bims-bac4me 2025-02-16 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2025–02–16
forty-one papers selected by
Chun-Chi Chang, Universitäts Spital Zürich

Computational and in vitro evaluation of probiotic treatments for nasal Staphylococcus aureus decolonization.
Corynebacteria from the respiratory microbiota modulate inflammatory responses and associate with a reduced pneumococcal burden in the lungs.
Bacterial translocation promotes trained immunity.
Macrophage memory emerges from coordinated transcription factor and chromatin dynamics.
Gram-positive pathogens, inflammation, and the host lipid environment.
A Trade-Off Between Antimicrobial Peptide Resistance and Sensitivity to Host Immune Effectors in Staphylococcus aureus In Vivo.
Protection acquired upon intraperitoneal group a Streptococcus immunization is independent of concurrent adaptive immune responses but relies on macrophages and IFN-γ.
Gut bacterial L-lysine alters metabolism and histone methylation to drive dendritic cell tolerance.
Mechanisms and Therapeutic Potential of Key Anti-inflammatory Metabiotics: Trans-Vaccenic Acid, Indole-3-Lactic Acid, Thiamine, and Butyric Acid.
Unveiling the Phenotypic Variability of Macrophages: Insights from Donor Diversity and Pooling Strategies.
IL-27 regulates macrophage ferroptosis by inhibiting the Nrf2/HO1 signaling pathway in sepsis-induced ARDS.
Convalescent COVID-19 monocytes exhibit altered steady-state gene expression and reduced TLR2, TLR4 and RIG-I induced cytokine expression.
A cellular danse macabre: the choreography of programmed cell death.
Evidence for altered immune-structural cell crosstalk in cystic fibrosis revealed by single cell transcriptomics.
Screening of Regulatory mRNAs and miRNAs that Suppress Staphylococcus aureus Proliferation via Macrophage Ferroptosis.
TREM2 protects against LPS-induced murine acute lung injury through suppressing macrophage ferroptosis.
Colonization island directs L. plantarum to its niche.
Development of a tri-species wound model for studying fungal-bacterial interactions and antimicrobial therapies.
Next generation lysosome: Brought to you by cGAS-STING.
Double-edged sword effect of GPX4 in skin homeostasis and diseases.
Raver1 links Ripk1 RNA splicing to caspase-8-mediated pyroptotic cell death, inflammation, and pathogen resistance.
Coactivation of innate immune suppressive cells induces acquired resistance against combined TLR agonism and PD-1 blockade.
Lactiplantibacillus plantarum ZJ316 Alleviates Helicobacter pylori-Induced Intestinal Inflammation by Sustaining Intestinal Homeostasis.
Macrophage-to-Myofibroblast Transition Contributes to Cutaneous Scarring Formation Through the TGF-β/Smad3 Signaling Pathways.
Effects of azithromycin on alleviating airway inflammation in asthmatic mice by regulating airway microbiota and metabolites.
A bacterial antiviral system detects and directly fights against infection.
The complexities of cell death mechanisms: a new perspective in systemic sclerosis therapy.
KLF12 inhibits lipopolysaccharide-induced inflammatory responses, oxidative stress, pyroptosis, and endoplasmic reticulum stress in human airway epithelial cells through inhibition of the NF-κB pathway.
Fungal Als proteins hijack host death effector domains to promote inflammasome signaling.
Genomic epidemiology and phenotypic characterization of Staphylococcus aureus isolated from atopic dermatitis patients in South China.
Skin-deep immune sensing.
Analysis of the dynamics of transition from non-colonization to colonization and Staphylococcus aureus bacteremia in hemodialysis patients using Markov models.
The Protective Role of DDIT4 in Helicobacter pylori-induced Gastric Metaplasia Through Metabolic Regulation of Ferroptosis.
Exploring the Role of Macrophages and Their Associated Structures in Rheumatoid Arthritis.
Current Perspectives of TLR2 Signalling in the Retina.
Mucus Physically Restricts Influenza A Viral Particle Access to the Epithelium.
Inhibitory effects of probiotic & gastro-intestinal bacteria on H. pylori in vitro.
Rapid Natural Killer Cell Gene Responses, Generated by TLR Ligand-Induced Trained Immunity, Provide Protection to Bacterial Infection in rag1-/- Mutant Zebrafish (Danio rerio).
Combating Pathogenic Immune Evasion: Sialidase-Activated Thermally Delayed Fluorescence for Probing and Modulating Host-Pathogen Interactions.
Lactobacillomics as a new notion in lactic acid bacteria research through omics integration.
AhR causes the release of proinflammatory cytokines and chemokines and airway epithelial barrier dysfunction in allergic rhinitis via upregulating SERPINB2.

Proc Natl Acad Sci U S A. 2025 Feb 18. 122(7): e2412742122

Computational and in vitro evaluation of probiotic treatments for nasal Staphylococcus aureus decolonization.

Burcu Tepekule, Weronika Barcik, Willy I Staiger, Judith Bergadà-Pijuan, Thomas Scheier, Laura Brülisauer, Alex R Hall, Huldrych F Günthard, Markus Hilty, Roger D Kouyos, Silvio D Brugger.

  Despite the rising challenge of antibiotic resistance, current approaches to eradicate nasal pathobionts Staphylococcus aureus and Streptococcus pneumoniae rely on antibacterials. An alternative is the artificial inoculation of commensal bacteria, i.e., probiotic treatment, supported by the increasing evidence for commensal-mediated inhibition of pathogens. To systematically investigate the potential of this approach, we developed a quantitative framework simulating the nasal microbiome dynamics by combining mathematical modeling with longitudinal microbiota data. By inferring community parameters using 16S ribosomal RNA (rRNA) amplicon sequencing data and simulating the nasal microbial dynamics of patients colonized with S. aureus, we compared the decolonization performance of probiotic and antibiotic treatments under different assumptions on patients' community composition and susceptibility profile. To further compare the robustness of these treatments, we simulated an S. aureus challenge and quantified the recolonization probability. Through in vitro experiments using nasal swabs of adults colonized with S. aureus, we confirmed that after antibiotic treatment, recolonization of S. aureus was inhibited in samples treated with a probiotic mixture compared to the nontreated control. Our results suggest that probiotic treatment outperforms antibiotics in terms of decolonization performance, recolonization robustness, and leads to less collateral reduction in the microbiome diversity. Thus, probiotic treatment may provide a promising alternative to combat antibiotic resistance, with the additional advantage of personalized treatment options via using the patient's own metagenomic data. The combination of an in silico framework with in vitro experiments using clinical samples reported in this work is an important step forward to further investigate this alternative in clinical trials.

Keywords:  antibiotic resistance; commensal-mediated inhibition; mathematical modeling; nasal microbiome; probiotic treatment

DOI:  https://doi.org/10.1073/pnas.2412742122
Front Cell Infect Microbiol. 2024 ;14 1530178

Corynebacteria from the respiratory microbiota modulate inflammatory responses and associate with a reduced pneumococcal burden in the lungs.

Caroline Bergenfelz, Phuong Do, Liv Larsson, Hanna Ivarsson, Kasper Malmborn, Anders P Håkansson.

   Background: Certain species from the normal respiratory tract microbiota have recently been proposed to positively influence human health. Corynebacterium propinquum and C. pseudodiphtheriticum (Corynebacteria) are two Gram-positive species that frequently colonize the upper respiratory tract and strongly associate with a reduced incidence of respiratory tract infections. The specific role of Corynebacteria during respiratory health and disease is, however, largely uncharacterized.
Method: Respiratory tract epithelial cells NCI-H292 and BALB/cByJ mice were inoculated with Corynebacteria (C. propinquum 2018M3 and 2019M4, and C. pseudodiphtheriticum 2019M8 and 2020M12) alone or with subsequent challenge with Streptococcus pneumoniae (pneumococci). The inflammatory response and the bacterial burden of both species over time were determined by Western blot, luciferase assay, cytokine bead array, flow cytometry and viable plate counts on blood agar plates.
Results: Clinical isolates of Corynebacteria were well tolerated by human cells and mice. Corynebacteria induced a transient inflammatory response during healthy conditions in the absence of known pathogens. Pre-exposure or nasal priming with Corynebacteria did not affect subsequent acquisition of pneumococci but were associated with a modulated inflammatory response in vitro and in vivo as well as with a reduced pneumococcal burden in the respiratory tract of mice. This indicates that the presence of C. propinquum or C. pseudodiphtheriticum may protect against severe pneumococcal infections.
Conclusions: In this study, we delineate the role of Corynebacteria from the normal microbiota that epidemiologically associate with respiratory health. We show that the presence of Corynebacteria modulates the inflammatory response to pneumococci and associate with faster decrease in pneumococcal burden, primarily in the lower respiratory tract. Our data indicate that Corynebacteria has potential to protect against severe pneumococcal infections.

Keywords:  Streptococcus pneumoniae; corynebacteria; inflammation; microbiota; pneumonia; respiratory tract

DOI:  https://doi.org/10.3389/fcimb.2024.1530178
Immunity. 2025 Feb 11. pii: S1074-7613(25)00036-6. [Epub ahead of print]58(2): 268-270

Bacterial translocation promotes trained immunity.

Maria Francesca Viola, Elvira Mass.

Can bacteria that breach mucosal barriers drive long-lasting changes in immunity? In this issue of Immunity, Robles-Vera et al. describe how, in the context of colitis, bacteria breaching the intestinal barrier reprogram precursors in the bone marrow via Mincle-dependent signaling.

