bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2024–11–10
eightteen papers selected by
Chun-Chi Chang, Universitäts Spital Zürich
  1. Resveratrol Potentiates BCG-induced Trained Immunity in Human Monocytes.
  2. Mycobacteria develop biofilms on airway epithelial cells and promote mucosal barrier disruption.
  3. Alveolar epithelial cells shape lipopolysaccharide-induced inflammatory responses and reprogramming of alveolar macrophages.
  4. Single high-fat challenge and trained innate immunity: A randomized controlled cross-over trial.
  5. Glycans in the oral bacteria and fungi: Shaping host-microbe interactions and human health.
  6. The role of the microbiota in respiratory virus-bacterial pathobiont relationships in the upper respiratory tract.
  7. Alveolar and Bone Marrow-derived Macrophages Differ in Metabolism and Glutamine Utilization.
  8. Immunometabolism: signaling pathways, homeostasis, and therapeutic targets.
  9. COQ6 defies immune and metabolic expectations.
  10. Calcium signals as regulators of ferroptosis in cancer.
  11. Recent Advances and Applications of Human Lung Alveolar Organoids.
  12. Neutrophil Elastase Activates Macrophage Calpain as a Mechanism for Phagocytic Failure.
  13. Research progress of probiotics and their protective strategy in the field of inflammatory bowel disease treatment: A review.
  14. Reduce, reinforce, and replenish: safeguarding the early-life microbiota to reduce intergenerational health disparities.
  15. New insights into the immunomodulatory potential of sialic acid on monocyte-derived dendritic cells.
  16. Linking metabolic and epigenetic changes in immune tolerance.
  17. Induction of a distinct macrophage population and protection from lung injury and fibrosis by Notch2 blockade.
  18. Mycobacterium tuberculosis exploits SIRT2 to trap iron for its intracellular survival.
  1. J Leukoc Biol. 2024 Nov 04. pii: qiae241. [Epub ahead of print]
    Resveratrol Potentiates BCG-induced Trained Immunity in Human Monocytes.
    Ozlem Bulut, Ilayda Baydemir, Gizem Kilic, Jorge Domínguez-Andrés, Mihai G Netea.
      Resveratrol is a natural polyphenol derived from plants such as grapes and berries. In addition to its role in plants during injury and infection, various cardioprotective, neuroprotective, and longevity-promoting effects were reported in diverse model organisms. The primary target of resveratrol is the deacetylase Sirtuin 1 (SIRT1), which regulates many immunological processes, including BCG-induced trained immunity response in humans. We, therefore, investigated the effect of resveratrol on trained immunity induced by BCG, β-glucan, C. albicans, or oxidized low-density lipoprotein (oxLDL). Using an in-vitro model of trained immunity with monocytes obtained from healthy donors, we demonstrate that resveratrol amplifies BCG-induced trained immunity regarding IL-6 and TNFα production after a secondary challenge. Although resveratrol did not improve and even limited glycolysis, oxidative phosphorylation, and reactive oxygen species production, it enhanced the permissive epigenetic mark H3K27Ac on IL-6 and TNFα promoters. In contrast to BCG-induced trained immunity, resveratrol potently inhibited training induced by β-glucan, C. albicans, oxLDL, and muramyl dipeptide (MDP), a peptidoglycan component of BCG. Resveratrol's unique boosting effect on BCG training depended on BCG being alive and metabolically active. These results suggest that resveratrol might amplify the effects of BCG vaccination, which should be mechanistically characterized further. In addition, resveratrol could alleviate oxLDL-induced training of innate immune cells in atherosclerosis, and in-vivo studies of trained immunity combined with resveratrol are warranted to explore these therapeutic possibilities.
    Keywords:  BCG; immunometabolism; resveratrol; trained immunity
    DOI:  https://doi.org/10.1093/jleuko/qiae241
  2. iScience. 2024 Nov 15. 27(11): 111063
    Mycobacteria develop biofilms on airway epithelial cells and promote mucosal barrier disruption.
