bims-traimu 2025-06-15 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2025–06–15
ten papers selected by
Yantong Wan, Southern Medical University

C1q reprograms innate immune memory.
No (innate immune) training without lactate.
Setdb2 Regulates Inflammatory Trigger-Induced Trained Immunity of Macrophages Through Two Different Epigenetic Mechanisms.
Tolerance to Lung Infection in TWIK2 K + Efflux Mediated Macrophage Trained Immunity.
H3K27me3 modulates trained immunity of monocytes in HDM-allergic diseases.
Immune pre-stimulation by injected yeast beta-glucan as a strategy to prevent calf diarrhea and bovine respiratory disease during the first 74 days of age.
Gene-specific regulation of inflammation via TLR-induced chromatin modifications.
Intestinal Stem Cells from Patients with Inflammatory Bowel Disease Retain an Epigenetic Memory of Inflammation.
TSLP pretreatment inhibits M1 macrophage polarization and attenuates LPS-induced iNKT cell-dependent acute lung injury.
Endothelial CLEC5A drives barrier dysfunction and vascular leakage responsible for lung injury in bacterial pneumonia and sepsis.

Front Immunol. 2025 ;16 1515127

C1q reprograms innate immune memory.

Inge Jonkman, Maaike M E Jacobs, Yutaka Negishi, Julia I P van Heck, Vasiliki Matzaraki, Joost H A Martens, Marijke Baltissen, Michiel Vermeulen, Zahi A Fayad, Abraham J P Teunissen, Willem J M Mulder, Luuk B Hilbrands, Leo A B Joosten, Mihai G Netea, Musa M Mhlanga, Nils Rother, Raphaël Duivenvoorden.

  Innate immune memory, also called trained immunity, is a metabolic and epigenetically regulated process that enables innate immune cells to recalibrate their inflammatory reactivity in response to pathogenic or endogenous stimuli. In addition to its function in host defense, trained immunity contributes to diverse immune-mediated diseases. We discovered that complement component 1q (C1q) is an effective modulator of innate immune memory, potently suppressing the responsiveness of myeloid cells. We found that C1q leads to profound reprogramming of myeloid cell metabolism, particularly glycolysis, and exerts control over the transcriptional regulation of important metabolic and inflammatory genes. We corroborate our findings by identifying single-nucleotide polymorphisms close to the C1q gene that are linked to induction of trained immunity by Bacillus Calmette-Guérin (BCG) or beta-glucan in healthy peripheral blood mononuclear cells. Our results reveal an immunomodulatory role for C1q and provide evidence of a molecular interaction between the complement system and innate immune memory. These findings expand our understanding of innate immune memory.

Keywords:  C1q; complement; immunometabolism; innate immune memory; tolerance; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2025.1515127
Mol Cell. 2025 Jun 05. pii: S1097-2765(25)00448-4. [Epub ahead of print]85(11): 2065-2067

No (innate immune) training without lactate.

Jan Van den Bossche.

A recent study in Cell unveils lactate production and downstream histone lactylation as a new player in the induction of trained immunity.1 It provides insight into the intricate metabolic-epigenetic interplay that governs innate immune memory and offers a potential target to reverse maladaptive trained immunity in chronic inflammatory diseases.

DOI: https://doi.org/10.1016/j.molcel.2025.05.014
Res Sq. 2025 May 28. pii: rs.3.rs-6702384. [Epub ahead of print]

Setdb2 Regulates Inflammatory Trigger-Induced Trained Immunity of Macrophages Through Two Different Epigenetic Mechanisms.

Timothy Osborne, Anant Jaiswal, Laszlo Halasz, David Williams.

"Trained immunity" of innate immune cells occurs through a sequential two-step process where an initial pathogenic or sterile inflammatory trigger is followed by an amplified response to a later un-related secondary pathogen challenge. The memory effect is mediated at least in part through epigenetic modifications of the chromatin landscape. Here, we investigated the role of the epigenetic modifier Setdb2 in microbial (β-glucan) or sterile trigger (Western-diet-WD/oxidized-LDL-oxLDL)-induced trained immunity of macrophages. Using genetic mouse models and genomic analysis, we uncovered a critical role of Setdb2 in regulating proinflammatory and metabolic pathway reprogramming. We further show that Setdb2 regulates trained immunity through two different complementary mechanisms: one where it positively regulates glycolytic and inflammatory pathway genes via enhancer-promoter looping, and is independent of its enzymatic activity; while the second mechanism is associated with both increased promoter associated H3K9 methylation and repression of interferon response pathway genes. Interestingly, while both mechanisms occur in response to pathogenic training, only the chromatin-looping mechanism operates in response to the sterile inflammatory stimulus. These results reveal a previously unknown bifurcation in the downstream pathways that distinguishes between pathogenic and sterile inflammatory signaling responses associated with the innate immune memory response and may provide potential therapeutic opportunities to target cytokine vs. interferon pathways to limit complications of chronic inflammation.

