bims-bac4me 2025-06-29 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2025–06–29
twelve papers selected by
Chun-Chi Chang, Lunds universitet

Alternative splicing of KLF4 in myeloid cells: implications for cellular plasticity and trained immunity in cancer and inflammatory disease.
Trained Immunity Induced by Oxidized Low-Density Lipoprotein Is Dependent on Glutaminolysis.
Quercetin attenuates the progression of chronic rhinosinusitis with nasal polyps by regulating macrophage M2 polarization and remodeling of nasal mucosa.
A fungal-derived adjuvant amplifies the antitumoral potency of Bacillus Calmette-Guérin via reprogramming granulopoiesis.
Gut bacteriophages induce specific-reprogramming of macrophages to generate a protective innate immunity response to lipopolysaccharide exposure.
M2-Like Macrophages Exhibit Sialic Acid-Enhanced Efferocytosis via the Siglec CD22.
BCG-Derived Outer Membrane Vesicles Induce TLR2-Dependent Trained Immunity to Protect Against Polymicrobial Sepsis.
Influence of Insert Brand and Culture Method on Ciliary Activity and Epithelial Cell Types in Human Nasal Air-Liquid Interface Cell Cultures.
Applications of human lung organoids to human respiratory virus research: advances, limitations and future directions.
Understanding and manipulating morphogenetic processes to generate in vitro models of airways.
Enhanced Trained Immunity in Peripheral Monocytes in Unstable Angina With Elevated High-Sensitivity C-Reactive Protein.
Inhibiting the expression of GPR43 in macrophages can alleviate osteoarthritis by suppressing the M1 polarization and suppressing ROS production.

Front Immunol. 2025 ;16 1585528

Alternative splicing of KLF4 in myeloid cells: implications for cellular plasticity and trained immunity in cancer and inflammatory disease.

Amanda Rosewell Shaw, Attoria Bennett, Daping Fan, Walden Ai.

  The role of transcription factor Krüppel-like factor 4 (KLF4) in the modulation of myeloid cells is well known. KLF4 is involved in the differentiation and polarization of monocytes and macrophages as part of the immune response after infection, in wound healing, and in cancer. In addition, KLF4 is essential in stem cell reprogramming and the phenomenon of trained immunity - a form of innate immune memory marked by epigenetic and metabolic reprogramming. A novel and underexplored dimension of KLF4 biology lies in its alternative splicing (AS), which generates distinct isoforms that may drive the transcription factor's functions, depending on specific cellular environments, disease states, or signaling programs. This review presents current knowledge of KLF4 splicing in myeloid cells and explores novel connections for how KLF4 isoform diversity may contribute to cellular plasticity and differential immune responses of myeloid cells across physiological and pathological conditions.

Keywords:  AS; Krüppel-like factor 4 (KLF4); cancer stem cells; cellular plasticity; epigenetics; innate immunity; myeloid-derived suppressor cells (MDSCs); trained immunity

DOI:  https://doi.org/10.3389/fimmu.2025.1585528
FASEB J. 2025 Jul 15. 39(13): e70774

Trained Immunity Induced by Oxidized Low-Density Lipoprotein Is Dependent on Glutaminolysis.

Alice Scarpa, Yerin Jung, Arslan Hamid, Vasiliki Matzaraki, Tushar More, Alexander Heinz, Laszlo Groh, Siroon Bekkering, Karsten Hiller, Leo A B Joosten, Mihai G Netea, Katarzyna Placek, Niels P Riksen.

  Atherosclerosis is a chronic inflammatory disease of the arterial wall that causes cardiovascular disease. Monocyte-derived macrophages are an important contributor to atherogenesis. Monocytes can become primed for higher responsiveness to secondary, unrelated stimuli-a phenomenon known as trained immunity-a process driven by intracellular metabolic and epigenetic reprogramming. Oxidized low-density lipoprotein (oxLDL) induces trained immunity by enhancing glycolysis and oxidative phosphorylation (OXPHOS). Glutamine is known to enter the Krebs cycle through glutaminolysis where it can be used for ATP synthesis via OXPHOS. We therefore explored the role of the glutaminolysis pathway in oxLDL-induced trained immunity. Primary human monocytes from healthy donors were exposed to oxLDL for 24 h, followed by differentiation into macrophages over 6 days in culture medium. Thereafter, cytokine production capacity was assessed by stimulating them with Toll-like receptor agonist. Co-administration of the glutaminase inhibitor CB-839 during oxLDL exposure reduces glutamine anaplerosis. This prevented oxLDL-induced trained immunity, with diminished cytokine production capacity, associated with a reduced oxygen consumption rate (OCR), and glycolysis rate (ECAR). The role of glutaminolysis for induction of trained immunity was validated genetically, by showing significant associations between several single-nucleotide polymorphisms in genes related to glutaminolysis and ex vivo cytokine production in oxLDL-trained monocytes from 243 healthy volunteers. Finally, we identified a positive correlation between glutamate and Krebs cycle metabolites with inflammatory circulating biomarkers and monocyte counts in an independent cohort of 302 obese individuals. Altogether, these data suggest a crucial role of glutaminolysis in the establishment of oxLDL-induced trained immunity.