    Amy M Barclay, Dennis K Ninaber, Ronald W A L Limpens, Kimberley V Walburg, Montserrat Bárcena, Pieter S Hiemstra, Tom H M Ottenhoff, Anne M van der Does, Simone A Joosten.
      Tuberculosis displays several features commonly linked to biofilm-associated infections, including recurrence of infection and resistance to antibiotic treatment. The respiratory epithelium represents the first line of defense against pathogens such as Mycobacterium tuberculosis (Mtb). Here, we use an air-liquid interface model of human primary bronchial epithelial cells (PBEC) to explore the capability of four species of mycobacteria (Mtb, M. bovis (BCG), M. avium, and M. smegmatis) to form biofilms on airway epithelial cells. Mtb, BCG, and M. smegmatis consistently formed biofilms with extracellular matrixes on PBEC cultures. Biofilms varied in biomass, matrix polysaccharide content, and bacterial metabolic activity between species. Exposure of PBEC to mycobacteria caused the disruption of the epithelial barrier and was accompanied by mostly apical non-apoptotic cell death. Structural analysis revealed pore-like structures in 7-day biofilms. Taken together, mycobacteria can form biofilms on human airway epithelial cells, and long-term infection negatively affects barrier function and promotes cell death.
    Keywords:  Bacteriology; Clinical microbiology; Medical microbiology; Microbiology
    DOI:  https://doi.org/10.1016/j.isci.2024.111063
  3. Eur J Immunol. 2024 Nov 05. e2350378
    Alveolar epithelial cells shape lipopolysaccharide-induced inflammatory responses and reprogramming of alveolar macrophages.
    Wei Jiang, Yeying Chen, Cheng-Yun Yu, Benkun Zou, Yimeng Lu, Qian Yang, Zihui Tang, Weiying Mao, Jing Li, Han Han, Lingyun Shao, Jiashun Zeng, Yiwei Chu, Jianguo Tang, Mingfang Lu.
      Alveolar macrophages (AMs) are sentinels in the airways, where they sense and respond to invading microbes and other stimuli. Unlike macrophages in other locations, AMs can remain responsive to Gram-negative lipopolysaccharides (LPS) after they have responded to LPS in vivo (they do not develop "endotoxin tolerance"), suggesting that the alveolar microenvironment may influence their responses. Although alveolar epithelial cells (AECs) normally limit AMs' innate responses, preventing inflammation induced by harmless antigens in the lung, how AECs influence the innate responses of AMs to infectious agents has been uncertain. Here we report that (1) after exposure to aspirated (intranasal instillation) LPS, AMs increase their responses to TLR agonists and elevate their phagocytic and bactericidal activities in mice; (2) Aspirated LPS pre-exposure increases host resistance to pulmonary infection caused by Gram-negative bacteria and the protection effect lasts for at least 35 days; (3) LPS stimulation of AECs both increases AMs' innate immune responses and prevents AMs from developing tolerance in vitro; (4) Upon LPS stimulation, AMs secreted TNF-α induces AECs to release GM-CSF, which potentiates AMs' response. These experiments have revealed a previously unappreciated role that AECs may play in boosting the innate responses of AMs and promoting resistance to pulmonary infections.
    Keywords:  Alveolar epithelial cells (AECs); Alveolar macrophages (AMs); Granulocyte‐macrophage colony‐stimulating factor (GM‐CSF); Macrophage reprogramming
    DOI:  https://doi.org/10.1002/eji.202350378
  4. iScience. 2024 Nov 15. 27(11): 111103
    Single high-fat challenge and trained innate immunity: A randomized controlled cross-over trial.
    Julia van Tuijl, Julia I P van Heck, Harsh Bahrar, Wieteke Broeders, Johan Wijma, Yvonne M Ten Have, Martin Giera, Heidi Zweers-van Essen, Laura Rodwell, Leo A B Joosten, Mihai G Netea, Lydia A Afman, Siroon Bekkering, Niels P Riksen.