DOI: https://doi.org/10.21203/rs.3.rs-6702384/v1
bioRxiv. 2025 May 28. pii: 2025.05.25.655979. [Epub ahead of print]

Tolerance to Lung Infection in TWIK2 K + Efflux Mediated Macrophage Trained Immunity.

Josh Thompson, Yufan Li, Yuanling Song, Ki-Wook Kim, Asrar B Malik, Jingsong Xu.

Alveolar macrophages (AMφ) are essential for innate immune function in the lungs. It is now apparent that macrophages can be trained to become better at attacking infections. Although trained immunity is thought to result from metabolic and epigenetic reprogramming, the underlying mechanisms remain unclear. Here, we report that AMφ can be trained by extracellular ATP, which is ubiquitously released during inflammation. ATP ligates the canonical Purinergic Receptor 2 subtype X7 receptor (P2X7) to mediate endosomal Two-pore domain Weak Inwardly rectifying K + channel 2 (TWIK2) translocation into the plasma membrane (PM). This endows the cells to transit to a 'ready' state for microbial killing in two directions: first, K + efflux via PM-TWIK2 induces NLRP3 inflammasome activation, which further activates metabolic pathways; second, upon bacterial phagocytosis, PM-TWIK2 internalizes into phagosome membrane with proper topological orientation, where TWIK2 mediates K + influx into phagosomes to control pH and ionic strength favoring bacterial killing. Therefore, the enhanced association of TWIK2 in phagosomal and plasma membranes signaled by danger-associated molecular patterns (DAMPs), such as ATP, mediates trained immunity in AMφ and enhances the microbiocidal activity.

DOI: https://doi.org/10.1101/2025.05.25.655979
Front Immunol. 2025 ;16 1572796

H3K27me3 modulates trained immunity of monocytes in HDM-allergic diseases.

Lingli Han, Lin Li, Liangjiao Yao, Huaqin Bu, Yajie Tian, Qifan Li, Ke Zhu, Haili Yao, Xiaochuan Wang, Maoxiang Qian, Wei Lu, Jinqiao Sun.

   Background: Monocytes have been confirmed to increase in persistently food-allergic children. A phenomenon of innate immune memory, called trained immunity, has also been observed in monocytes from allergic children. However, the underlying mechanism remains poorly understood.
Methods: We enrolled a cohort of HDM-allergic children alongside age-matched healthy controls and established an HDM-sensitized allergic mouse model. Flow cytometric analyses were conducted to quantify monocyte frequencies in clinical cohorts and experimental animals. We performed integrated transcriptomic profiling via RNA-seq combined with chromatin occupancy analysis using CUT&Tag technology in parallel human and murine samples to elucidate the molecular mechanisms.
Results: In our study, we demonstrated a reduced H3K27me3 methylation level accompanied by an increased proportion and a proinflammatory transcriptional memory in monocytes from house dust mite (HDM)-allergic human subjects. The same transcriptional and epigenetic phenotype was also confirmed in HDM-sensitized mice. Finally, the administration of GSK-J4, which upregulates H3K27me3 level in murine monocytes, attenuated the inflammatory response in vitro and in vivo.
Conclusions: Our study confirms that H3K27me3 methylation modulates the trained immunity in monocytes and regulates HDM-allergic diseases through an inflammatory-dependent mechanism.

Keywords:  H3K27me3; HDM; KDM6B; inflammation; monocytes

DOI:  https://doi.org/10.3389/fimmu.2025.1572796
Front Cell Infect Microbiol. 2025 ;15 1586121

Immune pre-stimulation by injected yeast beta-glucan as a strategy to prevent calf diarrhea and bovine respiratory disease during the first 74 days of age.

Fang Yan, Zhihong Zhang, Xiaorong Zhan, Wenqian Yang, Junhu Yao, Xiurong Xu.