Keywords:  Krebs cycle; atherosclerosis; glutamine; glutaminolysis; oxLDL; trained immunity

DOI:  https://doi.org/10.1096/fj.202500802R
Int Immunopharmacol. 2025 Jun 21. pii: S1567-5769(25)01110-5. [Epub ahead of print]162 115120

Quercetin attenuates the progression of chronic rhinosinusitis with nasal polyps by regulating macrophage M2 polarization and remodeling of nasal mucosa.

Xiaopeng Qu, Pengyu Tao, Jiajia Dong, Lingzhao Meng.

  Chronic rhinosinusitis with nasal polyps (CRSwNP) is chronic respiratory disease with high prevalence worldwide, especially in old people. Macrophage polarization-mediated inflammation and nasal mucosal epithelium remodeling are potential etiologic factors for CRSwNP. Quercetin is a natural plant-derived flavonoid and exerts the important function in chronic inflammatory disease. Nevertheless, its roles in CRSwNP remain elusive. The current study confirmed the higher levels of CD68+CD206+ M2 macrophages in CRSwNP patients relative to the control groups, but not changes in the contents of CD68+CD80+ M1 macrophages. Moreover, quercetin restrained IL-4-evoked increases in the numbers of CD68+CD206+ M2 macrophage, concomitant with the decrease in M2 macrophage marker CD206, CD163, MMP-9 and TGF-β expression. Moreover, the increased releases of chemokine CCL-18, CCL-24 and CCL-13 from M2 macrophages were reduced by quercetin. Furthermore, human nasal epithelial cells (hNECs) underwent epithelial-mesenchymal transition (EMT) occurrence after co-cultured with M2-like macrophages by decreasing E-cadherin expression and increasing vimentin expression. However, M2 macrophages-induced EMT in hNECs was reversed by quercetin treatment. Mechanistically, quercetin mitigated activation of the JAK2/STAT3 pathway in M2-like macrophages. Intriguingly, re-activating the above pathway via its activator RO8191 reversed quercetin-mediated inhibition in macrophage M2 polarization and their polarization-mediated EMT in hNECs. In vivo, Quercetin alleviated the progression of CRSwNP in mice model by attenuating nasal symptoms, polyp formation and inflammation. Moreover, administration with quercetin decreased the levels of CD68+CD206+ M2-like macrophages and chemokine in nasal mucosa tissues in CRSwNP mice model. Simultaneously, quercetin attenuated nasal mucosal remodeling by inhibiting EMT and MMP-2, MMP-9 levels. Re-activating the JAK2/STAT3 pathway antagonized quercetin-mediated protective efficacy against CRSwNP. Thus, quercetin may alleviate the progression of CRSwNP by regulating macrophage M2 polarization and nasal mucosal remodeling via the blockage of the JAK/STAT3 pathway, supporting a promising agent against CRSwNP.

Keywords:  CRSwNP; EMT; Macrophage M2 polarization; Mucosal epithelial remodeling; Quercetin

DOI:  https://doi.org/10.1016/j.intimp.2025.115120
Immunity. 2025 Jun 19. pii: S1074-7613(25)00247-X. [Epub ahead of print]

A fungal-derived adjuvant amplifies the antitumoral potency of Bacillus Calmette-Guérin via reprogramming granulopoiesis.

Leonardo F Jurado, Andrew W Daman, Ziyi Li, Vanessa M S Ross, Kristina Nikolaou, Kim A Tran, Oleg Loutochin, Victor A McPherson, Renaud Prével, Raquel Tarancón, Katalina Couto, Erwan Pernet, Nargis Khan, Jin-Gyu Cheong, Reshma Ramaiah, Mythili Ketavarapu, Eva Kaufmann, Michael S Glickman, Ajitha Thanabalasuriar, Steven Z Josefowicz, Maziar Divangahi.