      Brief exposure of monocytes to atherogenic molecules, such as oxidized lipoproteins, triggers a persistent pro-inflammatory phenotype, named trained immunity. In mice, transient high-fat diet leads to trained immunity, which aggravates atherogenesis. We hypothesized that a single high-fat challenge in humans induces trained immunity. In a randomized controlled cross-over study, 14 healthy individuals received a high-fat or reference shake, and blood was drawn before and after 1, 2, 4, 6, 24, and 72 h. Incubation of donor monocytes with the post-high-fat-shake serum induced trained immunity, regulated via Toll-like receptor 4. This was not mediated via triglyceride-rich lipoproteins, C12, 14, and 16, or metabolic endotoxemia. In vivo, however, the high-fat challenge did not affect monocyte phenotype and function. We conclude that a high-fat challenge leads to alterations in the serum composition that have the potential to induce trained immunity in vitro. However, this does not translate into a (persistent) hyperinflammatory monocyte phenotype in vivo.
    Keywords:  Health sciences; Human Physiology; Human metabolism
    DOI:  https://doi.org/10.1016/j.isci.2024.111103
  5. Int J Biol Macromol. 2024 Oct 25. pii: S0141-8130(24)07741-9. [Epub ahead of print] 136932
    Glycans in the oral bacteria and fungi: Shaping host-microbe interactions and human health.
    Xiameng Ren, Min Wang, Jiabao Du, Yu Dai, Liuyi Dang, Zheng Li, Jian Shu.
      The human oral cavity serves as the natural entry port to both the gastrointestinal and respiratory tracts, and hosts a diverse microbial community essential for maintaining health. Dysbiosis of this microbiome can lead to various diseases. Glycans, as vital carriers of biological information, are indispensable structural components of living organisms and play key roles in numerous biological processes. In the oral microbiome, glycans influence microbial binding to host receptors, promote colonization, and mediate communication among microbial communities, as well as between microbes and the host immune system. Targeting glycans may provide innovative strategies for modulating the composition of the oral microbiome, with broader implications for human health. Additionally, exogenous glycans regulate the oral microbiome by serving as carbon and energy sources for microbes, while certain specific glycans can inhibit microbial growth and activity. This review summarizes glycosylation pathways in oral bacteria and fungi, explores the regulation of host-microbiota interactions by glycans, and discusses the effects of exogenous glycans on oral microbiome. The review aims to highlight the multifaceted role of glycans in shaping the oral microbiome and its impact on the host, while also indicates potential future applications.
    Keywords:  Glycan-mediated interactions; Glycans; Glycoside hydrolases; Glycosyltransferase; Microbe-host interactions; Oral bacteria; Oral fungi
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.136932
  6. medRxiv. 2024 Oct 23. pii: 2024.10.22.24315478. [Epub ahead of print]
    The role of the microbiota in respiratory virus-bacterial pathobiont relationships in the upper respiratory tract.
    Matthew S Kelly, Pixu Shi, Sefelani C Boiditswe, Emily Qin, Andrew P Steenhoff, Tiny Mazhani, Mohamed Z Patel, Coleen K Cunningham, John F Rawls, Kathy Luinstra, Jodi Gilchrist, Julia Maciejewski, Jillian H Hurst, Patrick C Seed, David Bulir, Marek Smieja.
      The mechanisms by which respiratory viruses predispose to secondary bacterial infections remain poorly characterized. Using 2,409 nasopharyngeal swabs from 300 infants in Botswana, we performed a detailed analysis of factors that influence the dynamics of bacterial pathobiont colonization during infancy. We quantify the extent to which viruses increase the acquisition of Haemophilus influenzae , Moraxella catarrhalis , and Streptococcus pneumoniae . We provide evidence of cooperative interactions between these pathobionts while identifying host characteristics and environmental exposures that influence the odds of pathobiont colonization during early life. Using 16S rRNA gene sequencing, we demonstrate that respiratory viruses result in losses of putatively beneficial Corynebacterium and Streptococcus species that are associated with a lower odds of pathobiont acquisition. These findings provide novel insights into viral-bacterial relationships in the URT of direct relevance to respiratory infections and suggest that the URT bacterial microbiota is a potentially modifiable mechanism by which viruses promote bacterial respiratory infections.
