bims-bac4me 2024-09-01 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2024–09–01
39 papers selected by
Chun-Chi Chang, Universitäts Spital Zürich

Stroke alters the innate immune memory and drives inflammatory cardiac dysfunction.
A loss of function mutation in SOCS2 results in increased inflammatory response of macrophages to TLR ligands and Staphylococcus aureus.
Commensal-derived short-chain fatty acids disrupt lipid membrane homeostasis in Staphylococcus aureus.
Microbiota-Derived Extracellular Vesicle as Emerging Actors in Host Interactions.
Blockade of IKK signaling induces RIPK1-independent apoptosis in human macrophages.
Gasdermins as evolutionarily conserved executors of inflammation and cell death.
Role of Mitofusin 1 in mediating reactive oxygen species in alveolar macrophages during Streptococcuspneumoniae.
Heme oxygenase-1 binds gasdermin D to inhibit airway epithelium pyroptosis in allergic asthma.
Investigating group A Streptococcus antibiotic tolerance in necrotizing fasciitis.
Mononuclear Phagocytes, Cellular Immunity, and Nobel Prizes: A Historic Perspective.
Lipid transfer from tumour-associated macrophages supports glioblastoma.
CCL28 modulates neutrophil responses during infection with mucosal pathogens.
Gut Microbiota Dysbiosis, Oxidative Stress, Inflammation, and Epigenetic Alterations in Metabolic Diseases.
Targeting the microbiome to improve human health with the approach of personalized medicine: Latest aspects and current updates.
Unveiling multifaceted roles of myeloid innate immune cells in the pathogenesis of psoriasis.
Immunometabolism of ferroptosis in the tumor microenvironment.
Epithelial barrier dysfunction and microbial dysbiosis: exploring the pathogenesis and therapeutic strategies for Crohn's disease.
Phagosome Isolation with Magnetic Beads and Purification of Toll-Like Receptor (TLR) Complexes in Phagosomes.
The Interplay between Airway Cilia and Coronavirus Infection, Implications for Prevention and Control of Airway Viral Infections.
Metabolite-based inter-kingdom communication controls intestinal tissue recovery following chemotherapeutic injury.
Natural compound phloretin restores periodontal immune homeostasis via HIF-1α-regulated PI3K/Akt and glycolysis in macrophages.
Macrophage energy metabolism in cardiometabolic disease.
The Role of Proteomics in Identification of Key Proteins of Bacterial Cells with Focus on Probiotic Bacteria.
Landscape of Interactions between Stromal and Myeloid Cells in Ileal Crohn's Disease; Indications of an Important Role for Fibroblast-Derived CCL-2.
RSV and rhinovirus increase pneumococcal carriage acquisition and density, whereas nasal inflammation is associated with bacterial shedding.
Iron-laden macrophage-mediated paracrine pro-fibrotic signaling induces lung fibroblast activation.
Clinical implications of innate immune exhaustion in cystic fibrosis.
Complex Interactions between the Human Major Histocompatibility Complex (MHC) and Microbiota: Their Roles in Disease Pathogenesis and Immune System Regulation.
Reprogramming of breast tumor-associated macrophages with modulation of arginine metabolism.
An Update on the Study of the Molecular Mechanisms Involved in Autophagy during Bacterial Pathogenesis.
The complement system: A key player in the host response to infections.
Drp1 depletion protects against ferroptotic cell death by preserving mitochondrial integrity and redox homeostasis.
Immunomodulation of wound healing leading to efferocytosis.
Epigenetic regulation of diverse regulated cell death modalities in cardiovascular disease: Insights into necroptosis, pyroptosis, ferroptosis, and cuproptosis.
Elucidating human gut microbiota interactions that robustly inhibit diverse Clostridioides difficile strains across different nutrient landscapes.
OLAH connects fatty acid metabolism to the severity of respiratory viral disease.
Synergistic collaboration between AMPs and non-direct antimicrobial cationic peptides.
Visualizing inflammatory monocytes and macrophages in the human heart.
Prevotella are major contributors of sialidases in the human vaginal microbiome.

Nat Cardiovasc Res. 2024 Aug;3(8): 887

Stroke alters the innate immune memory and drives inflammatory cardiac dysfunction.

Gerburg Schwaerzer.

DOI: https://doi.org/10.1038/s44161-024-00526-9
Front Immunol. 2024 ;15 1397330

A loss of function mutation in SOCS2 results in increased inflammatory response of macrophages to TLR ligands and Staphylococcus aureus.

Laurence Guzylack-Piriou, Blandine Gausseres, Christian Tasca, Chervin Hassel, Guillaume Tabouret, Gilles Foucras.

   Introduction: The role of suppressor of cytokine signaling (SOCS)2 in anti-infective bacterial immunity has been poorly investigated compared to other members of the SOCS family.
Methods: We characterized the previously identified loss of function R96C point mutation of SOCS2 using a genome-edited mouse model that resumes the phenotype of Socs2 knockout mice. The response of macrophages to TLR-ligands and Staphylococcus aureus was examined.
Results and discussion: Conversely to previously published data using human monocyte-derived macrophages, the stimulation of bone-marrow-derived macrophages with various TLR ligands did not show any difference according to the SOCS2 variant. Upregulation of IL-6 and TNF-α pro-inflammatory cytokines production was only seen when the SOCS2 expression was promoted by the culture of macrophages in the presence of GM-CSF. Furthermore, we showed that the SOCS2 point mutation is associated with heightened STAT5 phosphorylation in a short time frame upon GM-CSF incubation. In mice, recruitment of neutrophil and F4/80int Ly6C+ inflammatory macrophage, as well as IFN-γ and IL-10 concentrations, are significantly increased upon S. aureus peritoneal infection. Altogether, these data support the idea that by lowering the pro-inflammatory environment, SOCS2 favors better control of bacterial burden during a systemic infection caused by S. aureus.

Keywords:  R96C mutation; SOCS2; inflammatory response; macrophages; mice

DOI:  https://doi.org/10.3389/fimmu.2024.1397330
bioRxiv. 2024 Aug 12. pii: 2024.08.12.607382. [Epub ahead of print]

Commensal-derived short-chain fatty acids disrupt lipid membrane homeostasis in Staphylococcus aureus.

Joshua R Fletcher, Lisa A Hansen, Richard Martinez, Christian D Freeman, Niall Thorns, Alex R Villareal, Mitchell R Penningroth, Grace A Vogt, Matthew Tyler, Kelly M Hines, Ryan C Hunter.

The role of commensal anaerobic bacteria in chronic respiratory infections is unclear, yet they can exist in abundances comparable to canonical pathogens in vivo. Their contributions to the metabolic landscape of the host environment may influence pathogen behavior by competing for nutrients and creating inhospitable conditions via toxic metabolites. Here, we reveal a mechanism by which the anaerobe-derived short chain fatty acids (SCFAs) propionate and butyrate negatively affect Staphylococcus aureus physiology by disrupting branched chain fatty acid (BCFA) metabolism. In turn, BCFA impairment results in impaired growth, diminished expression of the agr quorum sensing system, as well as increased sensitivity to membrane-targeting antimicrobials. Altered BCFA metabolism also reduces S. aureus fitness in competition with Pseudomonas aeruginosa, suggesting that airway microbiome composition and the metabolites they produce and exchange directly impact pathogen succession over time. The pleiotropic effects of these SCFAs on S. aureus fitness and their ubiquity as metabolites in animals also suggests that they may be effective as sensitizers to traditional antimicrobial agents when used in combination.

DOI: https://doi.org/10.1101/2024.08.12.607382
Int J Mol Sci. 2024 Aug 09. pii: 8722. [Epub ahead of print]25(16):

Microbiota-Derived Extracellular Vesicle as Emerging Actors in Host Interactions.

Paola Margutti, Antonella D'Ambrosio, Silvia Zamboni.