  In patients with non-muscle invasive bladder cancer, the standard immunotherapy involves intravesical Bacillus Calmette-Guérin (BCG). However, its success requires repeated doses, and ∼50% of patients do not benefit. Using a preclinical orthotopic bladder cancer model, we found that a single intravesical dose of combined BCG and β-glucan immunotherapy eradicated aggressive tumors, resulting in 100% survival. Through single-cell transcriptomic/epigenomic analysis, flow cytometry, and intravital imaging, we show that BCG and β-glucan reprogrammed hematopoietic stem and progenitor cells with imprinting in innate immune cells, particularly neutrophils. Reprogrammed neutrophils exhibited increased reactive oxygen species (ROS) production and infiltration into the tumor core, reducing tumor vascularization and growth. The tumor microenvironment can convert neutrophils into protumor cells; BCG and β-glucan prevented this conversion, promoting sustained antitumoral activity. These findings support β-glucan as a safe, effective adjuvant to enhance BCG immunotherapy in bladder cancer and other solid tumors.

Keywords:  BCG; bladder cancer; granulopoiesis; immunotherapy; innate immune memory; melanoma; neutrophils; trained immunity; β-glucan

DOI:  https://doi.org/10.1016/j.immuni.2025.05.026
Gut Microbes. 2025 Dec;17(1): 2524540

Gut bacteriophages induce specific-reprogramming of macrophages to generate a protective innate immunity response to lipopolysaccharide exposure.

Xiang Hou, Huiyan Ding, Heye Wang, Jing Wang, Hui Liu, Hao Hu, Craig Billington, Ran Wang, Lili Zhang.

  Macrophages play essential roles in generating a tolerogenic resident environment, but the interactions between bacteriophages and their action in macrophage tolerance memory remain unknown. Here, we find that gut bacteriophage exposure in vivo induces tolerance immunity via reprogrammed macrophages which significantly enhances protection against bacterial lipopolysaccharide (LPS). Bacteriophage-memory macrophages orchestrate LPS-challenge responses into tolerization or hyperresponsive gene expression clusters in a function-specific manner. The tolerized gene cluster encodes pro-inflammatory cytokines, while the induction cluster is a defense-specific response including anti-inflammatory cytokines, antiviral and antimicrobial effectors, and negative regulators of inflammation. Mechanistically, this augmented defense response is dependent on increased expression of IL-10, but not suppression of pro-inflammatory cytokines. Furthermore, bacteriophages suppressed LPS-induced pro-inflammatory genes by repressing histone acetylation target enhancers that coordinate chromatin accessibility to limit inflammation. Thus, our study identifies the function and mechanism of reprogramming actions for bacteriophage in moderating LPS immune responses.

Keywords:  Bacteriophage; IL-10; epigenetic mechanisms; innate immune memory; macrophage

DOI:  https://doi.org/10.1080/19490976.2025.2524540
FASEB J. 2025 Jul 15. 39(13): e70767

M2-Like Macrophages Exhibit Sialic Acid-Enhanced Efferocytosis via the Siglec CD22.

Emily N Kukan, Gabrielle L Fabiano, Leandre M Glendenning, Julie Y Zhou, Kevin A Telfer, James C Paulson, Brian A Cobb.

  The sialic acid/Siglec axis is an important immunologic regulatory pathway in which host-specific α2,6-sialylated glycans are recognized as markers of self. CD22, known primarily as a surface receptor on B cells, directly prevents autoantigen responses through concurrent recognition of α2,6-linked sialic acids. Here, we report that CD22 is expressed in macrophages polarized to an M2-like, immunomodulatory phenotype. Tissue-resident macrophage populations classically showing an M2-like skew, such as in the lung, were found to be significantly enriched for CD22 expression. We also discovered that CD22 promotes efferocytosis of sialylated glycoproteins and apoptotic debris and is associated with increased protein processing but reduced T cell activation. These findings support a model whereby CD22+ M2-like macrophages participate in the resolution of inflammation and a return to tissue homeostasis via the clearance of host-derived α2,6-sialylated debris, degrading this material without further exacerbation of T cell-mediated inflammation.

Keywords:  Siglec; efferocytosis; inflammation; macrophage; sialic acid

DOI:  https://doi.org/10.1096/fj.202500146RR
Adv Sci (Weinh). 2025 Jun 24. e04101

BCG-Derived Outer Membrane Vesicles Induce TLR2-Dependent Trained Immunity to Protect Against Polymicrobial Sepsis.