    DOI:  https://doi.org/10.1101/2024.10.22.24315478
  7. Am J Respir Cell Mol Biol. 2024 Nov 05.
    Alveolar and Bone Marrow-derived Macrophages Differ in Metabolism and Glutamine Utilization.
    Christine L Vigeland, Jordan D Link, Henry S Beggs, Yazan Alwarawrah, Brandie M Ehrmann, Hong Dang, Claire M Doerschuk.
      Changes in metabolic activity are key regulators of macrophage activity. Pro-inflammatory macrophages upregulate glycolysis, which promotes an inflammatory phenotype, whereas pro-repair macrophages rely upon oxidative metabolism and glutaminolysis to support their activity. Work to understand how metabolism regulates macrophage phenotype has been done primarily in macrophage cell lines and bone marrow-derived macrophages (BMDM). Our study sought to understand changes in metabolic activity of murine tissue-resident alveolar macrophages (AM) in response to LPS stimulation and to contrast them to BMDM. These studies also determined the contribution of glutamine metabolism using the glutamine inhibitor, DON. We found that compared to BMDM, AM have higher rates of oxygen consumption and contain a higher concentration of intracellular metabolites involved in fatty acid oxidation. In response to LPS, BMDM but not AM increased rates of glycolysis. Inhibition of glutamine metabolism using DON altered the metabolic activity of AM but not BMDM. Within AM, glutamine inhibition led to increases in intracellular metabolites involved in glycolysis, the TCA cycle, fatty acid oxidation, and amino acid metabolism. Glutamine inhibition also altered the metabolic response to LPS within AM but not BMDM. Our data reveal striking differences in the metabolic activity of AM and BMDM.
    Keywords:  glutamine; glycolysis; lipids; macrophage; metabolomics
    DOI:  https://doi.org/10.1165/rcmb.2023-0249OC
  8. MedComm (2020). 2024 Nov;5(11): e789
    Immunometabolism: signaling pathways, homeostasis, and therapeutic targets.
    Rongrong Xu, Xiaobo He, Jia Xu, Ganjun Yu, Yanfeng Wu.
      Immunometabolism plays a central role in sustaining immune system functionality and preserving physiological homeostasis within the organism. During the differentiation and activation, immune cells undergo metabolic reprogramming mediated by complex signaling pathways. Immune cells maintain homeostasis and are influenced by metabolic microenvironmental cues. A series of immunometabolic enzymes modulate immune cell function by metabolizing nutrients and accumulating metabolic products. These enzymes reverse immune cells' differentiation, disrupt intracellular signaling pathways, and regulate immune responses, thereby influencing disease progression. The huge population of immune metabolic enzymes, the ubiquity, and the complexity of metabolic regulation have kept the immune metabolic mechanisms related to many diseases from being discovered, and what has been revealed so far is only the tip of the iceberg. This review comprehensively summarized the immune metabolic enzymes' role in multiple immune cells such as T cells, macrophages, natural killer cells, and dendritic cells. By classifying and dissecting the immunometabolism mechanisms and the implications in diseases, summarizing and analyzing advancements in research and clinical applications of the inhibitors targeting these enzymes, this review is intended to provide a new perspective concerning immune metabolic enzymes for understanding the immune system, and offer novel insight into future therapeutic interventions.
    Keywords:  checkpoint; homeostasis; immune cells; immunometabolic enzymes; immunometabolism
    DOI:  https://doi.org/10.1002/mco2.789
  9. Nat Immunol. 2024 Nov 04.
    COQ6 defies immune and metabolic expectations.
