronic inflammation. Longitudinal analyses in mice and humans reveal a biphasic PEP trajectory, characterized by initial accumulation followed by progressive decline. Blocking PEP accumulation exacerbates inflammation and accelerates aging phenotypes, whereas PEP administration before its decline promotes healthy aging in mice. In aged humans, high PEP levels strongly correlate with lower inflammation and healthier traits. Mechanistically, PEP acts as an endogenous inhibitor of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway by competitively binding to cGAS. Moreover, PEP alleviates neuroinflammation and improves cognitive function in an Alzheimer's disease mouse model. Thus, our findings define PEP accumulation as an evolutionarily conserved geroprotective mechanism, positioning PEP as a promising intervention for aging and associated diseases.
    DOI:  https://doi.org/10.1038/s43587-026-01087-1
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