DOI: https://doi.org/10.1016/j.immuni.2025.01.011
Cell Syst. 2025 Feb 06. pii: S2405-4712(25)00004-3. [Epub ahead of print] 101171

Macrophage memory emerges from coordinated transcription factor and chromatin dynamics.

Andrew G Wang, Minjun Son, Aleksandr Gorin, Emma Kenna, Abinash Padhi, Bijentimala Keisham, Adam Schauer, Alexander Hoffmann, Savaş Tay.

  Cells of the immune system operate in dynamic microenvironments where the timing, concentration, and order of signaling molecules constantly change. Despite this complexity, immune cells manage to communicate accurately and control inflammation and infection. It is unclear how these dynamic signals are encoded and decoded and if individual cells retain the memory of past exposure to inflammatory molecules. Here, we use live-cell analysis, ATAC sequencing, and an in vivo model of sepsis to show that sequential inflammatory signals induce memory in individual macrophages through reprogramming the nuclear factor κB (NF-κB) network and the chromatin accessibility landscape. We use transcriptomic profiling and deep learning to show that transcription factor and chromatin dynamics coordinate fine-tuned macrophage responses to new inflammatory signals. This work demonstrates how macrophages retain the memory of previous signals despite single-cell variability and elucidates the mechanisms of signal-induced memory in dynamic inflammatory conditions like sepsis.

Keywords:  NF-κB; Toll-like receptors; dynamics; inflammatory signaling; innate immune memory; modeling; sepsis; signaling dynamics; systems biology

DOI:  https://doi.org/10.1016/j.cels.2025.101171
Curr Opin Microbiol. 2025 Feb 07. pii: S1369-5274(25)00003-7. [Epub ahead of print]83 102581

Gram-positive pathogens, inflammation, and the host lipid environment.

Reginald A Woods, Sarai Guzman Vela, Francis Alonzo.

The host lipid environment is a barrier to bacterial infection that comprises antimicrobial fatty acids and impermeable lipids that keep infectious agents from penetrating tissues. Bacterial and host lipids also signal to the immune system to regulate inflammation. Notably, bacterial lipids activate Toll-like receptors to initiate cytokine production, immune cell recruitment, and oxidative burst to control infection. Bacterial pathogens must adapt to the lipid environment, including bactericidal host fatty acids and inflammatory lipids, in ways that promote persistence in diverse tissues. Here, we discuss current advances in the understanding of Staphylococcus aureus lipid interactions that contribute to inflammation and innate immunity and consider the complex roles of host inflammatory lipids in driving immune defenses and antibacterial activity. In addition, we endeavor to introduce similar processes in other Gram-positive pathogens. These recent studies highlight the growing body of knowledge on the effects of lipid metabolism on host immunity and pathogenesis.

DOI: https://doi.org/10.1016/j.mib.2025.102581
Evol Appl. 2025 Feb;18(2): e70068

A Trade-Off Between Antimicrobial Peptide Resistance and Sensitivity to Host Immune Effectors in Staphylococcus aureus In Vivo.

Baydaa El Shazely, Jens Rolff.

  Antimicrobial peptides (AMPs) are essential immune effectors of multicellular organisms. Bacteria can evolve resistance to AMPs. Surprisingly, when used to challenge the yellow mealworm beetle, Tenebrio molitor, Staphylococcus aureus resistant to an abundant AMP (tenecin 1) of the very same host species did not increase host mortality or bacterial load compared to infections with wild-type S. aureus. A possible explanation is that antimicrobial resistance is costly due to the collaterally increased sensitivity of AMP-resistant strains to other immune effectors. Here, we study the sensitivity of a group of AMP-resistant S. aureus strains (resistant to tenecin 1 or a combination of tenecin 1 + 2) to other immune effectors such as phenoloxidase and other AMPs in vivo. Using RNAi-based knockdown, we investigate S. aureus survival in insect hosts lacking selected immune effectors. We find that all except one AMP-resistant strain displayed collateral sensitivity toward phenoloxidase. Some AMP-resistant strains show sensitivity to components of the yellow mealworm beetle AMP defense cocktail. Our findings are consistent with the idea that resistance to AMPs does not translate into changes in virulence because it is balanced by the collaterally increased sensitivity to other host immune effectors. AMP resistance fails to provide a net survival advantage to S. aureus in a host environment that is dominated by AMPs.

Keywords:  Tenebrio molitor; antimicrobial peptides; antimicrobial resistance; negative pleiotropy

DOI:  https://doi.org/10.1111/eva.70068
Virulence. 2025 Dec;16(1): 2457957

Protection acquired upon intraperitoneal group a Streptococcus immunization is independent of concurrent adaptive immune responses but relies on macrophages and IFN-γ.

Shiva Emami, Elsa Westerlund, Thiago Rojas Converso, Bengt Johansson-Lindbom, Jenny J Persson.

  Group A Streptococcus (GAS; Streptococcus pyogenes) is an important bacterial pathogen causing over 700 million superficial infections and around 500.000 deaths due to invasive disease or severe post-infection sequelae yearly. In spite of this major impact on society, there is currently no vaccine available against this bacterium. GAS strains can be separated into >250 distinct emm (M)-types, and protective immunity against GAS is believed to in part be dependent on type-specific antibodies. Here, we analyse the nature of protective immunity generated against GAS in a model of intraperitoneal immunization in mice. We demonstrate that multiple immunizations are required for the ability to survive a subsequent lethal challenge, and although significant levels of GAS-specific antibodies are produced, these are redundant for protection. Instead, our data show that the immunization-dependent protection in this model is induced in the absence of B and T cells and is accompanied by the induction of an altered acute cytokine profile upon subsequent infection, noticeable e.g. by the absence of classical pro-inflammatory cytokines and increased IFN-γ production. Further, the ability of immunized mice to survive a lethal infection is dependent on macrophages and the macrophage-activating cytokine IFN-γ. To our knowledge these findings are the first to suggest that GAS may have the ability to induce forms of trained innate immunity. Taken together, the current study proposes a novel role for the innate immune system in response to GAS infections that potentially could be leveraged for future development of effective vaccines.

Keywords:  Group A Streptococcus; adaptive immune memory; immunization; innate immune memory; protective immunity

DOI:  https://doi.org/10.1080/21505594.2025.2457957
Cell Rep. 2025 Jan 28. pii: S2211-1247(24)01476-1. [Epub ahead of print]44(1): 115125

Gut bacterial L-lysine alters metabolism and histone methylation to drive dendritic cell tolerance.

Qiang Tang, Guangyue Fan, Xianping Peng, Xinyu Sun, Xueting Kong, Lisong Zhang, Chunze Zhang, Yandi Liu, Jianming Yang, Kaiyuan Yu, Chunhui Miao, Zhi Yao, Long Li, Zhi-Song Zhang, Quan Wang.

  Dendritic cells (DCs) are responsible for maintaining tolerance to harmless antigens in the gut; however, the mechanism by which bacterial metabolites induce DC tolerance remains to be studied. Here, we observed that gut commensal bacterium-derived L-lysine stimulated the serine, glycine, one-carbon (SGOC) metabolism through the adenosine monophosphate (AMP)-activated protein kinase (AMPK)/acetyl-coenzyme A (AcCoA)-mechanistic target of rapamycin (mTOR) axis in DCs. This activation led to an increase in S-adenosyl methionine (SAM) and disruptor of telomeric silencing 1-like (DOT1L) expression, resulting in enhanced dimethylation on H3 lysine 79 (H3K79me2) enrichment at Tgfb and signal transducers and activator of transcription 3 (Stat3) gene promoters, which promote immune tolerance characteristics in DCs. The lysine-induced DC tolerance in restoring homeostasis was demonstrated using mouse models of immune-inflammatory diseases and phosphoglycerate dehydrogenase (Phgdh) conditional knockout mice. The single-cell RNA sequencing (scRNA-seq) analysis revealed that L-lysine restored homeostasis during inflammatory disorders by switching DCs to a tolerance state in vivo. Moreover, the enzyme by which bacteria effectively produce L-lysine is identified. The study reveals an unknown mechanism for regulating immune homeostasis through the intricate interplay of bacterial L-lysine, SGOC metabolism, histone methylation, and DC tolerance.

Keywords:  CP: Immunology; CP: Microbiology; H3K79me2; L-lysine; SGOC metabolism; dendritic cell; immune tolerance

DOI:  https://doi.org/10.1016/j.celrep.2024.115125
Probiotics Antimicrob Proteins. 2025 Feb 08.

Mechanisms and Therapeutic Potential of Key Anti-inflammatory Metabiotics: Trans-Vaccenic Acid, Indole-3-Lactic Acid, Thiamine, and Butyric Acid.

Muñoz-Olivos Cristina, Bautista-Rodriguez Elizabeth, Rivas-Arreola María Jose, Palacios-Gonzalez Berenice, Zacapa Diego, Cortez-Sanchez Jose Luis.

