bims-traimu 2026-05-10 papers

Issue of 2026–05–10
eight papers selected by
Yantong Wan, Southern Medical University

Front Immunol. 2026 ;17 1819744

Trained immunity in lung injury and repair.

Trained immunity refers to a phenomenon in which innate immune cells undergo long-lasting functional adaptation following an initial challenge. This paradigm shift in pulmonary immunology reveals that classical innate cells such as alveolar macrophages and hematopoietic progenitors, as well as structural cells including epithelial and endothelial populations, can acquire memory-like traits through sustained epigenetic and metabolic reprogramming. In the lung, these reprogrammed circuits influence host defense, lung injury, repair, and fibrotic remodeling through mechanisms involving histone H3K4 trimethylation, mTOR-HIF-1α-dependent metabolic shifts, and KLF4-MERTK-driven efferocytosis. Recent studies highlight the dual nature of this response: whereas appropriately tuned training accelerates pathogen clearance and supports epithelial repair, excessive or persistent activation can exacerbate maladaptive inflammation and fibrosis. In this Mini-Review, we summarize advances from 2020 to 2025 on the cellular and molecular regulation of pulmonary trained immunity, its emerging roles in acute respiratory distress syndrome (ARDS) and lung fibrosis, and novel therapeutic approaches that aim to modulate innate immune reprogramming for lung repair.

Keywords: ARDS; innate immune cells; lung injury and repair; memory; trained immunity

DOI: https://doi.org/10.3389/fimmu.2026.1819744

Microb Pathog. 2026 May 01. pii: S0882-4010(26)00247-0. [Epub ahead of print]216 108521

Flagellin pretreatment enhances host early innate immune responses against mycobacterial infection.

Congyi Dai, Jing Zhou, Wenjuan Guo, Haitao Wang, Tao Sun, Shu Song, Haiying Wang, Bo Yan.

Host-directed strategies that enhance early innate immune defense are increasingly recognized as important adjunct approaches for controlling mycobacterial infections. Flagellin, a classical ligand of Toll-like receptor 5 (TLR5), has been widely studied as a vaccine adjuvant. However, whether it can transiently modulate innate immunity to enhance host resistance against mycobacterial infection without inducing sustained inflammation remains unclear in vivo. In this study, we systematically evaluated this question using a zebrafish-Mycobacterium marinum infection model. Our results demonstrate that a single exposure to Escherichia coli-derived flagellin significantly reduces bacterial burden and improves host survival upon subsequent infection, without disrupting immune homeostasis. Mechanistically, this protective effect depends on the TLR5-MyD88 signaling pathway and is associated with enhanced early inflammatory responses, as well as accelerated recruitment of neutrophils and macrophages. Notably, even after the resolution of initial inflammation, the host exhibits an enhanced responsiveness to secondary stimulation, resembling features of trained immunity, suggesting that flagellin may act as an inducer of innate immune memory. Collectively, our findings provide in vivo evidence that flagellin enhances early host defense against mycobacterial infection by modulating innate immunity and support the utility of the zebrafish model for evaluating immunomodulator-induced protection.

Keywords: Flagellin; Immunomodulation; Innate immunity; Mycobacterial infection; TLR5

DOI: https://doi.org/10.1016/j.micpath.2026.108521

NPJ Sci Food. 2026 May 08.

Temporal intervention of yeast β-glucan and ellagic acid drives low-inflammatory trained immunity phenotype.

Rui Huo, Xue Bai, Ying Miao, Minjun Sun, Qixin Gu, Xiangbo Wu, Sarina Ma, Meili Zhang.

Trained immunity enhances the host innate immune response; however, prolonged stimulation or metabolic stress conditions such as a Western diet readily provoke persistent inflammation. In this study, we established a temporal intervention strategy in Western diet-fed mice by alternating yeast β-glucan and ellagic acid to generate repeated cycles of inflammatory activation and resolution, and evaluated whether this co-intervention could support a trained-immunity-associated phenotype while limiting inflammatory burden. Compared with single interventions, the temporal β-glucan-ellagic acid regimen induced coordinated lipid metabolic remodeling centered on sphingolipid and glycerophospholipid pathways, enhanced oxidative phosphorylation, and increased the expression of genes involved in amino acid and cofactor metabolism. These changes were accompanied by enrichment of Akkermansiaceae and Dubosiella, two taxa associated with barrier support and energy metabolism. At the phenotypic level, temporally coordinated intervention increased H3K4me3, p300, PGC-1α, and p-mTOR, elevated IL-10, and reduced NLRP3 expression, attenuated hepatic injury, and supported a low-inflammatory, energy metabolism-associated trained-immunity-like phenotype. The work provides mechanistic clues and a practical framework for rhythm-based immunometabolic intervention.

DOI: https://doi.org/10.1038/s41538-026-00877-6

Cell Host Microbe. 2026 May 06. pii: S1931-3128(26)00165-4. [Epub ahead of print]

Maternal helminths rewire the microbiota to promote offspring antiviral immunity.

Krist Antunes Fernandes, Felicia Sanders, Thomas R Cafiero, Chenyan Huang, Jojo Reyes, Abhishek Biswas, Ai Ing Lim.