   Introduction: The complexity of intestinal pathogens poses a great challenge to the prevention of infectious diarrhea in calves. Studies have shown that immune stimulants such as yeast beta-glucan can induce the innate immune system to acquire memory and improve their non-specific defense functions. This trial was conducted to evaluate the prophylactic effect of intraperitoneal injection of yeast β-glucan after birth on diarrhea in Holstein calves during the first 74 days of age.
Methods: A total of 52 healthy newborn Holstein calves (body weight 39.3 ± 0.82 kg) were enrolled and randomly assigned into two groups (n = 26 in per group): 1) placebo group (CON), and 2) intraperitoneal injection with yeast β-glucan solution (0.1 g/mL, 50 mg/kg body weight) at 3 and 6 days of age (IP). The CON group received an equal volume of sterile saline at the same time. Body weight was measured monthly, and health checks and fecal consistency were evaluated daily for every calf. Jugular blood and rectal feces were collected at 7 and 30 days of age.
Results: IP induced inflammation in calves, which was manifested as obvious increased levels of serum cytokines (IL-1β, IL-6, and TNF-a), immunoglobulin (IgG and IgM), and oxidative stress after 24 h, and the antimicrobial substance (defensin and secreted immunoglobulin A) in feces also significantly increased, but stimulation didn't lead to a higher level of serum diamine oxidase (DAO). The pre-stimulation had no positive effect on growth performance or feed efficiency, but reduced the frequencies of diarrhea and bovine respiratory disease, especially during 31-60 d. Furthermore, the pre-stimulation increased the levels of serum IL-6, fecal defensin and secreted immunoglobulin A, while decreased the levels of serum DAO and malonaldehyde at 30 d. In addition, compared with the ones in the CON group, calves in the IP group showed a better rectal bacterial structure at 30 d, with a more enrichment of beneficial bacteria such as Bifidobacterium.
Discussion: Our findings suggested that early stimulation with yeast β-glucan could be a promising strategy for reducing the frequencies of both diarrhea and BRD in calves.

Keywords:  bovine respiratory disease; calves; diarrhea; trained immunity; yeast β-glucan

DOI:  https://doi.org/10.3389/fcimb.2025.1586121
J Immunol. 2025 Jun 09. pii: vkaf115. [Epub ahead of print]

Gene-specific regulation of inflammation via TLR-induced chromatin modifications.

Joseph A Daccache, Shruti Naik.

  This Pillars of Immunology article revisits the landmark 2007 study by Foster, Hargreaves, and Medzhitov-the first to uncover the mechanistic basis of memory in the innate immune system. This pivotal study marks a fundamental shift in our understanding of innate immunity, revealing an epigenetic logic that enables immune memory beyond the adaptive immune system.

Keywords:  LPS tolerance; epigenetics; innate memory; macrophages

DOI:  https://doi.org/10.1093/jimmun/vkaf115
bioRxiv. 2025 Jun 06. pii: 2025.05.24.655923. [Epub ahead of print]

Intestinal Stem Cells from Patients with Inflammatory Bowel Disease Retain an Epigenetic Memory of Inflammation.

Feda H Hamdan, Isaiah Perez, Kimberlee Kossick, Hannah Smith, Adam Edwinson, Jose M de Hoyos-Vega, Michelle Gonzalez, David Chiang, Emily Klatt, Kristy Rumer, Mauricio Perez Pachon, Mary Sagstetter, Jessica Friton, Erin Kammer, Alana English, Lucas C S Chini, Jarl F Carnahan, Noah A Baca, Rohini Mopuri, Aditya Bhagwate, Laura E Raffals, Zhifu Sun, Madhusudan Grover, Alexander Revzin, William A Faubion, Brooke R Druliner.

Intestinal epithelial damage and impaired repair are hallmarks of ulcerative colitis (UC), even after inflammation resolves. Intestinal stem cells (ISCs) can retain stable epigenetic changes after inflammation, highlighting the potential for long-lived epithelial memory in the gut. Inflammatory injury in barrier tissues induces epigenetic memory in epithelial stem cells, and the tendency of UC to relapse at previously inflamed sites led us to hypothesize that ISCs from IBD patients acquire lasting memory of prior inflammation. To test this, we derived colonic organoids from inflamed and uninflamed regions of the same UC patients and propagated in long-term culture. Chromatin profiling revealed 2,252 accessible regions unique to prior-inflamed (PI) organoids, associated with stress response, repair, and inflammatory genes. Although these regions remained accessible, ∼95% of associated genes were not upregulated in PI organoids, indicating a primed state. Upon inflammatory or injury re-challenge, PI organoids exhibited heightened transcriptional responses and accelerated wound closure, despite reduced clonogenicity and impaired barrier function, indicating a retained inflammatory memory program. Our findings demonstrate that human ISCs retain a chromatin-based memory of inflammation that persists in the absence of immune cues and shapes future responses to injury. While this may support epithelial adaptation to secondary insults, it may predispose tissue to relapse in patients with UC.