  The human microbiota is an intricate micro-ecosystem comprising a diverse range of dynamic microbial populations mainly consisting of bacteria, whose interactions with hosts strongly affect several physiological and pathological processes. The gut microbiota is being increasingly recognized as a critical player in maintaining homeostasis, contributing to the main functions of the intestine and distal organs such as the brain. However, gut dysbiosis, characterized by composition and function alterations of microbiota with intestinal barrier dysfunction has been linked to the development and progression of several pathologies, including intestinal inflammatory diseases, systemic autoimmune diseases, such as rheumatic arthritis, and neurodegenerative diseases, such as Alzheimer's disease. Moreover, oral microbiota research has gained significant interest in recent years due to its potential impact on overall health. Emerging evidence on the role of microbiota-host interactions in health and disease has triggered a marked interest on the functional role of bacterial extracellular vesicles (BEVs) as mediators of inter-kingdom communication. Accumulating evidence reveals that BEVs mediate host interactions by transporting and delivering into host cells effector molecules that modulate host signaling pathways and cell processes, influencing health and disease. This review discusses the critical role of BEVs from the gut, lung, skin and oral cavity in the epithelium, immune system, and CNS interactions.

Keywords:  bacterial extracellular vesicles; dysbiosis; gut-brain axis; immune-cell-response; microbiota; neuroninflammation

DOI:  https://doi.org/10.3390/ijms25168722
PLoS Pathog. 2024 Aug 26. 20(8): e1012469

Blockade of IKK signaling induces RIPK1-independent apoptosis in human macrophages.

Neha M Nataraj, Reyna Garcia Sillas, Beatrice I Herrmann, Sunny Shin, Igor E Brodsky.

Regulated cell death in response to microbial infection plays an important role in immune defense and is triggered by pathogen disruption of essential cellular pathways. Gram-negative bacterial pathogens in the Yersinia genus disrupt NF-κB signaling via translocated effectors injected by a type III secretion system, thereby preventing induction of cytokine production and antimicrobial defense. In murine models of infection, Yersinia blockade of NF-κB signaling triggers cell-extrinsic apoptosis through Receptor Interacting Serine-Threonine Protein Kinase 1 (RIPK1) and caspase-8, which is required for bacterial clearance and host survival. Unexpectedly, we find that human macrophages undergo apoptosis independently of RIPK1 in response to Yersinia or chemical blockade of IKKβ. Instead, IKK blockade led to decreased cFLIP expression, and overexpression of cFLIP contributed to protection from IKK blockade-induced apoptosis in human macrophages. We found that IKK blockade also induces RIPK1 kinase activity-independent apoptosis in human T cells and human pancreatic cells. Altogether, our data indicate that, in contrast to murine cells, blockade of IKK activity in human cells triggers a distinct apoptosis pathway that is independent of RIPK1 kinase activity. These findings have implications for the contribution of RIPK1 to cell death in human cells and the efficacy of RIPK1 inhibition in human diseases.

DOI: https://doi.org/10.1371/journal.ppat.1012469
Nat Cell Biol. 2024 Aug 26.

Gasdermins as evolutionarily conserved executors of inflammation and cell death.

Kaiwen W Chen, Petr Broz.

The gasdermins are a family of pore-forming proteins that have recently emerged as executors of pyroptosis, a lytic form of cell death that is induced by the innate immune system to eradicate infected or malignant cells. Mammalian gasdermins comprise a cytotoxic N-terminal domain, a flexible linker and a C-terminal repressor domain. Proteolytic cleavage in the linker releases the cytotoxic domain, thereby allowing it to form β-barrel membrane pores. Formation of gasdermin pores in the plasma membrane eventually leads to a loss of the electrochemical gradient, cell death and membrane rupture. Here we review recent work that has expanded our understanding of gasdermin biology and function in mammals by revealing their activation mechanism, their regulation and their roles in autoimmunity, host defence and cancer. We further highlight fungal and bacterial gasdermin pore formation pointing to a conserved mechanism of cell death induction.

DOI: https://doi.org/10.1038/s41556-024-01474-z
Redox Biol. 2024 Aug 27. pii: S2213-2317(24)00307-0. [Epub ahead of print]76 103329

Role of Mitofusin 1 in mediating reactive oxygen species in alveolar macrophages during Streptococcuspneumoniae.

David Thomas, Jianjun Yang, Soo Jung Cho, Heather Stout-Delgado.

Alveolar macrophages (AM) are key effectors of the immune response and are essential for host responses to S. pneumoniae. Mitochondria are highly dynamic organelles whose function aids in regulating the cell cycle, innate immunity, autophagy, redox signaling, calcium homeostasis, and mitochondrial quality control in AM. In response to cellular stress, mitochondria can engage in stress-induced mitochondrial hyperfusion (SIMH). The current study aimed to investigate the role of Mfn1 on mitochondrial control of reactive oxygen species (ROS) in AMs and the role of Mfn1 deficiency on immune responses to S. pneumoniae. Compared to Mfn1FloxCre- controls, there were distinct histological differences in lung tissue collected from Mfn1Floxed; CreLysM mice, with less injury and inflammation observed in mice with Mfn1 deficient myeloid cells. There was a significant decrease in lipid peroxidation and ROS production in Mfn1 deficient AM that was associated with increased superoxide dismutase (SOD) and antioxidant activity. Our findings demonstrate that Mfn1 deficiency in myeloid cells decreased inflammation and lung tissue injury during S. pneumoniae infection.

DOI: https://doi.org/10.1016/j.redox.2024.103329
Apoptosis. 2024 Aug 27.

Heme oxygenase-1 binds gasdermin D to inhibit airway epithelium pyroptosis in allergic asthma.

Jiajia Lv, Min Wu, Zhenwei Xia.

This study explores how heme oxygenase-1 affects allergic airway inflammation, specifically focusing on airway epithelium pyroptosis. Findings suggest heme oxygenase-1 binds gasdermin D C-terminal to limit release of N-terminal, which affects NLRP3-caspase 1-gasdermin D trimer formation. This enhances comprehension of anti-inflammatory activity of heme oxygenase-1 in allergic disorders.

DOI: https://doi.org/10.1007/s10495-024-02016-6
mSphere. 2024 Aug 27. e0063424

Investigating group A Streptococcus antibiotic tolerance in necrotizing fasciitis.

Nadia Keller, Mathilde Boumasmoud, Federica Andreoni, Andrea Tarnutzer, Manuela von Matt, Thomas C Scheier, Jana Epprecht, David Weller, Alejandro Gómez-Mejia, Markus Huemer, Donata von Reibnitz, Duveken B Y Fontein, Ewerton Marques-Maggio, Reto A Schuepbach, Srikanth Mairpady-Shambat, Silvio D Brugger, Annelies S Zinkernagel.

  Group A Streptococcus (GAS) necrotizing fasciitis (NF) is a difficult-to-treat bacterial infection associated with high morbidity and mortality despite extensive surgery and targeted antibiotic treatment. Difficult-to-treat infections are often characterized by the presence of bacteria surviving prolonged antibiotic exposure without displaying genetic resistance, referred to as persisters. In the present study, we investigated the presence of GAS persisters in tissue freshly debrided from patients as well as in an in vivo mouse model of NF and examined the phenomenon of antibiotic tolerance. Time-lapse imaging of GAS plated directly upon isolation from NF debrided tissue and an antibiotic challenge-based persisters assay were used to assess the presence of persisters. We show for the first time that GAS recovered directly from freshly debrided NF tissue is characterized by heterogeneous and overall delayed colony appearance time, suggesting the presence of persisters. Acidic pH or nutrient stress exposure, mimicking the NF-like environment in vitro, led to a similar phenotypic heterogeneity and resulted in enhanced survival upon antibiotic challenge, confirming the presence of GAS persisters. GAS persisters might contribute to NF treatment failure, despite extensive surgery and adequate antibiotic treatment.IMPORTANCEDifficult-to-treat and recurrent infections are a global problem burdening society and the health care system alike. Unraveling the mechanisms by which bacteria can survive antibiotic treatment without developing genetic resistance is of utmost importance to lay the foundation for new, effective therapeutic approaches. For the first time, we describe the phenomenon of antibiotic tolerance in group A Streptococcus (GAS) isolated from necrotizing fasciitis (NF) patients. Dormant, non-replicating cells (persisters) are tolerant to antibiotics and their occurrence in vivo is reported in an increasing number of bacterial species. Tailored treatment options, including the use of persisters-targeting drugs, need to be developed to specifically target dormant bacteria causing difficult-to-treat and recurrent infections.