Maternal environmental exposures can alter microbiome composition and lead to changes in offspring immunity. Industrialization has led to significant shifts in the microbiome, but whether these have transgenerational impacts remains unclear. Here, we discovered that maternal helminths, an evolutionarily conserved mammalian partner lost in industrialized societies, confer broad and lasting protection against respiratory viruses in offspring. This heterologous antiviral immunity is mediated by helminth-induced changes in the maternal microbiota. The tryptophan metabolite indole-3-propionic acid (IPA), derived from helminth-altered microbiota, induces lung epithelial IFN-I responses and is sufficient to protect offspring from respiratory syncytial virus (RSV) and influenza A virus infections. Analysis of chronically helminth-infected human populations reveals gut microbiota enriched for tryptophan metabolic capacity. Additionally, IPA treatment is sufficient to enhance antiviral IFN-I signaling in human bronchial epithelial cells. Collectively, this work uncovers the importance of maternal helminth-driven trans-kingdom crosstalk across generations and highlights microbial metabolites as actionable strategies to strengthen antiviral defense.

Keywords: IPA; antiviral immunity; early life immunity; helminths; indole-3-propionic acid; maternal immune education; microbiota; respiratory syncytial virus; trained immunity; trans-kingdom

DOI: https://doi.org/10.1016/j.chom.2026.04.009

Trends Immunol. 2026 May 01. pii: S1471-4906(26)00097-9. [Epub ahead of print]

Cooling inflammation through metabolism with 4-octyl itaconate.

Hanna F Voß-Willenbockel, Thekla Cordes.

Itaconate is an immunomodulatory metabolite that links metabolism and inflammation. Li et al. uncover a mechanism by which itaconate and 4-octyl itaconate suppress cytokine signaling through the alkylation of tyrosine kinase 2 and Janus kinase 1. This study reveals a direct metabolic control of inflammation and highlights its therapeutic potential in sepsis.

Keywords: JAK–STAT signaling; immunometabolism; itaconate; mitochondria; post-translational modification; sepsis

DOI: https://doi.org/10.1016/j.it.2026.04.004

J Adv Res. 2026 May 04. pii: S2090-1232(26)00378-4. [Epub ahead of print]

4-Octyl itaconate-induced Nrf2 nuclear translocation mitigates Caspase-11-dependent noncanonical macrophage pyroptosis and acute lung injury.

Tingyu Wen, Jindian Shi, Minkang Guo, Bei Ma, Chen Zhang, Yisi Zhao, Fang Xu.

INTRODUCTION: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe inflammatory conditions, with mortality rates reaching 40%. A key driver of their pathogenesis is macrophage pyroptosis, which results in excessive inflammation and tissue damage.
OBJECTIVES: The aim of this study was to investigate the regulatory effect and underlying mechanism of the itaconate derivative 4-octyl itaconate (4-OI) on macrophage pyroptosis and sepsis-induced ALI/ARDS.
METHODS: The study employed a cecal ligation and puncture (CLP)-induced septic mouse model and LPS-stimulated RAW264.7 cells, and bone marrow-derived macrophages. Pyroptosis was assessed using propidium iodide (PI) staining to detect membrane pore formation, as well as quantitative fluorescence analysis and immunohistochemical quantitative analysis of GSDMD-NT. Additional evaluations included the western blot analysis of pyroptosis-related proteins (GSDMD-NT, IL-1β p17). Mechanistic insights were explored using the Nrf2 inhibitor ML385, Acod1⁻/⁻ mice, Casp4⁻/⁻ mice, and Nfe2l2⁻/⁻ mice, along with a parallel experiment of DOTAP-transfected LPS.
RESULTS: Based on the increase induced by LPS stimulation, 4-OI significantly reduced the proportion of PI-positive cells and also decreased the fluorescence expression of GSDMD-NT, thereby confirming its inhibition of pyroptotic pore formation. It alleviated pulmonary edema, cytokine release, and histological damage in CLP-induced septic mice. Mechanistically, Nrf2 specifically inhibited the transcription of Casp4, thereby reducing Caspase-11-dependent non-canonical macrophage pyroptosis. Casp4⁻/⁻ mice and Casp4 siRNA experiments demonstrated that 4‑OI specifically attenuates Caspase‑11‑dependent noncanonical pyroptosis. Mechanistically, experiments in Nfe2l2⁻/⁻ mice and with ML385 revealed that this effect is mediated by Nrf2‑dependent transcriptional inhibition of Casp4. Furthermore, Acod1 deficiency mice exacerbated Caspase‑11‑driven noncanonical pyroptosis.
CONCLUSION: The results demonstrate that 4-OI effectively inhibits Caspase-11-mediated pyroptosis and subsequent inflammation in experimental ALI/ARDS. This effect is mechanistically dependent on the activation of the Nrf2-Caspase-11 axis. The study thus identifies a novel therapeutic strategy whereby 4-OI targets pyroptotic pore formation, offering a potential therapeutic intervention for ALI/ARDS.

Keywords: 4-OI; ALI/ARDS; Caspase-11; Macrophage pyroptosis; Nrf2

DOI: https://doi.org/10.1016/j.jare.2026.05.011