    Samuel E Weinberg, Navdeep S Chandel.
      
    DOI:  https://doi.org/10.1038/s41590-024-02005-6
  10. Cell Calcium. 2024 Oct 29. pii: S0143-4160(24)00124-6. [Epub ahead of print]124 102966
    Calcium signals as regulators of ferroptosis in cancer.
    Ioana Stejerean-Todoran, Christine S Gibhardt, Ivan Bogeski.
      The field of ferroptosis research has grown exponentially since this form of cell death was first identified over a decade ago. Ferroptosis, an iron- and ROS-dependent type of cell death, is controlled by various metabolic pathways, including but not limited to redox and calcium (Ca2+) homeostasis, iron fluxes, mitochondrial function and lipid metabolism. Importantly, therapy-resistant tumors are particularly susceptible to ferroptotic cell death, rendering ferroptosis a promising therapeutic strategy against numerous malignancies. Calcium signals are important regulators of both cancer progression and cell death, with recent studies indicating their involvement in ferroptosis. Cells undergoing ferroptosis are characterized by plasma membrane rupture and the formation of nanopores, which facilitate influx of ions such as Ca2+ into the affected cells. Furthermore, mitochondrial Ca²⁺ levels have been implicated in directly influencing the cellular response to ferroptosis. Despite the remarkable progress made in the field, our understanding of the contribution of Ca2+ signals to ferroptosis remains limited. Here, we summarize key connections between Ca²⁺ signaling and ferroptosis in cancer pathobiology and discuss their potential therapeutic significance.
    Keywords:  Calcium; Cancer; Ferroptosis; Mitochondria; ROS
    DOI:  https://doi.org/10.1016/j.ceca.2024.102966
  11. Mol Cells. 2024 Oct 25. pii: S1016-8478(24)00165-1. [Epub ahead of print] 100140
    Recent Advances and Applications of Human Lung Alveolar Organoids.
    Sun Kyung Kim, Eunho Sung, Kyungtae Lim.
      Human lung alveolus is a well-structured and coordinated pulmonary unit, allowing them to perform diverse functions. While there has been significant progress in understanding the molecular and cellular mechanisms behind human alveolar development and pulmonary diseases, the underlying mechanisms of alveolar differentiation and disease development are still unclear, mainly due to the limited availability of human tissues and a lack of proper in vitro lung model systems mimicking human lung physiology. In this review, we summarise recent advances in creating human lung organoid models that mimic alveolar epithelial cell types. Moreover, we discuss how lung alveolar organoid systems are being applied to recent cutting-edge research on lung development, regeneration, and diseases.
    Keywords:  Human lung biology; gene editing; lung development and disease; lung organoid modelling; single-cell technology; stem/progenitor cell
    DOI:  https://doi.org/10.1016/j.mocell.2024.100140
  12. Am J Physiol Lung Cell Mol Physiol. 2024 Nov 05.
    Neutrophil Elastase Activates Macrophage Calpain as a Mechanism for Phagocytic Failure.
    Jonathan Ma, Apparao B Kummarapurugu, Shuo Zheng, Andrew J Ghio, Laxmikant S Deshpande, Judith A Voynow.
      Neutrophil elastase (NE), elevated in the cystic fibrosis (CF) airway, causes macrophage phagocytic failure. We previously reported that NE increases the release of protease Calpain-2 in macrophages. We hypothesized that NE mediates macrophage failure through activation of Calpains. We demonstrate that Calpain inhibition rescued NE induced macrophage phagocytic failure in murine alveolar macrophages in both cftr-null and wild type genotypes. We then sought to determine how NE regulates Calpain-2. Human monocyte derived macrophages (hMDM) from persons with CF (PwCF) and non-CF subjects, were treated with NE or control vehicle and cell lysates prepared to evaluate Calpain-2 protein abundance by Western, and Calpain activity by a specific activity kit. Calpain is activated by intracellular calcium and inactivated by an endogenous inhibitor, Calpastatin. Human MDM were thus treated with NE or control vehicle and cell lysates were analyzed for increased intracellular calcium by Fluo-4 assay and for Calpastatin protein abundance by Western. NE increased Calpain-2 protein and activity, degraded Calpastatin, and increased intracellular calcium in macrophages. At baseline there are no differences in Calpain activity, Calpain-2 and Calpastatin expression, and intracellular calcium between CF and non-CF macrophages. NE increased macrophage Calpain-2 protein and Calpain activity by two potential mechanisms: degradation of Calpastatin, and/or increased intracellular calcium. In summary, Calpain inhibition restored NE-induced macrophage phagocytic failure suggesting a potential CFTR-independent target for phagocytic failure in the CF airway.