DOI: https://doi.org/10.1101/2025.05.24.655923
Front Immunol. 2025 ;16 1583235

TSLP pretreatment inhibits M1 macrophage polarization and attenuates LPS-induced iNKT cell-dependent acute lung injury.

Ting Zhou, Ziyao Zhang, Yawen Zhan, Meiying Wang, Mi Wu, Xiufang Weng, Younian Xu.

   Introduction: Sepsis associated acute respiratory distress syndrome (ARDS), is a life-threatening condition characterized by severe pulmonary inflammation. Previous research has suggested that allergic immune diseases are associated with a lower risk of sepsis. Therefore, we hypothesized that certain molecules involved in type 2 inflammation are beneficial for the outcome of sepsis associated ARDS. Thymic stromal lymphopoietin (TSLP) is known to promote Th2 responses in allergic disease, however, its role in sepsis associated ARDS remains limited.
Methods: To investigate the role of TSLP in sepsis associated lung injury, we administered exogenous recombinant TSLP to wild-type mice, followed by lipopolysaccharide (LPS) challenge. At 24 hours post-treatment, bronchoalveolar lavage fluid (BALF) and lung tissues were collected for analysis. The ratio, number, phenotype, and function of immune cells and cytokine levels were measured. Additionally, murine bone marrow-derived macrophages (BMDMs) were prepared and stimulated with LPS and TSLP to further verify our findings experimentally. To explore the molecular mechanisms of TSLP's effect, analysis of transcriptome sequencing and single-cell transcriptome sequencing and subsequent experiments were performed.
Results: In LPS-induced acute lung injury models, pretreatment with TSLP significantly alleviated lung injury, suppressed inflammatory cytokines secretion, and reduced macrophages and neutrophils infiltration. In addition, TSLP treatment significantly inhibited M1 macrophage polarization and promoted M2 macrophage differentiation. Transcriptome sequencing suggested IFN-γ as a potential target of TSLP, and single-cell transcriptome sequencing showed that innate like T cells are important source of IFN-γ. Consistently, flow cytometry showed that proportion of IFN-γ-producing iNKT cells was decreased by TSLP administration in the acute lung injury model. Intriguingly, Jα18-/- mice, which are completely deficient in invariant natural killer T (iNKT) cells, exhibited not only significantly less severe lung inflammation but also a notably higher degree of anti-inflammatory Arg1+ M2 macrophages infiltration when compared with their LPS-sensitized wild-type counterparts.
Conclusions: These findings not only underscore the crucial role of TSLP in the regulation of sepsis-associated ARDS but also demonstrate its potential clinical value as both a predictive biomarker for early detection and a molecular target for therapeutic intervention.

Keywords:  ARDS; TSLP; acute lung injury; iNKT cells; macrophage

DOI:  https://doi.org/10.3389/fimmu.2025.1583235
Sci Adv. 2025 Jun 13. 11(24): eadt7589

Endothelial CLEC5A drives barrier dysfunction and vascular leakage responsible for lung injury in bacterial pneumonia and sepsis.

Tie-Ning Zhang, Xin-Mei Huang, Julie E Goodwin, Ri Wen, Yong-Ping Liu, Yu-Hang Yang, Tao Zhang, Yue Zheng, An-Yu Chen, Peng-Hui Hao, Xiao-Xu Tong, Ni Yang, Chun-Feng Liu.

Endothelial barrier dysfunction and the resulting vascular injury are responsible for multiorgan failure in sepsis. Myeloid C-type lectin domain family 5 member A (CLEC5A) is a pattern recognition receptor involved in host defense against infection. Mice lacking CLEC5A were resistant to cecal ligation and puncture (CLP)-induced polymicrobial sepsis and lipopolysaccharide (LPS)-induced endotoxemia, as observed by decreased mortality. Single-cell RNA sequencing revealed transcriptomic heterogeneity of vascular endothelial cells in CLEC5A-deficient lungs following CLP. Endothelial-specific knockdown of CLEC5A improved survival of CLP-challenged mice, which was completely ineffective with reexpression of endothelial CLEC5A. The survival benefits were attributed to alleviated inflammatory storm and vascular leakage. Furthermore, endothelial CLEC5A deficiency protected mice against Escherichia coli-induced pneumonia. In vitro, CLEC5A deletion maintained trans-endothelial electrical resistance, and inhibited adhesion and trans-endothelial migration of monocytes/neutrophils under LPS stimulation. The study unveils the importance of CLEC5A in regulating endothelial barrier function and suggests endothelial CLEC5A as a therapeutic target for pneumonia or sepsis-causing bacterial infection.

DOI: https://doi.org/10.1126/sciadv.adt7589