  Identifying metabolites produced by probiotic bacteria, also known as metabiotics, is becoming increasingly common due to their anti-inflammatory, anti-obesogenic, and immunomodulatory effects. Postbiotics alongside diet, regulate both physical and mental health, as the microbiota members can interact physically with host cells or through secretion of nutrients and metabiotics. These metabiotics also reduce the severity of certain metabolic disorders and support the proper functioning of various organs and systems. In this review, we describe the mechanisms of action of trans-vaccenic acid (TVA), indole-3-lactic acid (ILA), thiamine (vitamin B1), and butyric acid metabolites produced or induced by probiotics such as Lactobacillus and/or Bifidobacterium, among others and previously identified using analytical techniques such as mass spectrometry (LC-MS). Within their mechanisms of action, Trans-vaccenic acid exerts anti-inflammatory effects and helps alleviate complications associated with metabolic diseases. Indole metabolites promote IL-22 production and regulate epithelial cell proliferation and antimicrobial peptide production. Thiamin is essential for energy metabolism regulation, and butyric acid regulates the brain-gut axis and also regulates immune response. This review expands our understanding of the potential therapeutic use of metabiotics.

Keywords:  Anti-inflammatory effect; Immunity; Metabiotics; Microbial metabolites; Microbiota

DOI:  https://doi.org/10.1007/s12602-025-10475-9
Int J Mol Sci. 2025 Jan 31. pii: 1272. [Epub ahead of print]26(3):

Unveiling the Phenotypic Variability of Macrophages: Insights from Donor Diversity and Pooling Strategies.

Bartłomiej Taciak, Agnieszka Grochowska, Małgorzata Górczak, Emilia Górka, Marcin Skorzynski, Maciej Białasek, Tomasz P Rygiel, Magdalena Król.

  Macrophages are key players in inflammation and immune responses due to their phenotypic plasticity. This study examined the effects of pooling donor-derived macrophages on their phenotype and function, focusing on murine bone marrow-derived macrophages (BMDMs) and human monocyte-derived macrophages (hMDMs). Murine BMDMs were generated using L929-conditioned media and compared across single and pooled donors (two-to-five mice). Similarly, hMDMs cultured with M-CSF from individual donors were compared to pooled cultures. Pooling macrophages did not alter core phenotypic markers (CD11b, F4/80, CD64) or functional outputs such as cytokine secretion and nitric oxide production. In hMDMs, pooling reduced variability and led to slightly elevated or more-uniform marker expression. These findings demonstrate that pooling macrophages minimizes inter-individual variability without compromising cellular stability or function, enhancing reproducibility in immunological research while maintaining the option of single-donor studies for personalized analyses.

Keywords:  BMDM; donor diversity; macrophages

DOI:  https://doi.org/10.3390/ijms26031272
Inflamm Res. 2025 Feb 13. 74(1): 39

IL-27 regulates macrophage ferroptosis by inhibiting the Nrf2/HO1 signaling pathway in sepsis-induced ARDS.

Meng Xiong, Renjie Luo, Zhijiao Zhang, Panting Liu, Qiaozhi Peng, Fang Xu, Minkang Guo.

   OBJECTIVES: Acute respiratory distress syndrome (ARDS) is a clinical syndrome characterized by high morbidity and mortality rates. Sepsis-induced ARDS involves excessive inflammatory responses, which are modulated by macrophages. This study aimed to elucidate the effect of Recombinant Mouse IL-27 Protein on macrophage ferroptosis and polarization, as well as its impact on sepsis-induced ARDS.
METHODS: A cecal ligation and puncture (CLP)-induced sepsis model was established using wild-type (WT) or IL27R-/- mice. Then, the mice were randomly divided into 4 groups: a control group, a CLP group, an IL-27 + CLP combination group, and an IL-27, CLP, and Oltipraz combination group. RAW 264.7 cells and BMDMs were used to further determine the role and mechanism of IL-27 in vitro.
RESULTS: In vitro, IL-27 alone did not alter the expression of proteins linked to the ferroptosis pathway or macrophage polarization. Contrastingly, the combination of IL-27 with LPS further amplified LPS-induced alterations in the ferroptosis pathway, thereby promoting macrophage M1 polarization and inhibiting M2 polarization. Additionally, IL-27 + LPS increased ROS levels in macrophages. A sepsis-induced ARDS mouse model was then established via CLP. In vivo, IL-27 exacerbated CLP-induced lung injury in WT mice. Additionally, it decreased the expression levels of ferroptosis-related proteins (Nrf2, HO-1, GPX4) and increased those of Ptgs2 in the lung tissue of septic mice. Besides, GSH and SOD levels in lung tissue were also reduced. Moreover, IL-27 also promoted M1 polarization and inhibited M2 polarization in macrophages. In IL27R-/- mice, the effects of IL-27 were abrogated. Oltipraz inhibited IL-27-induced changes by up-regulating Nrf2 expression. Overall, this present study demonstrated that the combination of IL-27 and LPS-induced macrophage ferroptosis, promoted macrophage M1 polarization, and inhibited M2 polarization by inhibiting the Nrf2/HO-1 pathway.
CONCLUSION: Oltipraz may alleviate ARDS-related lung injury by up-regulating Nrf2 expression and concurrently inhibiting macrophage ferroptosis.

Keywords:  Acute respiratory distress syndrome (ARDS); Ferroptosis; IL-27; Nrf2/HO1; Sepsis

DOI:  https://doi.org/10.1007/s00011-024-01986-2
Hum Immunol. 2025 Feb 07. pii: S0198-8859(25)00020-5. [Epub ahead of print]86(2): 111249

Convalescent COVID-19 monocytes exhibit altered steady-state gene expression and reduced TLR2, TLR4 and RIG-I induced cytokine expression.

Sarah Unterberger, Nadia Terrazzini, Sandra Sacre.

  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19, can induce trained immunity in monocytes. Trained immunity is the result of metabolic and epigenetic reprogramming of progenitor cells leading to an altered inflammatory response to subsequent activation. To investigate the monocyte response 3-6 months post SARS-CoV-2 infection, steady-state gene expression and innate immune receptor stimulation were investigated in monocytes from unvaccinated SARS-CoV-2 naïve individuals and convalescent COVID-19 participants. The differentially expressed genes (DEGs) identified were involved in the regulation of innate immune signalling pathways associated with anti-viral defence. COVID-19 participants who had experienced severe symptoms exhibited a larger number of DEGs than participants that had mild symptoms. Interestingly, genes encoding receptors that recognise SARS-CoV-2 RNA were downregulated. DDX58, encoding retinoic-acid inducible gene I (RIG-I), was downregulated which corresponded with a reduced response to RIG-I activation. Furthermore, toll-like receptor (TLR)1/2 and TLR4 activation also exhibited reduced cytokine secretion from convalescent COVID-19 monocytes. These data suggest that following SARS-CoV-2 infection, monocytes exhibit altered steady-state gene expression and reduced responsiveness to innate immune receptor activation. As both RIG-I and TLRs recognise components of SARS-CoV-2, this may lead to a moderated inflammatory response to SARS-CoV-2 reinfection in the months following the initial infection.

Keywords:  COVID-19; Gene expression; Monocytes; RIG-I; SARS-CoV-2; Toll-like receptor

DOI:  https://doi.org/10.1016/j.humimm.2025.111249
Apoptosis. 2025 Feb 09.

A cellular danse macabre: the choreography of programmed cell death.

Arjan W Griffioen, Patrycja Nowak-Sliwinska.

  Research on cell death is getting diverse. Apoptosis and other forms of programmed cell death play a critical role in maintaining cellular homeostasis and defending an organism from infections, cancer, and degenerative diseases. Apoptosis, a well-known form of programmed cell death, involves non-inflammatory and orderly organized dismantling of a cell. Different pathways and mechanisms have emerged that challenge the traditional apoptosis-centric view, such as necroptosis, panoptosis, pyroptosis, paraptosis, ferroptosis and autophagic cell death. This editorial aims to highlight some of these emerging pathways, expanding our understanding of cellular death and its implications in health and disease. Over the years, Apoptosis has been at the forefront of publishing discoveries on these diverse and impactful processes.

Keywords:  Apoptosis; Cell death; Programmed death

DOI:  https://doi.org/10.1007/s10495-025-02076-2
J Cyst Fibros. 2025 Feb 12. pii: S1569-1993(25)00049-9. [Epub ahead of print]

Evidence for altered immune-structural cell crosstalk in cystic fibrosis revealed by single cell transcriptomics.

Marijn Berg, Lisette Krabbendam, Esmee K van der Ploeg, Menno van Nimwegen, Tjeerd van der Veer, Martin Banchero, Orestes A Carpaij, Remco Hoogenboezem, Maarten van den Berge, Eric Bindels, Joachim G J V Aerts, Antoine Collin, Pascal Barbry, Lieke S Kamphuis, Rudi W Hendriks, Martijn C Nawijn, Ralph Stadhouders.

   BACKGROUND: Chronic pulmonary inflammation strongly contributes to respiratory failure and mortality in patients with cystic fibrosis (pwCF). Effective anti-microbial immunity and maintaining lung homeostasis require continuous structural-immune cell communication. Whether and how this crosstalk is altered in CF remains poorly understood, obscuring potential new angles for therapy development to restore airway homeostasis in pwCF.
METHODS: We performed droplet-based single cell RNA-sequencing on bronchial biopsies from pwCF to investigate structural-immune cell crosstalk. Computational analyses were used to compare these data to samples obtained from healthy controls.
RESULTS: CF airway wall biopsies showed lower proportions and altered transcriptomes of basal cells, submucosal gland cells and endothelial cells, and a higher abundance of ciliated cells, monocytes, macrophages and T cells. Both B and T lymphocytes displayed aberrantly activated phenotypes with transcriptional changes linked to hypoxia and vascular endothelial growth factor signaling, indicative of crosstalk with endothelial cells. The CF lung displayed unique changes in intercellular communication potential involving ionocytes, macrophages, endothelial cells and lymphocytes. This included interactions between HLA-E on structural cells and the druggable CD94/NKG2A immune checkpoint on CD8+T cells.
CONCLUSIONS: We report the first single cell transcriptome atlas of the CF lung containing the full spectrum of structural and immune cells, providing a valuable resource for investigating changes to cellular composition, phenotypes and crosstalk linked to CF. Our analyses highlight dysregulated basal cell function and adaptive immunity in pwCF - despite favorable responses to CFTR modulator therapy. We identify novel aspects of CF pathophysiology and potential entry points for therapeutic strategies.