    Keywords:  Calpain-2; Calpastatin; cystic fibrosis; macrophage; phagocytosis
    DOI:  https://doi.org/10.1152/ajplung.00132.2024
  13. Medicine (Baltimore). 2024 Nov 01. 103(44): e40401
    Research progress of probiotics and their protective strategy in the field of inflammatory bowel disease treatment: A review.
    Ming Xiong, Wanlei Sun.
      Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disease characterized by recurrent episodes and difficult-to-cure symptoms. Although the pathogenesis of IBD is closely related to host genetic susceptibility, intestinal microbiota, environmental factors, and immune responses, leading to mucosal damage and increased intestinal permeability. Intestinal mucosal injury in IBD patients causes pathogenic bacteria and pathogenic factors to invade the intestine, leading to disturb the structure and metabolic products of intestinal flora. Researchers have found that probiotics, as live microbial agents, can effectively inhibit the growth of pathogenic bacteria, regulate intestinal flora, optimize intestinal microecology, restore intestinal homeostasis, and promote intestinal mucosal repairing. During the oral delivery process, probiotics are susceptible to adverse physiological factors, leading to reduced bioavailability. Additionally, the oxidative stress microenvironment induced by intestinal mucosal damage makes it difficult for probiotics to colonize the intestinal tract of IBD patients, thereby affecting their probiotic effect. This research mainly introduces and reviews the advantages and disadvantages of probiotics and their protective strategies in the treatment of IBD, and prospects the future development trends of probiotics and their protective strategies. Probiotics can effectively inhibit the growth of harmful microorganisms, regulate the structure of the intestinal microbiota, and promote mucosal repairing, thereby reducing immune stress and alleviating intestinal inflammation, providing a new perspective for the treatment of IBD. The development of single-cell encapsulation technology not only effectively maintaining the biological activity of probiotics during oral delivery, but also endowing probiotics with additional biological functions naturally achieved through surface programming, which has multiple benefits for intestinal health.
    DOI:  https://doi.org/10.1097/MD.0000000000040401
  14. Front Public Health. 2024 ;12 1455503
    Reduce, reinforce, and replenish: safeguarding the early-life microbiota to reduce intergenerational health disparities.
    Darlene L Y Dai, Charisse Petersen, Stuart E Turvey.
      Socioeconomic (SE) disparity and health inequity are closely intertwined and associated with cross-generational increases in the rates of multiple chronic non-communicable diseases (NCDs) in North America and beyond. Coinciding with this social trend is an observed loss of biodiversity within the community of colonizing microbes that live in and on our bodies. Researchers have rightfully pointed to the microbiota as a key modifiable factor with the potential to ease existing health inequities. Although a number of studies have connected the adult microbiome to socioeconomic determinants and health outcomes, few studies have investigated the role of the infant microbiome in perpetuating these outcomes across generations. It is an essential and important question as the infant microbiota is highly sensitive to external forces, and observed shifts during this critical window often portend long-term outcomes of health and disease. While this is often studied in the context of direct modulators, such as delivery mode, family size, antibiotic exposure, and breastfeeding, many of these factors are tied to underlying socioeconomic and/or cross-generational factors. Exploring cross-generational socioeconomic and health inequities through the lens of the infant microbiome may provide valuable avenues to break these intergenerational cycles. In this review, we will focus on the impact of social inequality in infant microbiome development and discuss the benefits of prioritizing and restoring early-life microbiota maturation for reducing intergenerational health disparities.