Keywords:  dormancy; group A Streptococcus; necrotizing fasciitis; persisters; tolerance

DOI:  https://doi.org/10.1128/msphere.00634-24
Cells. 2024 Aug 19. pii: 1378. [Epub ahead of print]13(16):

Mononuclear Phagocytes, Cellular Immunity, and Nobel Prizes: A Historic Perspective.

Siamon Gordon, Annabell Roberti, Stefan H E Kaufmann.

  The mononuclear phagocyte system includes monocytes, macrophages, some dendritic cells, and multinuclear giant cells. These cell populations display marked heterogeneity depending on their differentiation from embryonic and bone marrow hematopoietic progenitors, tissue location, and activation. They contribute to tissue homeostasis by interacting with local and systemic immune and non-immune cells through trophic, clearance, and cytocidal functions. During evolution, they contributed to the innate host defense before effector mechanisms of specific adaptive immunity emerged. Mouse macrophages appear at mid-gestation and are distributed throughout the embryo to facilitate organogenesis and clear cells undergoing programmed cell death. Yolk sac, AGM, and fetal liver-derived tissue-resident macrophages persist throughout postnatal and adult life, supplemented by bone marrow-derived blood monocytes, as required after injury and infection. Nobel awards to Elie Metchnikoff and Paul Ehrlich in 1908 drew attention to cellular phagocytic and humoral immunity, respectively. In 2011, prizes were awarded to Jules Hoffmann and Bruce Beutler for contributions to innate immunity and to Ralph Steinman for the discovery of dendritic cells and their role in antigen presentation to T lymphocytes. We trace milestones in the history of mononuclear phagocyte research from the perspective of Nobel awards bearing directly and indirectly on their role in cellular immunity.

Keywords:  Nobel prizes; dendritic cells; history; homeostasis; immunity; macrophages; mononuclear phagocyte system; multinucleated giant cells; phagocytosis; plasma membrane receptors

DOI:  https://doi.org/10.3390/cells13161378
Nat Rev Immunol. 2024 Aug 23.

Lipid transfer from tumour-associated macrophages supports glioblastoma.

Kirsty Minton.

DOI: https://doi.org/10.1038/s41577-024-01086-6
Elife. 2024 Aug 28. pii: e78206. [Epub ahead of print]13

CCL28 modulates neutrophil responses during infection with mucosal pathogens.

Gregory T Walker, Araceli Perez-Lopez, Steven Silva, Michael H Lee, Elisabet Bjånes, Nicholas Dillon, Stephanie L Brandt, Romana R Gerner, Karine Melchior, Grant J Norton, Felix A Argueta, Frenchesca Dela Pena, Lauren Park, Victor A Sosa-Hernandez, Rodrigo Cervantes-Diaz, Sandra Romero-Ramirez, Monica Cartelle Gestal, Jose L Maravillas-Montero, Sean-Paul Nuccio, Victor Nizet, Manuela Raffatellu.

  The chemokine CCL28 is highly expressed in mucosal tissues, but its role during infection is not well understood. Here we show that CCL28 promotes neutrophil accumulation in the gut of mice infected with Salmonella and in the lung of mice infected with Acinetobacter. Neutrophils isolated from the infected mucosa expressed the CCL28 receptors CCR3 and, to a lesser extent, CCR10, on their surface. The functional consequences of CCL28 deficiency varied between the two infections: Ccl28-/- mice were highly susceptible to Salmonella gut infection but highly resistant to otherwise lethal Acinetobacter lung infection. In vitro, unstimulated neutrophils harbored pre-formed intracellular CCR3 that was rapidly mobilized to the cell surface following phagocytosis or inflammatory stimuli. Moreover, CCL28 stimulation enhanced neutrophil antimicrobial activity, production of reactive oxygen species, and formation of extracellular traps, all processes largely dependent on CCR3. Consistent with the different outcomes in the two infection models, neutrophil stimulation with CCL28 boosted the killing of Salmonella but not Acinetobacter. CCL28 thus plays a critical role in the immune response to mucosal pathogens by increasing neutrophil accumulation and activation, which can enhance pathogen clearance but also exacerbate disease depending on the mucosal site and the infectious agent.

Keywords:  human; immunology; infectious disease; inflammation; microbiology; mouse

DOI:  https://doi.org/10.7554/eLife.78206
Antioxidants (Basel). 2024 Aug 14. pii: 985. [Epub ahead of print]13(8):

Gut Microbiota Dysbiosis, Oxidative Stress, Inflammation, and Epigenetic Alterations in Metabolic Diseases.

Hamid Mostafavi Abdolmaleky, Jin-Rong Zhou.

  Gut dysbiosis, resulting from an imbalance in the gut microbiome, can induce excessive production of reactive oxygen species (ROS), leading to inflammation, DNA damage, activation of the immune system, and epigenetic alterations of critical genes involved in the metabolic pathways. Gut dysbiosis-induced inflammation can also disrupt the gut barrier integrity and increase intestinal permeability, which allows gut-derived toxic products to enter the liver and systemic circulation, further triggering oxidative stress, inflammation, and epigenetic alterations associated with metabolic diseases. However, specific gut-derived metabolites, such as short-chain fatty acids (SCFAs), lactate, and vitamins, can modulate oxidative stress and the immune system through epigenetic mechanisms, thereby improving metabolic function. Gut microbiota and diet-induced metabolic diseases, such as obesity, insulin resistance, dyslipidemia, and hypertension, can transfer to the next generation, involving epigenetic mechanisms. In this review, we will introduce the key epigenetic alterations that, along with gut dysbiosis and ROS, are engaged in developing metabolic diseases. Finally, we will discuss potential therapeutic interventions such as dietary modifications, prebiotics, probiotics, postbiotics, and fecal microbiota transplantation, which may reduce oxidative stress and inflammation associated with metabolic syndrome by altering gut microbiota and epigenetic alterations. In summary, this review highlights the crucial role of gut microbiota dysbiosis, oxidative stress, and inflammation in the pathogenesis of metabolic diseases, with a particular focus on epigenetic alterations (including histone modifications, DNA methylomics, and RNA interference) and potential interventions that may prevent or improve metabolic diseases.

Keywords:  epigenetic; gut dysbiosis; inflammation; metabolic diseases; microbiome; microbiota; oxidative stress; transgenerational

DOI:  https://doi.org/10.3390/antiox13080985
Clin Nutr ESPEN. 2024 Aug 22. pii: S2405-4577(24)01276-2. [Epub ahead of print]63 813-820

Targeting the microbiome to improve human health with the approach of personalized medicine: Latest aspects and current updates.

Vani Shukla, Shikha Singh, Shrikant Verma, Sushma Verma, Aliya Abbas Rizvi, Mohammad Abbas.

  The intricate ecosystem of microorganisms residing within and on the human body, collectively known as the microbiome, significantly influences human health. Imbalances in this microbiome, referred to as dysbiosis, have been associated with various diseases, prompting the exploration of novel therapeutic approaches. Personalized medicine, Tailors treatments to individual patient characteristics, offers a promising avenue for addressing microbiome-related health issues. This review highlights recent developments in utilizing personalized medicine to target the microbiome, aiming to enhance health outcomes. Noteworthy strategies include fecal microbiota transplantation (FMT), where healthy donor microbes are transferred to patients, showing promise in treating conditions such as recurrent Clostridium difficile infection. Additionally, probiotics, which are live microorganisms similar to beneficial gut inhabitants, and prebiotics, non-digestible compounds promoting microbial growth, are emerging as tools to restore microbiome balance. The integration of these approaches, known as synbiotics, enhances microbial colonization and therapeutic effects. Advances in metagenomics and sequencing technologies provide the means to understand individual microbiome profiles, enabling tailored interventions. This paper aims to present the latest insights in leveraging personalized medicine to address microbiome-related health concerns, envisioning a future where microbiome-based therapies reshape disease management and promote human health.

