bims-traimu 2026-04-12 papers

Issue of 2026–04–12
four papers selected by
Yantong Wan, Southern Medical University

Front Aging. 2026 ;7 1750450

Targeting innate immunity to modulate bone metabolism: a novel strategy for osteoporosis treatment.

Wenjie Kou, Xiaomin Lu, Zhe Zhang, Kaiwen Liu, Zhihuan Liu, Bin Jiang, Hongping Wang, Jishu Li, Hu Lu, Chenglong Guo, Linzhong Cao, Xiaogang Zhang.

Osteoporosis is a systemic metabolic bone disorder characterized by reduced bone mass and impaired microarchitecture, with its core pathological mechanism being an imbalance between bone formation and resorption. Traditional therapies targeting osteoblast/osteoclast function have limited efficacy and safety concerns. Recent osteoimmunology advances reveal that the innate immune system regulates bone homeostasis via intercellular interactions, cytokine networks, and metabolic reprogramming. This systematic review examines the roles of innate immune cells (macrophages, neutrophils, NK cells, DCs), complement system, and emerging pathways (trained immunity, mitochondrial symbiosis disruption) in osteoporosis. It summarizes therapeutic strategies (immunometabolic modulators, complement antagonists, cytokine-targeted drugs, TCM components) and outlines challenges (target specificity, clinical translation) and future directions, providing theoretical foundations for novel OP treatments.

Keywords: bone metabolism; complement system; innate immunity; macrophages; osteoporosis; targeted therapy; trained immunity

DOI: https://doi.org/10.3389/fragi.2026.1750450

Nat Metab. 2026 Apr 10.

iNOS modulates inflammatory responses in an NO-independent manner through direct interaction with IRG1 in mitochondria.

Marina Diotallevi, Carlos Outeiral, Priyanka Patel, Gareth S D Purvis, Surawee Chuaiphichai, Thomas Nicol, Faseeha Ayaz, Daniel A Nissley, Ganna O Krasnoselska, Svenja Hester, John H McVey, Roman Fischer, Benedikt Kessler, Charlotte M Deane, Raymond J Owens, Keith M Channon, Mark J Crabtree.

Nitric oxide (NO) has fundamental roles in numerous physiological and pathophysiological processes. In macrophages, NO produced by inducible nitric oxide synthase (iNOS) modulates metabolic changes that are essential to macrophage activation and plasticity, driving the characteristic metabolic switch from oxidative phosphorylation to glycolysis1,2. Itaconate, derived from the TCA cycle by decarboxylation of cis-aconitate by IRG1 (also referred to as CAD, ACOD1), is one of the most upregulated metabolites during the inflammatory response3. Itaconate regulates macrophage polarization by electrophilically modifying cysteines of key enzymes that control inflammatory states (such as ATF3, Jak1, IFNβ), participate in glycolysis (for example, GAPDH, LDHA) and limit oxidative stress through structural competitive inhibition of succinate dehydrogenase4-9. We recently reported that macrophages that are deficient in iNOS, and subsequent NO generation, produce strikingly higher levels of intracellular itaconate (up to ~15-fold) compared to wild-type cells when stimulated with inflammatory cytokines1,2,10. Here we show that iNOS inhibits IRG1 activity and itaconate levels through a conformation-dependent protein-protein interaction rather than through the production of NO. Using a variety of biochemical and computational approaches, we show that a direct interaction between iNOS and IRG1 occurs within mitochondria, in mouse and human cells, and that it depends on binding of the cofactor BH4 to iNOS but does not require its capability to produce NO. Our findings reveal a non-canonical cellular function for iNOS that places it at the centre of a signalling hub, linking redox signalling and metabolism to modulation of the inflammatory response in macrophages.

DOI: https://doi.org/10.1038/s42255-026-01492-1

Front Immunol. 2026 ;17 1823350

Editorial: Regulation of inflammation: metabolic reprogramming and posttranslational modification.

Zhengyu Jiang, Tianliang Li, Jinjun Bian, Wanwan Huai.

Keywords: O-GlcNAcylation; ferroptosis; immunometabolism; inflammation; metabolic reprogramming; posttranslational modification

DOI: https://doi.org/10.3389/fimmu.2026.1823350

Front Immunol. 2026 ;17 1660646

Endotoxin tolerance enhances breast cancer aggressiveness and alters inflammatory marker expression in tumor and spleen of mice.

Konkonika Roy, Bartosz Maciejewski, Tomasz Jędrzejewski, Paulina Spisz, Justyna Sobocińska, Melania Di Pentima, Benedetta Passeri, Sylwia Wrotek.

Endotoxin tolerance (ET) is an immunological state in which repeated exposure to endotoxins such as lipopolysaccharide (LPS) leads to reprogramming of the immune system and a diminished inflammatory response. In this study, we used a murine model to explore the role of ET in breast cancer progression, hypothesizing that ET may foster a tumor-permissive immune environment. We compared endotoxin tolerant breast cancer-bearing mice (ETBC group) with non-endotoxin tolerant breast cancer-bearing controls (BC group). ETBC mice exhibit significantly faster tumor progression and earlier disease onset. Hematological analysis revealed reduced leukocyte counts in the ETBC group, indicating compromised immune cell recruitment. Additionally, ETBC mice showed decreased spleen weight relative to that in the BC group, further supporting systemic immune suppression. Gene expression profiling in both spleen and tumor tissues revealed marked immunological alterations in ETBC mice. In the spleen, there was notable downregulation of key pro-inflammatory cytokines, including interleukin (IL) 6 and interferon (IFN) γ. Conversely, genes associated with immune modulation and tumor progression such as IL-1β, inducible nitric oxide synthase (NOS2), cyclooxygenase (COX) 2, vascular endothelial growth factor (VEGF), and colony stimulating factor 1 (CSF-1) were upregulated. Notably, IL-1β, NOS2, COX-2, IL-10, and VEGF were consistently upregulated in tumor tissues of ETBC mice. We conclude that ET not only impairs immune surveillance but also reshapes the tumor microenvironment in favor of cancer growth. This highlights the potential role of ET in oncology and suggests that its modulation could represent a novel avenue for therapeutic intervention.

Keywords: cancer; endotoxin tolerance; immunosuppression; inflammation; tumor microenvironment

DOI: https://doi.org/10.3389/fimmu.2026.1660646