    Keywords:  SES inequity; early-life exposures; health disparity; intergenerational factors; microbiota; socioeconomic status
    DOI:  https://doi.org/10.3389/fpubh.2024.1455503
  15. Cancer Immunol Immunother. 2024 Nov 02. 74(1): 9
    New insights into the immunomodulatory potential of sialic acid on monocyte-derived dendritic cells.
    Zélia Silva, João Amorim Rabaça, Vanessa Luz, Rita Adubeiro Lourenço, Mariolina Salio, Alexandra Couto Oliveira, Pedro Bule, Sebastian Springer, Paula Alexandra Videira.
      Sialic acids at the cell surface of dendritic cells (DCs) play an important immunomodulatory role, and their manipulation enhances DC maturation, leading to heightened T cell activation. Particularly, at the molecular level, the increased stability of surface MHC-I molecules in monocyte-derived DCs (MoDCs) underpins an improved DC: T cell interaction. In this study, we focused on the impact of sialic acid remodelling by treatment with Clostridium perfringens sialidase on MoDCs' phenotypic and functional characteristics. Our investigation juxtaposes this novel approach with the conventional cytokine-based maturation regimen commonly employed in clinical settings.Notably, C. perfringens sialidase remarkably increased MHC-I levels compared to other sialidases having different specificities, supporting the idea that higher MHC-I is due to the cleavage of specific sialoglycans on cell surface proteins. Sialidase treatment induced rapid elevated surface expression of MHC-I, MHC-II and CD40 within an hour, a response not fully replicated by 48 h cytokine cocktail treatment. These increases were also observable 48 h post sialidase treatment. While CD86 and PD-L1 showed significant increases after 48 h of cytokine maturation, 48 h post sialidase treatment showed a higher increase in CD86 and shorter increase in PD-L1. CCR-7 expression was significantly increased 48 h after sialidase treatment but not significantly affected by cytokine maturation. Both treatments promoted higher secretion of the IL-12 cytokine. However, the cytokine cocktail induced a more pronounced IL-12 production. SNA lectin staining analysis demonstrated that the sialic acid profile is significantly altered by sialidase treatment, but not by the cytokine cocktail, which causes only slight sialic acid upregulation. Notably, the lipid-presenting molecules CD1a, CD1b and CD1c remained unaffected by sialidase treatment in MoDCs, a finding also further supported by experiments performed on C1R cells. Inhibition of endogenous sialidases Neu1 and Neu3 during MoDC differentiation did not affect surface MHC-I expression and cytokine secretion. Yet, sialidase activity in MoDCs was minimal, suggesting that sialidase inhibition does not significantly alter MHC-I-related functions. Our study highlights the unique maturation profile induced by sialic acid manipulation in MoDCs. These findings provide insights into the potential of sialic acid manipulation as a rapid immunomodulatory strategy, offering promising avenues for targeted interventions in inflammatory contexts.
    Keywords:  Antigen presentation; Dendritic cells; Immunomodulation; MHC-I; Sialic acid
    DOI:  https://doi.org/10.1007/s00262-024-03863-7
  16. Proc Natl Acad Sci U S A. 2024 Nov 12. 121(46): e2419751121
    Linking metabolic and epigenetic changes in immune tolerance.
    Frederick J Sheedy, Eva Kaufmann.
      
    DOI:  https://doi.org/10.1073/pnas.2419751121
  17. Nat Commun. 2024 Nov 06. 15(1): 9575
    Induction of a distinct macrophage population and protection from lung injury and fibrosis by Notch2 blockade.