Keywords:  Dysbiosis; FMT; Microbiome; Personalized medicine; Prebiotics; Probiotics; Synbiotics

DOI:  https://doi.org/10.1016/j.clnesp.2024.08.005
Mol Aspects Med. 2024 Aug 26. pii: S0098-2997(24)00065-7. [Epub ahead of print]99 101306

Unveiling multifaceted roles of myeloid innate immune cells in the pathogenesis of psoriasis.

Sohyeon Park, Jinsun Jang, Hee Joo Kim, YunJae Jung.

  Psoriasis is a chronic inflammatory skin disease occurring worldwide. Initially viewed as a keratinocyte disorder, psoriasis is now recognized to involve a complex interplay between genetic predisposition, environmental triggers, and a dysregulated immune system, with a significant role of CD4+ T cells producing IL-17. Recent genetic studies have identified susceptibility loci that underscore the importance of innate immune responses, particularly the roles of myeloid cells, such as dendritic cells, macrophages, and neutrophils. These cells initiate and sustain inflammation through cytokine production triggered by external stimuli. They influence keratinocyte behavior and interact with adaptive immune cells. Recent techniques have further revealed the heterogeneity of myeloid cells in psoriatic lesions, highlighting the contributions of less-studied subsets, such as eosinophils and mast cells. This review examines the multifaceted roles of myeloid innate immune cells in psoriasis, emphasizing their functional diversity in promoting psoriatic inflammation. It also describes current treatment targeting myeloid innate immune cells and explores potential new therapeutic strategies based on the functional characteristics of these subsets. Future research should focus on the detailed characterization of myeloid subsets and their interactions to develop targeted treatments that address the complex immune landscape of psoriasis.

Keywords:  Innate immunity; Myeloid cells; Psoriasis; Single-cell RNA sequencing; Skin

DOI:  https://doi.org/10.1016/j.mam.2024.101306
Front Oncol. 2024 ;14 1441338

Immunometabolism of ferroptosis in the tumor microenvironment.

Gian Luca Lupica-Tondo, Emily N Arner, Denis A Mogilenko, Kelsey Voss.

  Ferroptosis is an iron-dependent form of cell death that results from excess lipid peroxidation in cellular membranes. Within the last decade, physiological and pathological roles for ferroptosis have been uncovered in autoimmune diseases, inflammatory conditions, infection, and cancer biology. Excitingly, cancer cell metabolism may be targeted to induce death by ferroptosis in cancers that are resistant to other forms of cell death. Ferroptosis sensitivity is regulated by oxidative stress, lipid metabolism, and iron metabolism, which are all influenced by the tumor microenvironment (TME). Whereas some cancer cell types have been shown to adapt to these stressors, it is not clear how immune cells regulate their sensitivities to ferroptosis. In this review, we discuss the mechanisms of ferroptosis sensitivity in different immune cell subsets, how ferroptosis influences which immune cells infiltrate the TME, and how these interactions can determine epithelial-to-mesenchymal transition (EMT) and metastasis. While much focus has been placed on inducing ferroptosis in cancer cells, these are important considerations for how ferroptosis-modulating strategies impact anti-tumor immunity. From this perspective, we also discuss some promising immunotherapies in the field of ferroptosis and the challenges associated with targeting ferroptosis in specific immune cell populations.

Keywords:  TME; ferroptosis; immunometabolism; iron; metastasis

DOI:  https://doi.org/10.3389/fonc.2024.1441338
Tissue Barriers. 2024 Aug 26. 2390705

Epithelial barrier dysfunction and microbial dysbiosis: exploring the pathogenesis and therapeutic strategies for Crohn's disease.

Tunç Akkoç.

  Crohn's disease (CD), a chronic gastrointestinal inflammatory disease, is becoming more widespread worldwide. Crohn's disease is caused by gut microbiota changes, genetics, environmental stresses, and immunological responses. Current treatments attempt to achieve long-term remission and avoid complications, delaying disease progression. Immunosuppressive measures and combination medicines should be started early for high-risk patients. These medicines monitor inflammatory indicators and adjust as needed. The epithelial barrier helps defend against physical, chemical, and immunological threats. When tissues' protective barrier breaks down, the microbiome may reach the layer underneath. Unbalanced microbial populations and inflammation impair healing and adjustment. Inflammatory cells infiltrating sensitive tissues aggravate the damage and inflammation. This approach promotes chronic inflammatory diseases. The epithelial barrier hypothesis states that hereditary and environmental variables cause epithelial tissue inflammation. This review focuses on how epithelial barrier break-down and microbial dysbiosis cause Crohn's disease and current advances in understanding the epithelial barrier, immune system, and microbiome. Additionally, investigate treatments that restore barrier integrity and promote microbial balance. Overall, it stresses the role of epithelial barrier failure and microbial dysbiosis in Crohn's disease development and discusses current advances in understanding the barrier, immunological responses, and microbiota.

Keywords:  Crohn’s disease pathogenesis; epithelial barrier dysfunction; immune responses; microbial dysbiosis; therapeutic strategies

DOI:  https://doi.org/10.1080/21688370.2024.2390705
Methods Mol Biol. 2025 ;2854 171-175

Phagosome Isolation with Magnetic Beads and Purification of Toll-Like Receptor (TLR) Complexes in Phagosomes.

Wei Liu, Bo Liu.

  Phagocytosis is a central process by which macrophage cells internalize and eliminate microbes as well as apoptotic cells. The nascent phagosome undergoes a complex maturation process involving sequential fusion with endosomal compartments. The endosomal TLRs, including TLR3, -7, -8, and -9, play a critical role in innate immunity by sensing bacterial or viral nucleic acids and are preferentially transported to the phagosomal membrane of innate immune cells upon activation. Therefore, phagosome isolation is helpful for studies on pathogenic invasion and the functions of phagosome proteins, including endosomal TLRs.

Keywords:  Endosomal TLR; Organelle purification; Phagosome

DOI:  https://doi.org/10.1007/978-1-0716-4108-8_17
Cells. 2024 Aug 14. pii: 1353. [Epub ahead of print]13(16):

The Interplay between Airway Cilia and Coronavirus Infection, Implications for Prevention and Control of Airway Viral Infections.

Xuyao Dai, Ruodan Xu, Ning Li.

  Coronaviruses (CoVs) are a class of respiratory viruses with the potential to cause severe respiratory diseases by infecting cells of the upper respiratory tract, bronchial epithelium, and lung. The airway cilia are distributed on the surface of respiratory epithelial cells, forming the first point of contact between the host and the inhaled coronaviruses. The function of the airway cilia is to oscillate and sense, thereby defending against and removing pathogens to maintain the cleanliness and patency of the respiratory tract. Following infection of the respiratory tract, coronaviruses exploit the cilia to invade and replicate in epithelial cells while also damaging the cilia to facilitate the spread and exacerbation of respiratory diseases. It is therefore imperative to investigate the interactions between coronaviruses and respiratory cilia, as well as to elucidate the functional mechanism of respiratory cilia following coronavirus invasion, in order to develop effective strategies for the prevention and treatment of respiratory viral infections. This review commences with an overview of the fundamental characteristics of airway cilia, and then, based on the interplay between airway cilia and coronavirus infection, we propose that ciliary protection and restoration may represent potential therapeutic approaches in emerging and re-emerging coronavirus pandemics.

Keywords:  cilia; ciliogenesis; coronavirus; respiratory diseases

DOI:  https://doi.org/10.3390/cells13161353
Cell Host Microbe. 2024 Aug 20. pii: S1931-3128(24)00285-3. [Epub ahead of print]

Metabolite-based inter-kingdom communication controls intestinal tissue recovery following chemotherapeutic injury.

Christopher J Anderson, Laura Boeckaerts, Pricilla Chin, Javier Burgoa Cardas, Wei Xie, Amanda Gonçalves, Gillian Blancke, Sam Benson, Sebastian Rogatti, Mariska S Simpson, Anna Davey, Sze Men Choi, Sandrien Desmet, Summer D Bushman, Geert Goeminne, Peter Vandenabeele, Mahesh S Desai, Lars Vereecke, Kodi S Ravichandran.