Keywords:  Bronchial biopsies; Cystic fibrosis; Single-cell RNA-sequencing; structural-immune cell crosstalk

DOI:  https://doi.org/10.1016/j.jcf.2025.01.016
Curr Microbiol. 2025 Feb 11. 82(4): 133

Screening of Regulatory mRNAs and miRNAs that Suppress Staphylococcus aureus Proliferation via Macrophage Ferroptosis.

Lili Wang, Jiajia Bao, Danyang Yang, Sijia Gao, Xintong He, Dan He, Lin Liu, Yulian Xu, Qinya Yang, Sifei He, Lei Xu, Anlong Li.

Ferroptosis is a unique form of regulated cell death that results from unrestricted lipid peroxidation, and it enhances the production of intracellular oxidative stress molecules. In this study, we investigated the effect of macrophage ferroptosis on the proliferation of Staphylococcus aureus (S. aureus) and sought potential host-directed therapy (HDT) targets for S. aureus. The study findings revealed that erastin concentrations (< 20 μM), which do not have an impact on macrophage proliferation, can effectively impede the proliferation of S. aureus within macrophages. High-throughput sequencing was used to identify DEGs and DEMIs in infected macrophages. Subsequently, the mRNA-miRNA regulatory network was successfully constructed, and two sets of molecules were selected. Experimental findings confirmed that mmu-miR-6935-5p exhibited complementary binding to specific sequences within the GM867 mRNA, and mmu-miR-7082-3p specifically bound to the GPR176 mRNA. Inducing ferroptosis in macrophages can effectively impede the proliferation of drug-resistant S. aureus. Notably, our study has identified GM867, GPR176, mmu-miR-6935-5p, and mmu-miR-7082-3p as key regulators involved in this process. These findings highlight the potential of targeting these four molecules for HDT, offering novel ways to combat drug-resistant S. aureus infection.

DOI: https://doi.org/10.1007/s00284-025-04114-3
Int Immunopharmacol. 2025 Feb 12. pii: S1567-5769(25)00237-1. [Epub ahead of print]150 114247

TREM2 protects against LPS-induced murine acute lung injury through suppressing macrophage ferroptosis.

Dandan Li, Linyue Pan, Mengjie Chen, Xiaoju Zhang, Zhilong Jiang.

Triggering receptor expressed on myeloid cells-2 (TREM2) is a cell surface receptor, majorly expressed by granulocytes, monocytes and macrophages. We in this study showed that TREM2 was downregulated in the lipopolysaccharide (LPS)-treated macrophages and murine acute lung injury (ALI) through activation of p38 MAPK and STAT6 signaling. Over-expression of TREM2 reduced the expression of DNAX-activation protein 12 (DAP12), pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), Malondialdehyde (MDA) and hemosiderin accumulation in LPS-treated macrophages. Knockdown of TREM2 expression elevated the expression of IL-6, reactive oxygen species (ROS), lactate dehydrogenases (LDH) and hemosiderin accumulation. Intratracheal adoptive transfer of TREM2-overexpressing macrophages effectively suppressed the lung inflammation and pro-inflammatory cytokine expression in murine ALI. While downregulation of TREM2 enhanced the lung inflammation in the lung tissues of murine ALI. Therefore, TREM2/DAP12 axis is involved in macrophage ferroptosis and attenuation of murine ALI. TREM2 would be a novel therapeutic target in murine ALI and patients with acute respiratory distress syndrome (ARDS).

DOI: https://doi.org/10.1016/j.intimp.2025.114247
Cell Host Microbe. 2025 Feb 12. pii: S1931-3128(25)00023-X. [Epub ahead of print]33(2): 168-170

Colonization island directs L. plantarum to its niche.

Aryan Rahimi-Midani, Igor Iatsenko.

Symbiotic gut bacteria have evolved mechanisms to selectively recognize and colonize an appropriate host. In a recent issue of Science, Gutiérrez-García et al. reported a colonization island that encodes sugar-binding adhesins used by Lactiplantibacillus plantarum to colonize its symbiotic niche in the foregut of its host, Drosophila melanogaster.

DOI: https://doi.org/10.1016/j.chom.2025.01.005
Biofilm. 2025 Jun;9 100256

Development of a tri-species wound model for studying fungal-bacterial interactions and antimicrobial therapies.

Stine Sørensen, Lasse Kvich, Yijuan Xu, Trine R Thomsen, Thomas Bjarnsholt, Ida Thaarup.

  Chronic wounds are increasing in numbers and biofilm-producing bacteria are highly prevalent in these wounds and often create resilient polymicrobial infections. Moreover, estimates suggest that up to 23 % of wounds contain fungi, particularly Candida albicans. Currently, inter-kingdom chronic wound models are scarce; thus, this study presents one of the few in vitro models that incorporate both bacterial and fungal species in a wound-relevant environment, addressing a critical gap in current biofilm research. The newly developed model contained the commonly isolated wound bacteria Pseudomonas aeruginosa and Staphylococcus aureus, and the fungus Candida albicans. Inter-species interactions were investigated through selective plate counting and pH and oxygen measurements, as well as confocal microscopy. Investigations were carried out before and after exposure to commonly used clinical antimicrobial treatments, including silver-infused bandages. When grown in a tri-species consortium, P. aeruginosa and S. aureus exhibited a higher tolerance towards silver-infused bandages than when they were grown individually. This suggests that C. albicans plays a protective role for the bacteria. In addition, the treatment also caused a shift in species ratios, moving from a P. aeruginosa-dominated consortium to a S. aureus-dominated consortium. Moreover, confocal microscopy revealed a change in biofilm architecture when comparing single-species models to tri-species models. Finally, we observed that silver-infused bandages increased the pH in the tri-species model as well as partially restoring the oxygenation within the wound model. In conclusion, our novel model exemplifies how inter-kingdom interactions in fungal-bacterial infections can complicate both the microenvironment and treatment efficacy.

Keywords:  Biofilms; In vitro models; Inter-kingdom interactions; Multispecies; Silver-infused bandages; Wound models

DOI:  https://doi.org/10.1016/j.bioflm.2025.100256
Immunity. 2025 Feb 11. pii: S1074-7613(25)00037-8. [Epub ahead of print]58(2): 265-267

Next generation lysosome: Brought to you by cGAS-STING.

Lei Wang, Wen Zhou.

Renowned for driving interferon responses, the cGAS-STING pathway reveals a surprising role: lysosomal biogenesis. In this issue of Immunity, Xu et al. uncover how STING activates the transcription factor TFEB, linking innate immune sensing to enhanced pathogen clearance through lysosomal activity.

DOI: https://doi.org/10.1016/j.immuni.2025.01.012
Arch Dermatol Res. 2025 Feb 14. 317(1): 404

Double-edged sword effect of GPX4 in skin homeostasis and diseases.

Hanzhang Xu, Li Yang, Yingli Wu, Hu Lei.

  Glutathione peroxidase 4 (GPX4) is a crucial antioxidant enzyme that plays a vital role in protecting cells from oxidative damage and lipid peroxidation. In the context of skin diseases, GPX4 serves as a key regulator of oxidative stress and inflammation, both of which are significant features of various skin conditions. By preventing lipid peroxidation and maintaining membrane integrity, GPX4 acts as a safeguard against cell death pathways, particularly ferroptosis, in skin diseases. Dysregulation of GPX4 in conditions such as dermatitis, psoriasis, and skin cancer is linked to heightened oxidative stress, inflammation, and tissue damage. Understanding the role of GPX4 and its intricate interactions in skin disease pathogenesis can aid in more effectively targeting oxidative stress and inflammation, leading to promising therapeutic interventions. This review summarizes the role of GPX4 in maintaining skin homeostasis and its involvement in disease, proposing strategies to target GPX4, including its post-translational modifications. Investigate the precise mechanism through which GPX4 influences the onset of skin diseases, and utilize GPX4 agonists or inhibitors as potential treatments.

Keywords:  Ferroptosis; GPX4; Glutathione peroxidase 4; Skin disease; Skin homeostasis

DOI:  https://doi.org/10.1007/s00403-025-03903-x
Proc Natl Acad Sci U S A. 2025 Feb 18. 122(7): e2420802122

Raver1 links Ripk1 RNA splicing to caspase-8-mediated pyroptotic cell death, inflammation, and pathogen resistance.

Boyao Zhang, Pontus Orning, Jesse W Lehman, Alexandre Dinis, Leslie Torres-Ulloa, Roland Elling, Michelle A Kelliher, John Bertin, Megan K Proulx, Jon D Goguen, Liv Ryan, Richard K Kandasamy, Terje Espevik, Athma A Pai, Katherine A Fitzgerald, Egil Lien.