Yuan Gong, Wenyan Hao, Lingqi Xu, Yingyi Yang, Zhenzhen Dong, Peng Pan, Zhenjiang Bai, Jie Huang, Kaidi Yang, Zhu Jin, Rui Kang, Qiang Shan, Jiang Huai Wang, Zijian Zhou, Daolin Tang, Jian Wang, Huiting Zhou.

  Trained immunity, an innate immune memory, has emerged as a promising strategy to enhance host defense against sepsis, a leading cause of mortality in critical care. While Bacillus Calmette-Guérin (BCG) is the most widely used vaccine for tuberculosis prevention, its broader use as an inducer of trained immunity is limited by adverse reactions. Here, it is reported that BCG-derived outer membrane vesicles (B-OMVs) effectively trigger trained immunity to protect against experimental polymicrobial sepsis. Comprehensive characterization and safety assessments confirmed that B-OMVs exhibited no significant toxicity or pathological effects, positioning them as a promising alternative to conventional BCG vaccines and E. coli-derived outer membrane vesicles (E-OMVs) in terms of both efficacy and safety. Mechanistically, B-OMVs enhanced trained immunity by promoting hematopoietic stem cell expansion and myelopoiesis via toll like receptor 2 (TLR2)-dependent activation of aerobic glycolysis and epigenetic reprogramming. This led to an amplified immune response and enhanced phagocytic activity in bone marrow-derived macrophages. Together, these findings establish B-OMVs as a novel immunomodulatory agent against sepsis-induced immune dysfunction, with translational potential.

Keywords:  BCG; OMVs; sepsis; trained immunity

DOI:  https://doi.org/10.1002/advs.202504101
Life (Basel). 2025 Jun 14. pii: 958. [Epub ahead of print]15(6):

Influence of Insert Brand and Culture Method on Ciliary Activity and Epithelial Cell Types in Human Nasal Air-Liquid Interface Cell Cultures.

Patricia Celkova, Emilie Seydoux, Susan De Groof, Loretta Müller.

  Cultures of primary human nasal epithelial cells (hNECs) differentiated at the air-liquid interface (ALI) represent a sophisticated and widely used model of the human upper respiratory epithelium. Despite the availability of various cell culture insert types and the well-established understanding that different culture media influence the cell culture characteristics, the possible impact of the insert brand remains rather underexplored. We cultured hNECs from nineteen healthy adult donors on three distinct brands of commercially available inserts-Corning® Transwell®, CELLTREAT®, and ThinCert®-and compared the ciliary activity and cellular composition of the cultures using high-speed video microscopy and flow cytometry, respectively. Additionally, we employed an alternative method of hNEC culture setup-the inverted condition-wherein the hNECs were seeded on the basal side of the insert with the idea to avoid mucus accumulation. Our results show that ciliary activity and cell type composition did not differ between insert types for both culture conditions. However, we found a higher ciliary beat frequency and a lower active (ciliated) area in the inverted setup compared to the conventional setup across all three insert brands. These findings indicate that all three mentioned insert types yield comparable cell cultures.

Keywords:  air–liquid interface; cell culture; cell culture insert; nasal epithelial cells; respiratory epithelium

DOI:  https://doi.org/10.3390/life15060958
Infection. 2025 Jun 23.

Applications of human lung organoids to human respiratory virus research: advances, limitations and future directions.

Qi Chen, Huaiqing Qi, Jun Guo.

  Human respiratory viruses (HRVs) can cause a spectrum of respiratory infections, which pose a significant challenge to global public health and are associated with a substantial economic impact. Traditional studies have often relied on in vitro culture systems utilizing transformed cell lines and animal models. However, there has been a shift towards emerging research models. Organoids are three-dimensional cell cultures that self-organize and differentiate into functional cell types, closely mimicking the structure and function of organs in vivo. Increasing evidence suggests that human lung organoids serve as reliable and effective models for studying HRVs. In this review, we compare common research models for HRVs, outline the establishment of human lung organoids, and explore their applications in HRV studies.

Keywords:  Human respiratory viruses; Infection; Lung organoids; Research model

DOI:  https://doi.org/10.1007/s15010-025-02587-9
Am J Physiol Lung Cell Mol Physiol. 2025 Jun 27.

Understanding and manipulating morphogenetic processes to generate in vitro models of airways.