  Cytotoxic chemotherapies have devastating side effects, particularly within the gastrointestinal tract. Gastrointestinal toxicity includes the death and damage of the epithelium and an imbalance in the intestinal microbiota, otherwise known as dysbiosis. Whether dysbiosis is a direct contributor to tissue toxicity is a key area of focus. Here, from both mammalian and bacterial perspectives, we uncover an intestinal epithelial cell death-Enterobacteriaceae signaling axis that fuels dysbiosis. Specifically, our data demonstrate that chemotherapy-induced epithelial cell apoptosis and the purine-containing metabolites released from dying cells drive the inter-kingdom transcriptional re-wiring of the Enterobacteriaceae, including fundamental shifts in bacterial respiration and promotion of purine utilization-dependent expansion, which in turn delays the recovery of the intestinal tract. Inhibition of epithelial cell death or restriction of the Enterobacteriaceae to homeostatic levels reverses dysbiosis and improves intestinal recovery. These findings suggest that supportive therapies that maintain homeostatic levels of Enterobacteriaceae may be useful in resolving intestinal disease.

Keywords:  Enterobacteriaceae; apoptosis; chemotherapy; dysbiosis; intestinal epithelium

DOI:  https://doi.org/10.1016/j.chom.2024.07.026
Int Immunopharmacol. 2024 Aug 25. pii: S1567-5769(24)01454-1. [Epub ahead of print]141 112933

Natural compound phloretin restores periodontal immune homeostasis via HIF-1α-regulated PI3K/Akt and glycolysis in macrophages.

Xinyi Zeng, Tiancheng Li, Kuan Yang, Yukun Jiang, Shuo Chen, Shuxian Yang, Shujuan Zou, Jingping Liu, Peipei Duan.

  Periodontitis is a chronic inflammatory disease that affects about 45 %-50 % of adults worldwide, but the efficacy of current clinical therapies is unsatisfactory due to the complicated periodontal immune microenvironment. Thus, developing drugs that can regulate innate immune cells (e.g., macrophages) is a potent strategy to treat periodontitis. Here, we report that phloretin, a food plant-derived natural compound, is sufficient to alleviate periodontitis through immune regulation. In vivo, phloretin treatment could significantly reduce alveolar bone resorption and periodontal inflammation in mouse periodontitis models. In vitro, phloretin could suppress proinflammatory (M1-like) polarization and cytokine release in macrophages induced by LPS. Mechanistically, the immune regulatory role of phloretin in macrophages may be due to its metabolic regulation effect. Phloretin might restore the balance of M1/M2 macrophage transition in periodontitis by inhibiting HIF-1α-mediated glycolysis and PI3k/Akt pathways, thereby reducing the proinflammatory effect and immune disorder caused by over-activated M1 macrophages. Together, this study highlights that natural compound, such as phloretin, can restore periodontal immune homeostasis by metabolic regulation of macrophages, which may provide novel insight into the treatment of periodontitis.

Keywords:  Alveolar bone loss; Immune homeostasis; Inflammation; Macrophages; Metabolism; Periodontal diseases

DOI:  https://doi.org/10.1016/j.intimp.2024.112933
Mol Cell Biochem. 2024 Aug 29.

Macrophage energy metabolism in cardiometabolic disease.

Angela Wong, Qiuyu Sun, Ismail I Latif, Qutuba G Karwi.

  In a rapidly expanding body of literature, the major role of energy metabolism in determining the response and polarization status of macrophages has been examined, and it is currently a very active area of research. The metabolic flux through different metabolic pathways in the macrophage is interconnected and complex and could influence the polarization of macrophages. Earlier studies suggested glucose flux through cytosolic glycolysis is a prerequisite to trigger the pro-inflammatory phenotypes of macrophages while proposing that fatty acid oxidation is essential to support anti-inflammatory responses by macrophages. However, recent studies have shown that this understanding is oversimplified and that the metabolic control of macrophage polarization is highly complex and not fully defined yet. In this review, we systematically reviewed and summarized the literature regarding the role of energy metabolism in controlling macrophage activity and how that might be altered in cardiometabolic diseases, namely heart failure, obesity, and diabetes. We critically appraised the experimental studies and methodologies in the published studies. We also highlighted the challenging concepts in macrophage metabolism and identified several research questions yet to be addressed in future investigations.

Keywords:  Diabetes; Heart failure; Macrophage; Metabolism; Obesity

DOI:  https://doi.org/10.1007/s11010-024-05099-6
Int J Mol Sci. 2024 Aug 06. pii: 8564. [Epub ahead of print]25(16):

The Role of Proteomics in Identification of Key Proteins of Bacterial Cells with Focus on Probiotic Bacteria.

Miroslava Stastna.

  Probiotics can affect human health, keep the balance between beneficial and pathogenic bacteria, and their colonizing abilities enable the enhancement of the epithelial barrier, preventing the invasion of pathogens. Health benefits of probiotics were related to allergy, depression, eczema, cancer, obesity, inflammatory diseases, viral infections, and immune regulation. Probiotic bacterial cells contain various proteins that function as effector molecules, and explaining their roles in probiotic actions is a key to developing efficient and targeted treatments for various disorders. Systematic proteomic studies of probiotic proteins (probioproteomics) can provide information about the type of proteins involved, their expression levels, and the pathological changes. Advanced proteomic methods with mass spectrometry instrumentation and bioinformatics can point out potential candidates of next-generation probiotics that are regulated under pharmaceutical frameworks. In addition, the application of proteomics with other omics methods creates a powerful tool that can expand our understanding about diverse probiotic functionality. In this review, proteomic strategies for identification/quantitation of the proteins in probiotic bacteria were overviewed. The types of probiotic proteins investigated by proteomics were described, such as intracellular proteins, surface proteins, secreted proteins, and the proteins of extracellular vesicles. Examples of pathological conditions in which probiotic bacteria played crucial roles were discussed.

Keywords:  bacterial proteins; health-promoting effect; mass spectrometry-based proteomics; probiotics

DOI:  https://doi.org/10.3390/ijms25168564
Biomedicines. 2024 Jul 26. pii: 1674. [Epub ahead of print]12(8):

Landscape of Interactions between Stromal and Myeloid Cells in Ileal Crohn's Disease; Indications of an Important Role for Fibroblast-Derived CCL-2.

Nikolas Dovrolis, Vassilis Valatas, Ioannis Drygiannakis, Eirini Filidou, Michail Spathakis, Leonidas Kandilogiannakis, Gesthimani Tarapatzi, Konstantinos Arvanitidis, Giorgos Bamias, Stergios Vradelis, Vangelis G Manolopoulos, Vasilis Paspaliaris, George Kolios.

   BACKGROUND AND AIMS: Monocyte recruitment in the lamina propria and inflammatory phenotype driven by the mucosal microenvironment is critical for the pathogenesis of inflammatory bowel disease. However, the stimuli responsible remain largely unknown. Recent works have focused on stromal cells, the main steady-state cellular component in tissue, as they produce pro-inflammatory chemokines that contribute to the treatment-resistant nature of IBD.
METHODS: We studied the regulation of these processes by examining the communication patterns between stromal and myeloid cells in ileal Crohn's disease (CD) using a complete single-cell whole tissue sequencing analysis pipeline and in vitro experimentation in mesenchymal cells.
RESULTS: We report expansion of S4 stromal cells and monocyte-like inflammatory macrophages in the inflamed mucosa and describe interactions that may establish sustained local inflammation. These include expression of CCL2 by S1 fibroblasts to recruit and retain monocytes and macrophages in the mucosa, where they receive signals for proliferation, survival, and differentiation to inflammatory macrophages from S4 stromal cells through molecules such as MIF, IFNγ, and FN1. The overexpression of CCL2 in ileal CD and its stromal origin was further demonstrated in vitro by cultured mesenchymal cells and intestinal organoids in the context of an inflammatory milieu.
CONCLUSIONS: Our findings outline an extensive cross-talk between stromal and myeloid cells, which may contribute to the onset and progression of inflammation in ileal Crohn's disease. Understanding the mechanisms underlying monocyte recruitment and polarization, as well as the role of stromal cells in sustaining inflammation, can provide new avenues for developing targeted therapies to treat IBD.