  Multiple cell death and inflammatory signaling pathways converge on two critical factors: receptor-interacting serine/threonine kinase 1 (RIPK1) and caspase-8. Careful regulation of these molecules is critical to control apoptosis, pyroptosis, and inflammation. Here, we found a pivotal role of Raver1 as an essential regulator of Ripk1 pre-mRNA splicing, expression, and functionality and the subsequent caspase-8-dependent inflammatory cell death. We show that Raver1 influences mRNA diversity primarily by repressing alternative exon inclusion. Macrophages from Raver1-deficient mice exhibit altered splicing of Ripk1. As a result, Raver1-deficient primary macrophages display diminished cell death and decreased interleukin-18 and interleukin-1ß production, when infected with Yersinia bacteria, or by restraining TGF-ß-activated kinase 1 or IKKβ in the presence of lipopolysaccharide, tumor necrosis factor family members, or interferon-γ. These responses are accompanied by reduced activation of caspase-8, Gasdermin D and E, and caspase-1 in the absence of Raver1. Consequently, Raver1-deficient mice showed heightened susceptibility to Yersinia infection. Raver1 and RIPK1 also controlled the expression and function of the C-type lectin receptor Mincle. Our study underscores the critical regulatory role of Raver1 in modulating innate immune responses and highlights its significance in directing in vivo and in vitro inflammatory processes.

Keywords:  IL-1ß; RIPK1; caspase-8; gasdermin; pyroptosis

DOI:  https://doi.org/10.1073/pnas.2420802122
Sci Transl Med. 2025 Feb 12. 17(785): eadk3160

Coactivation of innate immune suppressive cells induces acquired resistance against combined TLR agonism and PD-1 blockade.

Hitomi Nishinakamura, Sayoko Shinya, Takuma Irie, Shugo Sakihama, Takeo Naito, Keisuke Watanabe, Daisuke Sugiyama, Motohiro Tamiya, Tatsuya Yoshida, Tetsunari Hase, Takao Yoshida, Kennosuke Karube, Shohei Koyama, Hiroyoshi Nishikawa.

Immune checkpoint blockade therapy has been successfully applied in clinical settings as a standard therapy for many cancer types, but its clinical efficacy is restricted to patients with immunologically hot tumors. Various strategies to modify the tumor microenvironment (TME), such as Toll-like receptor (TLR) agonists that can stimulate innate immunity, have been explored but have not been successful. Here, we show a mechanism of acquired resistance to combination treatment consisting of an agonist for multiple TLRs, OK-432 (Picibanil), and programmed cell death protein 1 (PD-1) blockade. Adding the TLR agonist failed to convert the TME from immunogenically cold to hot and did not augment antitumor immunity, particularly CD8+ T cell responses, in multiple animal models. The failure was attributed to the coactivation of innate suppressive cells, such as polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) expressing CXCR2, through high CXCL1 production by macrophages in the TME upon OK-432 treatment. A triple combination treatment with OK-432, PD-1 blockade, and a CXCR2 neutralizing antibody overcame the resistance induced by PMN-MDSCs, resulting in a stronger antitumor effect than that of any dual combinations or single treatments. The accumulation of PMN-MDSCs was similarly observed in the pleural effusions of patients with lung cancer after OK-432 administration. We propose that successful combination cancer immunotherapy intended to stimulate innate antitumor immunity requires modulation of unwanted activation of innate immune suppressive cells, including PMN-MDSCs.

DOI: https://doi.org/10.1126/scitranslmed.adk3160
Probiotics Antimicrob Proteins. 2025 Feb 13.

Lactiplantibacillus plantarum ZJ316 Alleviates Helicobacter pylori-Induced Intestinal Inflammation by Sustaining Intestinal Homeostasis.

Shiying Wu, Fangtong Wei, Yongqiang Chen, Ziqi Chen, Yuenuo Luo, Jiayi Fan, Yang Xu, Mingyang Hu, Ping Li, Qing Gu.

  Helicobacter pylori (H. pylori) infection poses significant risks for gastric cancer and intestinal inflammation, yet effective prevention strategies for intestinal inflammation remain elusive. Here, we aimed to investigate the protective effects and underlying mechanisms of Lactiplantibacillus plantarum ZJ316 (L. plantarum ZJ316) in a mouse model of H. pylori-induced intestinal inflammation. The reverse transcription‑quantitative polymerase chain reaction (RT-qPCR) analysis showed that treatment with L. plantarum ZJ316 significantly upregulated the mRNA levels of tight junction proteins, including Zonula occludens-1 (ZO-1), Occludin, and Claudin-1, while simultaneously decreasing the expression levels of pro-inflammatory cytokines interleukin-1β (IL-1β), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α). Additionally, 16S rDNA sequencing analysis revealed that administration of L. plantarum ZJ316 reduced relative abundance of pathogenic bacteria, Staphylococcus and Desulfovibrio by 69% and 42%, respectively, while enhancing beneficial bacteria including Ligilactobacillus, Akkermansia, and Lactobacillus associated with short-chain fatty acids (SCFAs) synthesis by 88%, 85%, and 16%, respectively. Gas chromatography-mass spectrometry (GC-MS) analysis confirmed L. plantarum ZJ316 restored SCFA levels reduced by H. pylori infection. In vitro, L. plantarum ZJ316 inhibited the IκBα/NF-κB pathway, thereby reducing TNF-α and IL-8 production in HT-29 cells following H. pylori infection. These findings collectively suggest that L. plantarum ZJ316 ameliorates H. pylori-induced intestinal inflammation by enhancing gut barrier function, improving flora structure, increasing SCFA levels, and mitigating inflammation through NF-κB pathway inhibition, offering promise for therapeutic development.

Keywords:   Helicobacter pylori ; Lactiplantibacillus plantarum ZJ316; Gut microbiota; Intestinal inflammation; NF-κB signaling pathway; Short-chain fatty acids

DOI:  https://doi.org/10.1007/s12602-025-10474-w
Cell Biol Int. 2025 Feb 13.

Macrophage-to-Myofibroblast Transition Contributes to Cutaneous Scarring Formation Through the TGF-β/Smad3 Signaling Pathways.

Yuan Jia, Yi Qin, Feng-Lai Yuan, Jie-Hong Shen.

  Cutaneous scarring typically arises after surgery, trauma, and infection, occurring when normal skin tissue is replaced by fibrous tissue during the healing process. Myofibroblasts have been identified as a significant contributor to this scarring. While the differentiation of fibroblasts into myofibroblasts is well-recognized as essential for wound healing and tissue repair, the mechanisms underlying the macrophage-myofibroblast transition (MMT) remain largely unexplored. This study aimed to investigate the role and potential mechanisms of MMT in cutaneous scarring. In specimens of hypertrophic scars, keloid and scleroderma, we confirmed the coexistence of MMT markers CD68 and α-smooth muscle actin (α-SMA) in areas of skin fibrosis. Additionally, most MMT cells in human cutaneous scar co-expressed the M2-type macrophage marker CD206. Fate-mapping in Lyz2-Cre/Rosa26-tdTomato mice further demonstrated that the majority of myofibroblasts in cutaneous scars were derived from bone marrow macrophages. Furthermore, higher levels of TGF-β were released from scar fibroblasts, which contributed to MMT through the Smad3 pathways. In vivo studies inhibiting Smad3 reduced MMT and scarring. Macrophage depletion with clodronate liposomes also reduced cutaneous scar formation. Our findings indicate that MMT plays a pivotal role in cutaneous scarring through the TGF-β/Smad3 pathways. Consequently, inhibiting MMT may be a novel strategy for the treatment of cutaneous scarring.

Keywords:  M2 macrophages; TGF‐β/Smad3; cutaneous scaring; extracellular matrix; macrophage‐to‐myofibroblast transition

DOI:  https://doi.org/10.1002/cbin.70002
Microbiol Spectr. 2025 Feb 11. e0221724

Effects of azithromycin on alleviating airway inflammation in asthmatic mice by regulating airway microbiota and metabolites.

Danhui Hunag, Lingyan Xie, Tingyue Luo, Lishan Lin, QianNan Ren, Zhaojin Zeng, Haohua Huang, Hua Liao, XiaoDan Chang, Yuehua Chen, Haijin Zhao, Shaoxi Cai, Hangming Dong.

  Asthma is a chronic respiratory disease with increasing global prevalence, often linked to disrupted airway microbiota. Azithromycin has shown promise in asthma treatment, but whether its effect is owing to its antimicrobial capacity remains largely unknown. A house dust mite (HDM)-induced asthmatic mouse model was used to evaluate the effects of azithromycin on airway inflammation and microbiota. Mice were divided into control, HDM-induced asthma, HDM + azithromycin, and azithromycin-alone groups. Airway microbiota was analyzed using 16S rRNA sequencing, and metabolomic profiles were assessed via liquid chromatography-tandem mass spectrometry. Azithromycin alleviated type 2 airway inflammation in HDM-induced asthma, restoring microbiota diversity by modulating specific genera, including Streptococcus, Staphylococcus, Ruminococcus, Coprococcus, Bifidobacterium, etc. Combination analysis with metabolomics revealed that azithromycin significantly regulated airway microbiota-associated sphingomyelin metabolism. Azithromycin's therapeutic effects in asthma are associated with its ability to regulate airway microbiota and its associated sphingomyelin metabolism, highlighting the potential for microbiota-targeted therapies in asthma.IMPORTANCEAsthma, a prevalent chronic respiratory condition, poses a significant global health challenge due to its increasing prevalence and associated morbidity. The role of airway microbiota in asthma pathogenesis is gaining attention, with evidence suggesting that disruptions in this microbial community contribute to disease severity. Our study investigates the impact of azithromycin, a macrolide antibiotic, on airway inflammation and microbiota in a mouse model of asthma. The findings reveal that azithromycin not only alleviates airway inflammation but also restores microbiota diversity and modulates microbiota-associated sphingomyelin metabolism. This research underscores the potential of microbiota-targeted therapies in asthma management, offering a novel therapeutic strategy that could improve patient outcomes and reduce the healthcare burden associated with asthma.