    Mayra Cruz Tleugabulova, Sandra P Melo, Aaron Wong, Alexander Arlantico, Meizi Liu, Joshua D Webster, Julia Lau, Antonie Lechner, Basak Corak, Jonathan J Hodgins, Venkata S Garlapati, Marco De Simone, Ben Korin, Shimrit Avraham, Jessica Lund, Surinder Jeet, Alexander Reiss, Hannah Bender, Cary D Austin, Spyros Darmanis, Zora Modrusan, Hans Brightbill, Steffen Durinck, Michael S Diamond, Christoph Schneider, Andrey S Shaw, Maximilian Nitschké.
      Macrophages are pleiotropic and diverse cells that populate all tissues of the body. Besides tissue-specific resident macrophages such as alveolar macrophages, Kupffer cells, and microglia, multiple organs harbor at least two subtypes of other resident macrophages at steady state. During certain circumstances, like tissue insult, additional subtypes of macrophages are recruited to the tissue from the monocyte pool. Previously, a recruited macrophage population marked by expression of Spp1, Cd9, Gpnmb, Fabp5, and Trem2, has been described in several models of organ injury and cancer, and has been linked to fibrosis in mice and humans. Here, we show that Notch2 blockade, given systemically or locally, leads to an increase in this putative pro-fibrotic macrophage in the lung and that this macrophage state can only be adopted by monocytically derived cells and not resident alveolar macrophages. Using a bleomycin and COVID-19 model of lung injury and fibrosis, we find that the expansion of these macrophages before lung injury does not promote fibrosis but rather appears to ameliorate it. This suggests that these damage-associated macrophages are not, by themselves, drivers of fibrosis in the lung.
    DOI:  https://doi.org/10.1038/s41467-024-53700-9
  18. Free Radic Biol Med. 2024 Oct 28. pii: S0891-5849(24)01008-6. [Epub ahead of print]225 794-804
    Mycobacterium tuberculosis exploits SIRT2 to trap iron for its intracellular survival.
    Sharmila Talukdar, Radheshyam Modanwal, Gaurav Kumar Chaubey, Asmita Dhiman, Rahul Dilawari, Chaaya Iyengar Raje, Manoj Raje.
      Iron is a critical nutrient for all organisms ranging from bacteria to humans. Ensuring control of this strategic vital resource significantly influences the dynamics of the struggle between host and invading pathogen. Mycobacterium tuberculosis (Mtb), the causative agent of the pulmonary disease tuberculosis (TB), has been plaguing humans for millennia and has evolved to successfully persist and multiply within host cells evading the mammalian immune defences. Invading Mtb appropriates host iron for its survival while the host innate immune response attempts to prevent its stores of this strategic mineral from being appropriated. SIRT2 is a member of the Sirtuin family. These are evolutionary conserved NAD+-dependent deacetylases involved in various cellular processes including regulation of cellular iron homeostasis. Upon Mtb infection of macrophages, SIRT2 expression is enhanced and it translocates from cytosol to nucleus. This is accompanied with a breakdown of the host's iron restriction strategy that compromises host defence mechanisms. However, the underlying mechanism as to how invading Mtb exploits SIRT2 for commandeering host iron remains unknown. In the current study, we report that the decreased bacillary load in cells wherein SIRT2 had been chemically inhibited or knocked down is due to diminished availability of iron. Inhibition or knockdown of SIRT2 in infected cells displays differential modulation of iron import and export proteins suggesting an ongoing struggle by host to limit the bioavailability of iron to pathogen. Flow cytometry analysis of infected macrophages revealed that these cells utilize a non-canonical pathway for evacuation of intracellular iron. This involves the recruitment of a specific pleioform of the moonlighting protein glyceraldehyde-3 phosphate dehydrogenase (GAPDH) to cell surface for capture of iron transporter protein apo-transferrin. Collectively, our findings reveal the process of SIRT2-mediated iron regulation in Mtb pathogenesis and could provide leads for design of novel host-targeted therapeutics.
    Keywords:  ApoTf; Flow cytometry; GAPDH; Iron; Mtb; Pathogenesis; Sirtuin 2
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.10.300
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