Keywords:  Crohn’s disease (CD); cell–cell communication; pro-inflammatory differentiation; single-cell transcriptomics; stromal cells

DOI:  https://doi.org/10.3390/biomedicines12081674
Cell Host Microbe. 2024 Aug 17. pii: S1931-3128(24)00283-X. [Epub ahead of print]

RSV and rhinovirus increase pneumococcal carriage acquisition and density, whereas nasal inflammation is associated with bacterial shedding.

Elena Mitsi, Elissavet Nikolaou, Andre Goncalves, Annie Blizard, Helen Hill, Madlen Farrar, Angela Hyder-Wright, Oluwasefunmi Akeju, Josh Hamilton, Ashleigh Howard, Filora Elterish, Carla Solorzano, Ryan Robinson, Jesus Reiné, Andrea M Collins, Stephen B Gordon, Richard E Moxon, Jeffrey N Weiser, Debby Bogaert, Daniela M Ferreira.

  Epidemiological studies report the impact of co-infection with pneumococcus and respiratory viruses upon disease rates and outcomes, but their effect on pneumococcal carriage acquisition and bacterial load is scarcely described. Here, we assess this by combining natural viral infection with controlled human pneumococcal infection in 581 healthy adults screened for upper respiratory tract viral infection before intranasal pneumococcal challenge. Across all adults, respiratory syncytial virus (RSV) and rhinovirus asymptomatic infection confer a substantial increase in secondary infection with pneumococcus. RSV also has a major impact on pneumococcal density up to 9 days post challenge. We also study rates and kinetics of bacterial shedding through the nose and oral route in a subset. High levels of pneumococcal colonization density and nasal inflammation are strongly correlated with increased odds of nasal shedding as opposed to cough shedding. Protection against respiratory viral infections and control of pneumococcal density may contribute to preventing pneumococcal disease and reducing bacterial spread.

Keywords:  RSV; Rhinovirus; S.pneumoniae; bacterial shedding; co-infection; nasal inflammation; pneumococcal carriage; transmission

DOI:  https://doi.org/10.1016/j.chom.2024.07.024
Am J Physiol Cell Physiol. 2024 Aug 26.

Iron-laden macrophage-mediated paracrine pro-fibrotic signaling induces lung fibroblast activation.

Yunqi Li, Xinqian Du, Yue Hu, Dan Wang, Luo Duan, Hanxiao Zhang, Ruoyang Zhang, Yingjie Xu, Ruonan Zhou, Xinyu Zhang, Muzhi Zhang, Jie Liu, Zhe Lv, Yan Chen, Wei Wang, Ying Sun, Ye Cui.

  Idiopathic pulmonary fibrosis (IPF) is a devastating condition characterized by progressive lung scarring and uncontrolled fibroblast proliferation, inevitably leading to organ dysfunction and mortality. While elevated iron levels have been observed in patients and animal models of lung fibrosis, the mechanisms linking iron dysregulation to lung fibrosis pathogenesis, particularly the role of macrophages in orchestrating this process, remain poorly elucidated. Here we evaluate iron metabolism in macrophages during pulmonary fibrosis using both in vivo and in vitro approaches. In murine bleomycin- and amiodarone-induced pulmonary fibrosis models, we observed significant iron deposition and lipid peroxidation in pulmonary macrophages. Intriguingly, the ferroptosis regulator glutathione peroxidase 4 (GPX4) was upregulated in pulmonary macrophages following bleomycin instillation, a finding corroborated by single-cell RNA sequencing analysis. Moreover, macrophages isolated from fibrotic mouse lungs exhibited increased transforming growth factor (TGF)-β1 expression that correlated with lipid peroxidation. In vitro, iron overload in bone marrow-derived macrophages triggered lipid peroxidation and TGF-β1 upregulation, which was effectively suppressed by ferroptosis inhibitors. When co-cultured with iron-overloaded macrophages, lung fibroblasts exhibited heightened activation, evidenced by increased α-smooth muscle actin and fibronectin expression. Importantly, this pro-fibrotic effect was attenuated by treating macrophages with a ferroptosis inhibitor or blocking TGF-β receptor signaling in fibroblasts. Collectively, our study elucidates a novel mechanistic paradigm in which the accumulation of iron within macrophages initiates lipid peroxidation, thereby amplifying TGF-β1 production, subsequently instigating fibroblast activation through paracrine signaling. Thus, inhibiting iron overload and lipid peroxidation warrants further exploration as a strategy to suppress fibrotic stimulation by disease-associated macrophages.

Keywords:  Fibroblast activation; Iron overload; Lung fibrosis; Macrophages; Transforming growth factor-beta

DOI:  https://doi.org/10.1152/ajpcell.00675.2023
ERJ Open Res. 2024 Jul;pii: 00256-2024. [Epub ahead of print]10(4):

Clinical implications of innate immune exhaustion in cystic fibrosis.

Rikke Møller, Bibi Uhre Nielsen, Elio Rossi, Mads Lausen, Marianne Skov, Tacjana Pressler, Sisse Rye Ostrowski, Helle Krogh Johansen.

Objectives: Lung disease progression in people with cystic fibrosis (pwCF) varies from one individual to another. Different immunological characteristics have been suggested to explain this variation, and we hypothesised that lung capacity may be associated with the innate immune response in pwCF. In an exploratory study, we aimed to investigate potential links between the innate immune response and lung function in pwCF using the standardised immune function assay TruCulture.
Methods: In a single-centre study with combined cross-sectional and longitudinal data before and after intravenous antibiotics, blood was sampled from Pseudomonas aeruginosa-infected pwCF. Whole blood was analysed by TruCulture to reveal the unstimulated and stimulated cytokine release. Tobit regressions and Spearman's correlations were used to estimate the associations between lung function and cytokine release.
Results: We included 52 pwCF in the cross-sectional study and 24 in the longitudinal study. In the cross-sectional study, we found that compared to a healthy population, the release of toll-like receptor (TLR)3, TLR4- and TLR7/8-stimulated interferon-γ, and interleukin (IL)-12p40 was reduced. Although TLR3-stimulated IL-1β and IL-6 release increased with lung function, overall, cytokine release did not correlate well with lung function. In the longitudinal study, the cytokine release was modified by antibiotic treatment, but the cytokine release before antibiotic treatment did not associate with changes in lung function after treatment.
Conclusion: The stimulated cytokine release could not predict lung function levels or changes in pwCF, but our data indicate that pwCF experience exhaustion in the innate immune response after years of chronic bacterial infection.

DOI: https://doi.org/10.1183/23120541.00256-2024
Biomedicines. 2024 Aug 22. pii: 1928. [Epub ahead of print]12(8):

Complex Interactions between the Human Major Histocompatibility Complex (MHC) and Microbiota: Their Roles in Disease Pathogenesis and Immune System Regulation.

Antonio Arnaiz-Villena, Ignacio Juarez, Christian Vaquero-Yuste, Tomás Lledo, José Manuel Martin-Villa, Fabio Suarez-Trujillo.

  The relationship between microbiota and the immune system is complex and characterized by the ways in which microbiota directs immune function interactions, both innate and acquired and also keeps activating the immune system throughout an individual's life. In this respect, the human Major Histocompatibility Complex (MHC, referred to as HLA in humans) plays a crucial role and is also established in self-defense against microbes by presenting microbial-derived peptides to the immune cells. However, this assumption has some unclear aspects that should be investigated. For example, how is the microbiota shaped by microbe species diversity, quantity and functions of the immune system, as well as the role and molecular mechanisms of the HLA complex during this process. There are autoimmune diseases related to both HLA and specific microbiota changes or alterations, many of which are mentioned in the present review. In addition, the HLA peptide presenting function should be put in a framework together with its linkage to diseases and also with HLA compatibility necessary for transplants to be successful. These are still quite an enigmatically statistical and phenomenological approach, but no firm pathogenic mechanisms have been described; thus, HLA's real functioning is still to be fully unveiled. After many years of HLA single-genes studies, firm pathogenesis mechanisms underlying disease linkage have been discovered. Finally, microbiota has been defined as conformed by bacteria, protozoa, archaea, fungi, and viruses; notwithstanding, endogenous viral sequences integrated into the human genome and other viral particles (obelisks) recently found in the digestive mucosa should be taken into account because they may influence both the microbiome and the immune system and their interactions. In this context, we propose to integrate these microbial-genetic particle components into the microbiome concept and designate it as "microgenobiota".