Keywords:  airway microbiota; asthma; azithromycin; sphingomyelin metabolism

DOI:  https://doi.org/10.1128/spectrum.02217-24
Nature. 2025 Feb 12.

A bacterial antiviral system detects and directly fights against infection.



Keywords:  Immunology; Microbiology; Structural biology

DOI:  https://doi.org/10.1038/d41586-025-00416-5
Apoptosis. 2025 Feb 09.

The complexities of cell death mechanisms: a new perspective in systemic sclerosis therapy.

Xue Xia, Chenfei Kong, Xiaoming Zhao, Kelin Zhao, Naixu Shi, Jinlan Jiang, Ping Li.

  Systemic sclerosis, also termed scleroderma, is a severe and debilitating autoimmune disease characterized by fibrosis, an aberrant immune response, and vascular dysfunction. Cell death is essential to the body's continued normal development as it removes old or damaged cells. This process is governed by several mechanisms, including programmed cell death through apoptosis, necrosis, and pyroptosis, as well as metabolic processes, such as ferroptosis and cuproptosis. This review describes the signaling pathways associated with each form of cell death, examining the linkages between these pathways, and discussing how the dysregulation of cell death processes is involved in the development of autoimmune disorders such as systemic sclerosis. Existing and promising therapeutic strategies aimed at restoring the balance of cell death in systemic sclerosis and other autoimmune disorders are also emphasized.

Keywords:  Apoptosis; Autophagy; Cuproptosis; Ferroptosis; Regulated cell death; Systemic sclerosis

DOI:  https://doi.org/10.1007/s10495-025-02082-4
Biochim Biophys Acta Mol Cell Res. 2025 Feb 10. pii: S0167-4889(25)00022-9. [Epub ahead of print] 119917

KLF12 inhibits lipopolysaccharide-induced inflammatory responses, oxidative stress, pyroptosis, and endoplasmic reticulum stress in human airway epithelial cells through inhibition of the NF-κB pathway.

Xiujuan Xu, Yiping Yu.

  Asthma is a common and frequent chronic disease in pediatrics with obvious pathological features, particularly inflammation, oxidative stress, pyroptosis, and endoplasmic reticulum (ER) stress. Some Krüppel-like factors (KLFs), such as KLF2, KLF4, KLF5, and KLF10, have been reported to be associated with several respiratory diseases, including asthma. However, the role of KLF12 in asthma pathogenesis is unknown. Based on the GEO analysis, KLF12 mRNA expression was reduced in asthma patients. We further assessed the role of KLF12 in protecting airway epithelial cells (BEAS-2B cells) against stimuli using an in vitro model of asthma. The results showed that lipopolysaccharide (LPS) stimulation caused a decrease in KLF12 expression. LPS-induced increase in the mRNA levels of inflammatory cytokines TNF-α, IL-6, and IL-8 were attenuated by KLF12 overexpression. LPS induced the production ROS and MDA and reduced the activities of enzymatic antioxidants SOD, CAT, and GSH-Px, which were prevented by KLF12 overexpression. KLF12 overexpression also blocked LPS-induced pyroptosis, as shown by decreased levels of IL-1β, IL-18, and LDH, as well as downregulated expression levels of pyroptosis-related proteins including NLRP3, ASC, cleaved caspase-1, and GSDMD-N. LPS-induced expression levels of ER stress markers GRP78, CHOP, p-eIF2α, and ATF-4 were inhibited by KLF12 overexpression. In addition, the protective effects of KLF12 on LPS-stimulated cells were enhanced by PDTC, an inhibitor of NF-κB. KLF12 knockdown showed an opposite effect to KLF12 overexpression. These results indicated that KLF12 suppressed LPS-induced inflammatory response, oxidative stress, pyroptosis, and ER stress, which were mediated by the inactivation of the NF-κB pathway.

Keywords:  Endoplasmic reticulum stress; Inflammation; KLF12; NF-κB; Oxidative stress; Pyroptosis

DOI:  https://doi.org/10.1016/j.bbamcr.2025.119917
Nat Commun. 2025 Feb 12. 16(1): 1562

Fungal Als proteins hijack host death effector domains to promote inflammasome signaling.

Tingting Zhou, Norma V Solis, Michaela Marshall, Qing Yao, Eric Pearlman, Scott G Filler, Haoping Liu.

High-damaging Candida albicans strains tend to form hyphae and exacerbate intestinal inflammation in ulcerative colitis patients through IL-1β-dependent mechanisms. Fungal agglutinin-like sequence (Als) proteins worsen DSS-induced colitis in mouse models. FADD and caspase-8 are important regulators of gut homeostasis and inflammation. However, whether they link directly to fungal proteins is not fully understood. Here, we report that Als proteins induce IL-1β release in immune cells. We show that hyphal Als3 is internalized in macrophages and interacts with caspase-8 and the inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC). Caspase-8 is essential for Als3-mediated ASC oligomerization and IL-1β processing. In non-immune cells, Als3 is associated with cell death core components FADD and caspase-8. N-terminal Als3 (N-Als3) expressed in Jurkat cells partially inhibits apoptosis. Mechanistically, N-Als3 promotes oligomerization of FADD and caspase-8 through their death effector domains (DEDs). N-Als3 variants with a mutation in the peptide-binding cavity or amyloid-forming region are impaired in DED oligomerization. Together, these results demonstrate that DEDs are intracellular sensors of Als3. This study identifies additional potential targets to control hypha-induced inflammation.

DOI: https://doi.org/10.1038/s41467-025-56657-5
Sci Rep. 2025 Feb 08. 15(1): 4773

Genomic epidemiology and phenotypic characterization of Staphylococcus aureus isolated from atopic dermatitis patients in South China.

Chao Yang, Xiaowei Chen, Min Li, Wenchang Yuan, Shunguang Li, Dexing Han, Junhui Feng, Haimin Luo, Minling Zheng, Jiaqi Liang, Cha Chen, Pinghua Qu, Song Li.

  Atopic dermatitis (AD) is a multifactorial, chronic relapsing disease. Staphylococcus aureus is the key microbial factor in AD, linked to disease activity. However, there is limited knowledge of genomic prevalence characteristics and phenotypic features of S. aureus in AD patients in China. We investigated 108 S. aureus of AD in China and globally publicly available genome sequences of 579 S. aureus of AD. Sequence type (ST) 7, ST15 and ST188 were the major lineages in China. Genes esaC, esxB, and sea were only detected in ST7, potentially contributing to its prevalence in AD. ST188 exhibited high virulence and adhesion, possibly due to the cna gene. Phylogenetic and population structure analysis revealed that 579 strains of global AD were classified into 15 sequence clusters (SCs), with SC5, SC2, and SC7 dominating. S. aureus of Chinese AD patients was mainly distributed in SC2, SC7, and SC12. Comparative genomic highlighted genes linked to AD, including enterotoxins (seh, selk, selq, entH), adhesion genes (fnbA, fnbB, sdrD, map, fib, narH). From China and global perspectives, we analyzed S. aureus's genomic epidemic traits, phylogeny, and population structure in AD skin. These findings contribute to understanding S. aureus-host interactions and genomic diversity in AD.

Keywords:   Staphylococcus aureus ; Atopic dermatitis; PGWAS; Phylogenetic analysis; Whole-genome sequencing

DOI:  https://doi.org/10.1038/s41598-025-87317-9
Cell Host Microbe. 2025 Feb 12. pii: S1931-3128(25)00025-3. [Epub ahead of print]33(2): 167-168

Skin-deep immune sensing.

Nonhlanhla Lunjani, Liam O'Mahony.

Two recent studies by Gribonika et al. and Bousbaine et al., published in Nature, describe the mechanisms underpinning skin autonomous B cell antibody responses to skin microbes and the immunodominant antibody target in Staphylococcus epidermidis that can be utilized to engineer novel topical vaccination strategies.

DOI: https://doi.org/10.1016/j.chom.2025.01.007
F1000Res. 2024 ;13 837

Analysis of the dynamics of transition from non-colonization to colonization and Staphylococcus aureus bacteremia in hemodialysis patients using Markov models.

Daniela Montoya-Urrego, Johanna M Vanegas, J Natalia Jiménez, Difariney González-Gómez.