Katharina Raasch, Pauline Henrot, Alice Hadchouel, Maeva Zysman, Isabelle Dupin.

  Branching morphogenesis, the process by which cells and tissues organise into complex branched tubular structures, is fundamental to the development of functional organs, including the respiratory airways in mammalian lungs. Advances in understanding the molecular and cellular mechanisms driving morphogenetic processes have enabled the development of sophisticated in vitro models that mimic the structure and function of airways. This review recapitulates developmental principles guiding airway morphogenesis, including the key signalling pathways, cellular interactions and the different biochemical and mechanical cues. We discuss how these principles have been harnessed to engineer in vitro models of airways, providing a comprehensive overview of current artificial lung culture systems. We consider fully morphogenetic-mimicking strategies such as organoid modelling to more reductionist strategies, such as airway-on-a-chip systems. By examining both the breakthroughs and current limitations, we highlight the potential of these models to reproduce airway physiology and diseases, such as congenital pulmonary airway malformation and chronic obstructive pulmonary disease. Furthermore, we consider future directions in the field, emphasising the need for controlling complex environmental cues and integrating multiple cellular components to create increasingly accurate and functional airway models.

Keywords:  3D culture; airway diseases; lung bioengineering; lung development; stem cells

DOI:  https://doi.org/10.1152/ajplung.00015.2025
JACC Basic Transl Sci. 2025 Jun 24. pii: S2452-302X(25)00220-7. [Epub ahead of print]10(7): 101300

Enhanced Trained Immunity in Peripheral Monocytes in Unstable Angina With Elevated High-Sensitivity C-Reactive Protein.

Jiyu Zhang, Fen Yang, Yuhan Liao, Xinyi Xia, Miao Yu, Desheng Hu, Weimin Wang, Li Zhang, Chaolong Wang, Huirong Liu, Chen Chen, Qing K Wang, Zhilei Shan, Peter Libby, Xiang Cheng.

  Despite effective secondary prevention for coronary heart diseases, recurrent events remain high. Elevated high-sensitivity C-reactive protein (hsCRP) indicates increased inflammation risk. This study aimed to investigate the trained immunity of circulating monocytes in unstable angina (UA) patients with elevated hsCRP. We analyzed CD14+ monocytes from UA patients, comparing high-risk (hsCRP ≥3 mg/L) and low-risk (hsCRP <1 mg/L) groups. We assessed cytokine production and conducted metabolic, transcriptional, and epigenetic profiling. Patients with elevated hsCRP exhibited enhanced proinflammatory responses, glycolytic activity, and altered immune profiles, indicating sustained monocyte trained immunity, which contributes to residual inflammation risk in cardiovascular disease.

Keywords:  hsCRP; inflammatory risk; monocyte; trained immunity; unstable angina

DOI:  https://doi.org/10.1016/j.jacbts.2025.04.014
Int Immunopharmacol. 2025 Jun 21. pii: S1567-5769(25)01086-0. [Epub ahead of print]162 115096

Inhibiting the expression of GPR43 in macrophages can alleviate osteoarthritis by suppressing the M1 polarization and suppressing ROS production.

Haokun Mo, Yanjun Hou, Junchen He, Zhaoxuan Ruan, Liang Li, Jun Qi, Chenwen Wang, Fengjing Guo, Peng Cheng.

  G-protein-coupled receptor 43 (GPR43) plays an important role in immunomodulation, metabolic regulation and ROS production. Our research aims to explore the role and mechanism of GPR43 in osteoarthritis (OA). We experimentally determined that following the intervention of macrophages with lipopolysaccharide (LPS), there is a significant upregulation in the expression of GPR43. GPR43 knockdown in macrophages can inhibit the M1 polarization and reactive oxygen species (ROS) production. Meanwhile, GPR43 knockdown can alleviate osteoarthritis in destabilized medial meniscus (DMM) induced OA mouse models. In mechanism, GPR43 knockdown in macrophages can inhibit the expression of CX3C chemokine ligand 1 (CX3CL1) and the activation of NF-κB signaling pathway, thereby exerting a therapeutic effect on OA. Overall, knockdown of GPR43 in macrophages can alleviate OA by inhibiting M1 polarization and ROS production via the CX3CL1/NF-κB signaling pathway. GPR43 is a potential therapeutic target for OA.

Keywords:  CX3CL1; GPR43; Macrophage; NF-κB signaling pathway; Osteoarthritis; ROS

DOI:  https://doi.org/10.1016/j.intimp.2025.115096