Keywords:  HLA; HLA-disease; HLA-pharmacogenomics; MHC; autoimmunity; microbiome; microbiota; microgenobiota

DOI:  https://doi.org/10.3390/biomedicines12081928
Life Sci Alliance. 2024 Nov;pii: e202302339. [Epub ahead of print]7(11):

Reprogramming of breast tumor-associated macrophages with modulation of arginine metabolism.

Veani Fernando, Xunzhen Zheng, Vandana Sharma, Osama Sweef, Eun-Seok Choi, Saori Furuta.

HER2+ breast tumors have abundant immune-suppressive cells, including M2-type tumor-associated macrophages (TAMs). Although TAMs consist of the immune-stimulatory M1 type and immune-suppressive M2 type, the M1/M2-TAM ratio is reduced in immune-suppressive tumors, contributing to their immunotherapy refractoriness. M1- versus M2-TAM formation depends on differential arginine metabolism, where M1-TAMs convert arginine to nitric oxide (NO) and M2-TAMs convert arginine to polyamines (PAs). We hypothesize that such distinct arginine metabolism in M1- versus M2-TAMs is attributed to different availability of BH4 (NO synthase cofactor) and that its replenishment would reprogram M2-TAMs to M1-TAMs. Recently, we reported that sepiapterin (SEP), the endogenous BH4 precursor, elevates the expression of M1-TAM markers within HER2+ tumors. Here, we show that SEP restores BH4 levels in M2-like macrophages, which then redirects arginine metabolism to NO synthesis and converts M2 type to M1 type. The reprogrammed macrophages exhibit full-fledged capabilities of antigen presentation and induction of effector T cells to trigger immunogenic cell death of HER2+ cancer cells. This study substantiates the utility of SEP in the metabolic shift of the HER2+ breast tumor microenvironment as a novel immunotherapeutic strategy.

DOI: https://doi.org/10.26508/lsa.202302339
Biomedicines. 2024 Aug 05. pii: 1757. [Epub ahead of print]12(8):

An Update on the Study of the Molecular Mechanisms Involved in Autophagy during Bacterial Pathogenesis.

Md Ataur Rahman, Amily Sarker, Mohammed Ayaz, Ananya Rahman Shatabdy, Nabila Haque, Maroua Jalouli, M D Hasanur Rahman, Taslin Jahan Mou, Shuvra Kanti Dey, Ehsanul Hoque Apu, Muhammad Sohail Zafar, Md Anowar Khasru Parvez.

  Autophagy is a unique catabolic process that degrades irrelevant or damaged components in eukaryotic cells to maintain homeostasis and eliminate infections from pathogenesis. Pathogenic bacteria have developed many autophagy manipulation techniques that affect host immune responses and intracellular bacterial pathogens have evolved to avoid xenophagy. However, reducing its effectiveness as an innate immune response has not yet been elucidated. Bacterial pathogens cause autophagy in infected cells as a cell-autonomous defense mechanism to eliminate the pathogen. However, harmful bacteria have learned to control autophagy and defeat host defenses. Intracellular bacteria can stimulate and control autophagy, while others inhibit it to prevent xenophagy and lysosomal breakdown. This review evaluates the putative functions for xenophagy in regulating bacterial infection, emphasizing that successful pathogens have evolved strategies to disrupt or exploit this defense, reducing its efficiency in innate immunity. Instead, animal models show that autophagy-associated proteins influence bacterial pathogenicity outside of xenophagy. We also examine the consequences of the complex interaction between autophagy and bacterial pathogens in light of current efforts to modify autophagy and develop host-directed therapeutics to fight bacterial infections. Therefore, effective pathogens have evolved to subvert or exploit xenophagy, although autophagy-associated proteins can influence bacterial pathogenicity outside of xenophagy. Finally, this review implies how the complex interaction between autophagy and bacterial pathogens affects host-directed therapy for bacterial pathogenesis.

Keywords:  autophagy; bacteria; bacterial toxins; pathogenesis; xenophagy

DOI:  https://doi.org/10.3390/biomedicines12081757
Eur J Immunol. 2024 Aug 27. e2350814

The complement system: A key player in the host response to infections.

Archana Jayaraman, Sarah Walachowski, Markus Bosmann.

  Infections are one of the most significant healthcare and economic burdens across the world as underscored by the recent coronavirus pandemic. Moreover, with the increasing incidence of antimicrobial resistance, there is an urgent need to better understand host-pathogen interactions to design effective treatment strategies. The complement system is a key arsenal of the host defense response to pathogens and bridges both innate and adaptive immunity. However, in the contest between pathogens and host defense mechanisms, the host is not always victorious. Pathogens have evolved several approaches, including co-opting the host complement regulators to evade complement-mediated killing. Furthermore, deficiencies in the complement proteins, both genetic and therapeutic, can lead to an inefficient complement-mediated pathogen eradication, rendering the host more susceptible to certain infections. On the other hand, overwhelming infection can provoke fulminant complement activation with uncontrolled inflammation and potentially fatal tissue and organ damage. This review presents an overview of critical aspects of the complement-pathogen interactions during infection and discusses perspectives on designing therapies to mitigate complement dysfunction and limit tissue injury.

Keywords:  Complement deficiency; Complement hyperactivation; Immune defense; Pneumonia; Sepsis

DOI:  https://doi.org/10.1002/eji.202350814
Cell Death Dis. 2024 Aug 27. 15(8): 626

Drp1 depletion protects against ferroptotic cell death by preserving mitochondrial integrity and redox homeostasis.

Stephan Tang, Anneke Fuß, Zohreh Fattahi, Carsten Culmsee.

Mitochondria are highly dynamic organelles which undergo constant fusion and fission as part of the mitochondrial quality control. In genetic diseases and age-related neurodegenerative disorders, altered mitochondrial fission-fusion dynamics have been linked to impaired mitochondrial quality control, disrupted organelle integrity and function, thereby promoting neural dysfunction and death. The key enzyme regulating mitochondrial fission is the GTPase Dynamin-related Protein 1 (Drp1), which is also considered as a key player in mitochondrial pathways of regulated cell death. In particular, increasing evidence suggests a role for impaired mitochondrial dynamics and integrity in ferroptosis, which is an iron-dependent oxidative cell death pathway with relevance in neurodegeneration. In this study, we demonstrate that CRISPR/Cas9-mediated genetic depletion of Drp1 exerted protective effects against oxidative cell death by ferroptosis through preserved mitochondrial integrity and maintained redox homeostasis. Knockout of Drp1 resulted in mitochondrial elongation, attenuated ferroptosis-mediated impairment of mitochondrial membrane potential, and stabilized iron trafficking and intracellular iron storage. In addition, Drp1 deficiency exerted metabolic effects, with reduced basal and maximal mitochondrial respiration and a metabolic shift towards glycolysis. These metabolic effects further alleviated the mitochondrial contribution to detrimental ROS production thereby significantly enhancing neural cell resilience against ferroptosis. Taken together, this study highlights the key role of Drp1 in mitochondrial pathways of ferroptosis and expose the regulator of mitochondrial dynamics as a potential therapeutic target in neurological diseases involving oxidative dysregulation.

DOI: https://doi.org/10.1038/s41419-024-07015-8
Smart Med. 2024 Feb;3(1): e20230036

Immunomodulation of wound healing leading to efferocytosis.