   Background: Hemodialysis patients are frequently colonized by Staphylococcus aureus, leading to severe infections with high mortality rates. However, little is known about transition from non-colonization to colonization or bacteremia over time. The aim was to analyze the behavior of S. aureus colonization, identifying the probability of transition from non-colonized to colonized state or bacteremia, and the influence of specific covariates.
Methods: The study was conducted in a dialysis unit associated with a tertiary care hospital in Medellín between October 2017 and October 2019. An initial measurement was taken to evaluate S. aureus colonization, and follow-up measurements were performed 2 and 6 months later. Bacteremia evolution was monitored for 12 months. A two-state recurrent continuous-time Markov model was constructed to model transition dynamics from non-colonization to S. aureus colonization in hemodialysis patients. Subsequently, the model was applied to a third state of bacteremia.
Results: Of 178 patients on hemodialysis, 30.3% were colonized by S. aureus. Transition intensity from non-colonization to colonization was three times higher (0.21; CI: 0.14-0.29) than from colonization to non-colonization (0.07; CI: 0.05-0.11). The colonization risk increased in patients with previous infections (HR: 2.28; CI: 0.78-6.68), hospitalization (HR: 1.29; CI: 0.56-2.99) and antibiotics consumption (HR: 1.17; CI: 0.53-2.58). Mean non-colonized state duration was 10.9 months, while in the colonized state was 5.2 months. In the 3-state model, it was found that patients colonized were more likely to develop S. aureus infection (13.9%).
Conclusion: A more likely transition from non-colonization to colonization was found, which increases with factors such as previous infection. In addition, the development of bacteremia was more likely in colonized than in non-colonized patients. These results underline the importance of surveillance and proper management of S. aureus colonization to prevent serious complications, such as bacteremia, and improve prognosis in this vulnerable population.

Keywords:  Bacteremia.; Colonization; Hemodialysis; Markov models; Multistate models; Staphylococcus aureus

DOI:  https://doi.org/10.12688/f1000research.151896.3
Cell Mol Gastroenterol Hepatol. 2024 Dec 27. pii: S2352-345X(24)00203-0. [Epub ahead of print] 101448

The Protective Role of DDIT4 in Helicobacter pylori-induced Gastric Metaplasia Through Metabolic Regulation of Ferroptosis.

Huan Wang, Xinbo Xu, Yaobin Ouyang, Xiao Fei, Cong He, Xianhe Yang, Yuping Ren, Yanan Zhou, Sihai Chen, Yi Hu, Jianping Liu, Zhongming Ge, William Ka Kei Wu, Nonghua Lu, Chuan Xie, Xidong Wu, Yin Zhu, Nianshuang Li.

   BACKGROUND & AIMS: Helicobacter pylori (H. pylori) infection is a significant factor leading to gastric atrophy, metaplasia and cancer development. Here, we investigated the role of the stress response gene DDIT4 in the pathogenesis of H. pylori infection.
METHODS: Cell lines, transgenic mice, and human tissue samples were implemented. Proteomics were performed on Ddit4+/+ and Ddit4-/- mice infected with H. pylori strain PMSS1. C57BL/6 mice were administered with tamoxifen to induce gastric metaplasia. Stomach tissues were analyzed for histopathologic features, reactive oxygen species, Fe2+, lipid peroxidation, expression of DDIT4, and ferroptosis-related proteins.
RESULTS: DDIT4 expression was upregulated at 6 hours but significantly decreased at 24 hours in response to H. pylori infection in gastric epithelial cells. Gastric DDIT4 were downregulated in INS-GAS mice at 4 months post H. pylori infection. Notably, H. pylori infection led to more severe gastric metaplasia lesion in Ddit4-knockout mice. The proteomic profiling revealed an increase in ferroptosis in the gastric tissues of infected Ddit4-deficient mice, compared with infected wild-type mice. Mechanistically, knockout of DDIT4 promoted H. pylori-induced ferroptosis through the accumulation of lipid peroxides and ROS levels, and alterations in proteins such as GPX4, ALOX15, and HMOX1. Overexpression of DDIT4 counteracted H. pylori-induced stem cell marker CD44V9 through modulation of ferroptosis. Similarly, in another mouse model of gastric metaplasia treated with tamoxifen, as well as in human GIM tissues, we observed the loss of DDIT4 and induction of ferroptosis.
CONCLUSIONS: Our results indicate that DDIT4 serves as a protective factor against H. pylori-induced gastric metaplasia by metabolic resistance to ferroptosis.

Keywords:  DDIT4; Ferroptosis; Gastric Metaplasia; H. pylori; Metabolic Reprogramming

DOI:  https://doi.org/10.1016/j.jcmgh.2024.101448
J Innate Immun. 2025 ;17(1): 95-111

Exploring the Role of Macrophages and Their Associated Structures in Rheumatoid Arthritis.

Xin Tian, Jingjing Chen, Yujie Hong, Yang Cao, Jing Xiao, Yan Zhu.

   BACKGROUND: Rheumatoid arthritis (RA) is a chronic, invasive autoimmune disease characterized by symmetrical polyarthritis involving synovial inflammation. Epidemiological studies indicate that the incidence of RA continues to rise, yet the pathogenesis of this disease remains not fully understood. A significant infiltration of macrophages is observed in the synovium of RA patients. It can be inferred that macrophages likely play a crucial role in the onset and progression of RA.
SUMMARY: This review aims to summarize the research progress on the mechanisms by which macrophages and their associated structures contribute to RA, as well as potential therapeutic approaches, aiming to provide new insights into the study of RA pathogenesis and its clinical treatment.
KEY MESSAGES: During the course of RA, besides the inherent roles of macrophages, these cells respond to microenvironmental changes such as pathogen invasion or tissue damage by undergoing polarization, pyroptosis, or forming macrophage extracellular traps (METs), all of which influence inflammatory responses and immune homeostasis, thereby mediating the occurrence and development of RA. Additionally, macrophages secrete exosomes, which participate in intercellular communication and signal transduction processes, thus contributing to the progression of RA. Therefore, it is critical to elucidate how macrophages and their related structures function in RA.
BACKGROUND: Rheumatoid arthritis (RA) is a chronic, invasive autoimmune disease characterized by symmetrical polyarthritis involving synovial inflammation. Epidemiological studies indicate that the incidence of RA continues to rise, yet the pathogenesis of this disease remains not fully understood. A significant infiltration of macrophages is observed in the synovium of RA patients. It can be inferred that macrophages likely play a crucial role in the onset and progression of RA.
SUMMARY: This review aims to summarize the research progress on the mechanisms by which macrophages and their associated structures contribute to RA, as well as potential therapeutic approaches, aiming to provide new insights into the study of RA pathogenesis and its clinical treatment.
KEY MESSAGES: During the course of RA, besides the inherent roles of macrophages, these cells respond to microenvironmental changes such as pathogen invasion or tissue damage by undergoing polarization, pyroptosis, or forming macrophage extracellular traps (METs), all of which influence inflammatory responses and immune homeostasis, thereby mediating the occurrence and development of RA. Additionally, macrophages secrete exosomes, which participate in intercellular communication and signal transduction processes, thus contributing to the progression of RA. Therefore, it is critical to elucidate how macrophages and their related structures function in RA.

Keywords:  Macrophage exosome; Macrophage extracellular traps; Macrophage polarization; Macrophage pyroptosis; Rheumatoid arthritis

DOI:  https://doi.org/10.1159/000543444
Adv Exp Med Biol. 2025 ;1468 127-131

Current Perspectives of TLR2 Signalling in the Retina.

Rachel Dalton, Sarah Doyle.

  Toll-like receptor 2 (TLR2) signalling is crucial in initiating the innate immune response. Under normal conditions, TLR2 can recognise and respond to danger signals in the body and protect against damaging pathogens and molecules. However, dysregulation of this tightly controlled cascade has been implicated in various retinal disorders. There are many endogenous sterile ligands present in a degenerating retina that could lead to aberrant TLR2 activation. This culminates in an overaction of the innate immune response, which leads to an excess of pro-inflammatory cytokine production and results in a dangerous cycle of chronic inflammation. Here, we will review the evidence behind TLR2's involvement in retinal diseases such as age-related macular degeneration (AMD) and diabetic retinopathy (DR) and investigate the potential therapeutic benefit of TLR2 inhibition in the retina.

Keywords:  AMD; CNV; Chronic inflammation; DAMPs; Diabetic retinopathy; Innate immune response; MyD88; RPE; Retina; TLR2

DOI:  https://doi.org/10.1007/978-3-031-76550-6_21
Adv Biol (Weinh). 2025 Feb 12. e2400329

Mucus Physically Restricts Influenza A Viral Particle Access to the Epithelium.

Logan Kaler, Elizabeth M Engle, Maria Corkran, Ethan Iverson, Allison Boboltz, Maxinne A Ignacio, Taj Yeruva, Margaret A Scull, Gregg A Duncan.

  Prior work suggests influenza A virus (IAV) crosses the airway mucus barrier in a sialic acid-dependent manner through the actions of the viral envelope proteins, hemagglutinin, and neuraminidase. However, host and viral factors that influence how efficiently mucus traps IAV remain poorly defined. In this work, how the physicochemical properties of mucus influence its ability to effectively capture IAV is assessed using fluorescence video microscopy and multiple particle tracking. Our studies suggest an airway mucus gel layer must be produced with virus-sized pores to physically constrain IAV. While sialic acid binding by IAV may improve mucus trapping efficiency, sialic acid binding preference is found to have little impact on IAV mobility and the fraction of viral particles expected to penetrate the mucus barrier. Further, synthetic polymeric hydrogels engineered with mucus-like architecture are similarly protective against IAV infection despite their lack of sialic acid decoy receptors. Together, this work provides new insights on mucus barrier function toward IAV with important implications on innate host defense and transmission of respiratory viruses.

Keywords:  diffusion; influenza virus; mucus; sialic acid

DOI:  https://doi.org/10.1002/adbi.202400329
Digestion. 2025 Feb 13. 1-30

Inhibitory effects of probiotic & gastro-intestinal bacteria on H. pylori in vitro.

Johannes Raphael Westphal, Nadine Koch, Lukas Macke, Riccardo Vasapolli, Didem Saka, Ramiro Vilchez-Vargas, Tianjun Song, Peter Malfertheiner, Christian Schulz.

INTRODUCTION: Helicobacter pylori is a highly prevalent pathogen affecting approximately 50% of the world population, causing chronic gastritis and subsequently adenocarcinoma. Antibiotic resistance rates in H. pylori are increasing, thus demanding alternative treatment options. Some beneficial bacteria, including probiotics and gastrointestinal commensals, were shown to inhibit H. pylori growth, viability, and initial attachment to the gastric epithelium.
METHODS: In this review we systematically summarized the currently available literature for in vitro inhibition of H. pylori through beneficial bacteria from the Lactobacillales order. We performed research on PubMed and Google scholar in accordance with the PRISMA guidelines.
RESULTS: A multitude of species was shown to possess anti-H. pylori activity although the majority of investigated bacteria belonged to only one bacterial genus: Lactobacillus. Anti-H. pylori activity was mediated through transcriptional modulation of virulence factors, a competition for binding sites, an induction of a dormancy state of H. pylori and the secretion of anti-H. pylori compounds.
CONCLUSION: Many bacterial compounds that show probiotic properties are capable of inhibiting H. pylori in in vitro experiments. However, a huge variety of test methods to detect anti-H. pylori effects demands for a standardization.

DOI: https://doi.org/10.1159/000543447
Int J Mol Sci. 2025 Jan 23. pii: 962. [Epub ahead of print]26(3):

Rapid Natural Killer Cell Gene Responses, Generated by TLR Ligand-Induced Trained Immunity, Provide Protection to Bacterial Infection in rag1-/- Mutant Zebrafish (Danio rerio).

Preeti J Muire, Larry A Hanson, Lora Petrie-Hanson.

  T and B cell-deficient rag1-/- mutant zebrafish develop protective immunity mediated by trained immunity. In mammals, trained immune responses can be induced by Toll-like receptor (TLR) ligands. This study evaluated protective trained immunity in rag1-/- zebrafish through exposure to TLR ligands (beta glucan, R848, poly I:C), RE33® (a live-attenuated Edwardsiella ictaluri vaccine), or combinations thereof, followed by wild-type E. ictaluri challenge one month later. Survival analyses revealed that all TLR ligands and vaccine treatments provided significantly higher protection than the control, with beta glucan inducing significantly greater protection than RE33®, while R848 and poly I:C were equivalent to the vaccine. Survivals for the treatments were beta glucan 70%, beta glucan + RE33® 60%, R848 + RE33® 54%, poly I:C + RE33® 50%, R848 49%, poly I:C 32%, RE33® 24%, and control 0%. Gene expression analysis of kidney and liver tissues post challenge revealed that beta glucan training elicited early and strong increased expressions of nklb (5536 fold @ 6 hpi), nkld (147 fold @ 12 hpi), and ifng (575 fold @ 12 hpi) in the kidney, and ifng (1369 fold @ 6 hpi), nkla (250 fold @ 6 hpi), nklb (734 fold @ 6 hpi), nklc (2135 fold @ 6 hpi) and nkld (589 fold @ 6 hpi) in the liver. Principal component analysis (PCA) revealed that early kidney gene expressions at 6-12 h post secondary infection (nkla @ 12 hpi, nklb @ 6 and 12 hpi, nklc @ 6 and 12 hpi, nkld @ 6 and 12 hpi, ifng @ 6 and 12 hpi, t-bet @ 6, 12 and 48 hpi, and nitr9 @24 hpi) in the kidney and liver (nkla, nklb, nklc, nkld, ifng, t-bet and nitr9 @ 6 hpi) were associated with the highest survival. This study highlights that TLR ligand-induced trained immunity boosts innate immunity and survival, with NK cell subpopulations in kidney and liver tissues responding differently to mediate protective responses.

Keywords:  Danio rerio; TLR ligands; beta glucan; tissue-resident NK cell subsets; trained immunity; vaccine adjuvants

DOI:  https://doi.org/10.3390/ijms26030962
ACS Sens. 2025 Feb 14.

Combating Pathogenic Immune Evasion: Sialidase-Activated Thermally Delayed Fluorescence for Probing and Modulating Host-Pathogen Interactions.

Qian Liu, Qinghua Wang, Xiangchuan Meng, Xiang Wang, Qingyang Zhang, Hai-Yu Hu.

  Innate immunity represents the primary defense against invasive pathogens with phagocytosis playing a central role in host defense and mediating immune and inflammatory responses. However, pathogens such as Clostridium perfringens have developed strategies to overcome phagocytic clearance. Developing molecular tools to identify and target key factors in pathogenic immune evasion can deepen our understanding of host-pathogen interactions and aid in exploring novel therapeutic strategies. As a key enzyme in the sialylation process of C. perfringens, the virulence factor sialidase is a potential target for investigating pathogenic immune evasion. Herein, a "turn-on" thermally activated delayed fluorescent probe SA-HBT-PXZ is developed as a highly selective and sensitive sialidase sensor, enabling time-resolved fluorescence imaging of C. perfringens in live bacterial cells, tissue sections, and even infected mice. Furthermore, SA-HBT-PXZ is successfully employed to screen sialidase inhibitors based on prompt and delayed fluorescence emissions. The identified lead compounds effectively inhibit the activity of sialidases from C. perfringens, leading to an increased level of differentiation of macrophages into the M1 subtype. This, in turn, enhances the phagocytosis of C. perfringens and ultimately suppresses the immune escape of the bacteria. Our study provides a potential target and lead compounds for novel therapeutic strategies against C. perfringens infections.

Keywords:  TADF probe; bacterial immune evasion; inhibitor screening; macrophage polarization; sialidase

DOI:  https://doi.org/10.1021/acssensors.4c02917
World J Microbiol Biotechnol. 2025 Feb 11. 41(2): 68

Lactobacillomics as a new notion in lactic acid bacteria research through omics integration.

Özge Kahraman Ilıkkan.

  Omics technologies are a set of disciplines that analyze large-scale molecular data to understand biological systems in a holistic way. These technologies aim to reveal the structure, functions and interactions of organisms by studying processes at many levels of biomolecules, from the genome to metabolism. Lactobacillomics is introduced as an interdisciplinary field that integrates multiple "omics" technologies-including genomics, transcriptomics, proteomics, metabolomics, and metagenomics- to provide a comprehensive insight into "lactic acid bacteria" species. Lactobacillomics aims to elucidate the genetic, metabolic, and functional characteristics of lactic acid bacteria (LAB) species, providing insights into the mechanisms underlying their probiotic effects and contributions to the host microbiome. By analyzing genomes and metabolic pathways, researchers can identify specific genes responsible for health-promoting functions and desirable fermentation characteristics, which can guide the development of targeted probiotic strains with optimized health benefits. The integration of these omics data allows facilitating the discovery of biomarkers for health and disease states, the development of new probiotics tailored to specific populations or health conditions, and the optimization of fermentation processes to enhance the safety, flavor, and nutritional profile of fermented foods. A comprehensive review and bibliometric analysis were conducted to provide an overview of this promising field between 2005 and 2025 by examining Web of Science Core Collection data. Research results reveal trending topics, future perspectives, and key areas of growth within lactic acid bacteria (LAB) studies, particularly as they intersect with omics technologies.

Keywords:  LAB; Lactic acid bacteria; Lactobacillomics; Omics; Probiotics

DOI:  https://doi.org/10.1007/s11274-025-04285-y
Int Arch Allergy Immunol. 2025 Feb 08. 1-17

AhR causes the release of proinflammatory cytokines and chemokines and airway epithelial barrier dysfunction in allergic rhinitis via upregulating SERPINB2.

Xinhong Lu, Gang Gao, Jiaxin Jin, Xiaobo Huang, Liwei Lin, Maohua Qian, Nimei Shen.

Introduction Allergic rhinitis (AR) remains a kind of nasal hypersensitivity illness with a considerable surge in incidence across the globe. Plasminogen activator inhibitor type 2 (SERPINB2) is an inflammatory mediator that can be also activated by aryl hydrocarbon receptor (AhR), a nuclear receptor that modulates the response to environmental stimuli. This work was devoted to the investigation into the role of SERPINB2 in AR and its relationship with AhR. Methods In human nasal epithelial cells (HNEpCs) stimulated with interleukin-4 (IL-4) or histamine, ELISA was adopted for quantifying proinflammatory cytokines and chemokines. Epithelial barrier function was assessed by transepithelial electrical resistance (TER). Western blot and immunofluorescence staining evaluated tight junction proteins. RT-qPCR and Western blot determined SERPINB2 and AhR expressions. Results The release of proinflammatory cytokines and chemokines was aggravated, TER value was reduced and the expressions of tight junction proteins were downregulated in HNEpCs when induced by IL-4 or histamine. SERPINB2 and AhR were both overexpressed and SERPINB2 depletion relieved inflammatory response and preserved epithelial barrier function in IL-4- or histamine-treated HNEpCs. Besides, AhR knockdown decreased SERPINB2 expression and SERPINB2 upregulation reverted the protective role of AhR silencing in the inflammatory response and epithelial barrier dysfunction in HNEpCs in response to IL-4 or histamine. Conclusion Collectively, AhR might activate SERPINB2 to exacerbate inflammation and airway epithelial barrier dysfunction in AR.

DOI: https://doi.org/10.1159/000543410