Yun Zhao, Minxiong Li, Jiayi Mao, Yinghong Su, Xin Huang, Wenzheng Xia, Xiangfeng Leng, Tao Zan.

  Effectively eliminating apoptotic cells is precisely controlled by a variety of signaling molecules and a phagocytic effect known as efferocytosis. Abnormalities in efferocytosis may bring about the development of chronic conditions, including angiocardiopathy, chronic inflammatory diseases and autoimmune diseases. During wound healing, failure of efferocytosis leads to the collection of apoptosis, the release of necrotic material and chronic wounds that are difficult to heal. In addition to the traditional phagocytes-macrophages, other important cell species including dendritic cells, neutrophils, vascular endothelial cells, fibroblasts and keratinocytes contribute to wounding healing. This review summarizes how efferocytosis-mediated immunomodulation plays a repair-promoting role in wound healing, providing new insights for patients suffering from various cutaneous wounds.

Keywords:  apoptotic cell; efferocytosis; immune cell; phagocytosis; wound healing

DOI:  https://doi.org/10.1002/SMMD.20230036
Redox Biol. 2024 Aug 19. pii: S2213-2317(24)00299-4. [Epub ahead of print]76 103321

Epigenetic regulation of diverse regulated cell death modalities in cardiovascular disease: Insights into necroptosis, pyroptosis, ferroptosis, and cuproptosis.

Cong Chen, Jie Wang, Shan Zhang, Xueying Zhu, Jun Hu, Chao Liu, Lanchun Liu.

  Cell death constitutes a critical component of the pathophysiology of cardiovascular diseases. A growing array of non-apoptotic forms of regulated cell death (RCD)-such as necroptosis, ferroptosis, pyroptosis, and cuproptosis-has been identified and is intimately linked to various cardiovascular conditions. These forms of RCD are governed by genetically programmed mechanisms within the cell, with epigenetic modifications being a common and crucial regulatory method. Such modifications include DNA methylation, RNA methylation, histone methylation, histone acetylation, and non-coding RNAs. This review recaps the roles of DNA methylation, RNA methylation, histone modifications, and non-coding RNAs in cardiovascular diseases, as well as the mechanisms by which epigenetic modifications regulate key proteins involved in cell death. Furthermore, we systematically catalog the existing epigenetic pharmacological agents targeting novel forms of RCD and their mechanisms of action in cardiovascular diseases. This article aims to underscore the pivotal role of epigenetic modifications in precisely regulating specific pathways of novel RCD in cardiovascular diseases, thus offering potential new therapeutic avenues that may prove more effective and safer than traditional treatments.

Keywords:  Cuproptosis; Epigenetic modification; Ferroptosis; Necroptosis; Pyroptosis

DOI:  https://doi.org/10.1016/j.redox.2024.103321
Nat Commun. 2024 Aug 28. 15(1): 7416

Elucidating human gut microbiota interactions that robustly inhibit diverse Clostridioides difficile strains across different nutrient landscapes.

Jordy Evan Sulaiman, Jaron Thompson, Yili Qian, Eugenio I Vivas, Christian Diener, Sean M Gibbons, Nasia Safdar, Ophelia S Venturelli.

The human gut pathogen Clostridioides difficile displays substantial inter-strain genetic variability and confronts a changeable nutrient landscape in the gut. We examined how human gut microbiota inter-species interactions influence the growth and toxin production of various C. difficile strains across different nutrient environments. Negative interactions influencing C. difficile growth are prevalent in an environment containing a single highly accessible resource and sparse in an environment containing C. difficile-preferred carbohydrates. C. difficile toxin production displays significant community-context dependent variation and does not trend with growth-mediated inter-species interactions. C. difficile strains exhibit differences in interactions with Clostridium scindens and the ability to compete for proline. Further, C. difficile shows substantial differences in transcriptional profiles in co-culture with C. scindens or Clostridium hiranonis. C. difficile exhibits massive alterations in metabolism and other cellular processes in co-culture with C. hiranonis, reflecting their similar metabolic niches. C. hiranonis uniquely inhibits the growth and toxin production of diverse C. difficile strains across different nutrient environments and robustly ameliorates disease severity in mice. In sum, understanding the impact of C. difficile strain variability and nutrient environments on inter-species interactions could help improve the effectiveness of anti-C. difficile strategies.

DOI: https://doi.org/10.1038/s41467-024-51062-w
Cell. 2024 Aug 22. pii: S0092-8674(24)00826-2. [Epub ahead of print]187(17): 4549-4551

OLAH connects fatty acid metabolism to the severity of respiratory viral disease.

Rohan Palanki, Hannah Yamagata, Michael J Mitchell.

Respiratory virus infections may cause profound respiratory illness, yet the factors that underlie disease severity are not well understood. In this issue of Cell, Jia, Crawford, et al.1 identify the role of oleoyl-ACP-hydrolase (OLAH) in mediating life-threatening inflammation associated with viral respiratory disease severity.

DOI: https://doi.org/10.1016/j.cell.2024.07.032
Nat Commun. 2024 Aug 25. 15(1): 7319

Synergistic collaboration between AMPs and non-direct antimicrobial cationic peptides.

Zifan Ye, Lei Fu, Shuangyu Li, Ziying Chen, Jianhong Ouyang, Xinci Shang, Yanli Liu, Lianghui Gao, Yipeng Wang.

Non-direct antimicrobial cationic peptides (NDACPs) are components of the animal innate immune system. But their functions and association with antimicrobial peptides (AMPs) are incompletely understood. Here, we reveal a synergistic interaction between the AMP AW1 and the NDACP AW2, which are co-expressed in the frog Amolops wuyiensis. AW2 enhances the antibacterial activity of AW1 both in vitro and in vivo, while mitigating the development of bacterial resistance and eradicating biofilms. AW1 and AW2 synergistically damage bacterial membranes, facilitating cellular uptake and interaction of AW2 with the intracellular target bacterial genomic DNA. Simultaneously, they trigger the generation of ROS in bacteria, contributing to cell death upon reaching a threshold level. Moreover, we demonstrate that this synergistic antibacterial effect between AMPs and NDACPs is prevalent across diverse animal species. These findings unveil a robust and previously unknown correlation between AMPs and NDACPs as a widespread antibacterial immune defense strategy in animals.

DOI: https://doi.org/10.1038/s41467-024-51730-x
Nat Cardiovasc Res. 2023 Oct;2(10): 869-870

Visualizing inflammatory monocytes and macrophages in the human heart.

DOI: https://doi.org/10.1038/s44161-023-00345-4
Proc Natl Acad Sci U S A. 2024 Sep 03. 121(36): e2400341121

Prevotella are major contributors of sialidases in the human vaginal microbiome.

Paula Pelayo, Fatima A Hussain, Caroline A Werlang, Chloe M Wu, Benjamin M Woolston, Claire M Xiang, Lindsay Rutt, Michael T France, Jacques Ravel, Katharina Ribbeck, Douglas S Kwon, Emily P Balskus.

  Elevated bacterial sialidase activity in the female genital tract is strongly associated with poor health outcomes including preterm birth and bacterial vaginosis (BV). These negative effects may arise from sialidase-mediated degradation of the protective mucus layer in the cervicovaginal environment. Prior biochemical studies of vaginal bacterial sialidases have focused solely on the BV-associated organism Gardnerella vaginalis. Despite their implications for sexual and reproductive health, sialidases from other vaginal bacteria have not been characterized. Here, we show that vaginal Prevotella species produce sialidases that possess variable activity toward mucin substrates. The sequences of sialidase genes and their presence are largely conserved across clades of Prevotella from different geographies, hinting at their importance globally. Finally, we find that Prevotella sialidase genes and transcripts, including those encoding mucin-degrading sialidases from Prevotella timonensis, are highly prevalent and abundant in human vaginal genomes and transcriptomes. Together, our results identify Prevotella as a critical source of sialidases in the vaginal microbiome, improving our understanding of this detrimental bacterial activity.

Keywords:  Prevotella; bacterial vaginosis; mucin; sialidase; vaginal microbiome

DOI:  https://doi.org/10.1073/pnas.2400341121