bims-traimu 2024-05-26 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2024–05–26
ten papers selected by
Yantong Wan, Southern Medical University

Bacille Calmette-Guérin vaccination to prevent febrile and respiratory illness in adults (BRACE): secondary outcomes of a randomised controlled phase 3 trial.
Immunogenicity and efficacy of CNA25 as a potential whole-cell vaccine against systemic candidiasis.
β-Glucan Subverts the Function of Myeloid Cells in Neonates.
Generation of specific immune memory by bacterial exposure in the major malaria vector Anopheles arabiensis (Diptera: Culicidae).
Melatonin alleviates septic ARDS by inhibiting NCOA4-mediated ferritinophagy in alveolar macrophages.
Disruption of TIGAR-TAK1 alleviates immunopathology in a murine model of sepsis.
Lipopolysaccharide pretreatment increases the sensitivity of the TRPV1 channel and promotes an anti-inflammatory phenotype of capsaicin-activated macrophages.
IRG1/itaconate alleviates acute liver injury in septic mice by suppressing NLRP3 expression and its mediated macrophage pyroptosis via regulation of the Nrf2 pathway.
LPS exposure alleviates multiple tissues damage by facilitating macrophage efferocytosis.
Pathways for macrophage uptake of cell-free circular RNAs.

EClinicalMedicine. 2024 Jun;72 102616

Bacille Calmette-Guérin vaccination to prevent febrile and respiratory illness in adults (BRACE): secondary outcomes of a randomised controlled phase 3 trial.

BRACE Trial Consortium Group

   Background: Bacille Calmette-Guérin (BCG) vaccination has off-target (non-specific) effects that are associated with protection against unrelated infections and decreased all-cause mortality in infants. We aimed to determine whether BCG vaccination prevents febrile and respiratory infections in adults.
Methods: This randomised controlled phase 3 trial was done in 36 healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom. Healthcare workers were randomised to receive BCG-Denmark (single 0.1 ml intradermal injection) or no BCG in a 1:1 ratio using a web-based procedure, stratified by stage, site, age, and presence of co-morbidity. The difference in occurrence of febrile or respiratory illness were measured over 12 months (prespecified secondary outcome) using the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, NCT04327206.
Findings: Between March 30, 2020, and April 1, 2021, 6828 healthcare workers were randomised to BCG-Denmark (n = 3417) or control (n = 3411; no intervention or placebo) groups. The 12-month adjusted estimated risk of ≥1 episode of febrile or respiratory illness was 66.8% in the BCG group (95% CI 65.3%-68.2%), compared with 63.4% in the control group (95% CI 61.8%-65.0%), a difference of +3.4 percentage points (95% CI +1.3% to +5.5%; p 0.002). The adjusted estimated risk of a severe episode (defined as being incapacitated for ≥3 consecutive days or hospitalised) was 19.4% in the BCG group (95% CI 18.0%-20.7%), compared with 18.8% in the control group (95% CI 17.4%-20.2%) a difference of +0.6 percentage points (95% CI -1.3% to +2.5%; p 0.6). Both groups had a similar number of episodes of illness, pneumonia, and hospitalisation. There were three deaths, all in the control group. There were no safety concerns following BCG vaccination.
Interpretation: In contrast to the beneficial off-target effects reported following neonatal BCG in infants, a small increased risk of symptomatic febrile or respiratory illness was observed in the 12 months following BCG vaccination in adults. There was no evidence of a difference in the risk of severe disease.
Funding: Bill & Melinda Gates Foundation, Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, the National Health and Medical Research Council, the Swiss National Science Foundation and individual donors.

Keywords:  Bacille Calmette-Guérin (BCG) vaccine; Health personnel; Heterologous; Immunity; Placebo; Primary prevention; Randomised controlled trial

DOI:  https://doi.org/10.1016/j.eclinm.2024.102616
EMBO Mol Med. 2024 May 23.

Immunogenicity and efficacy of CNA25 as a potential whole-cell vaccine against systemic candidiasis.

Satya Ranjan Sahu, Abinash Dutta, Doureradjou Peroumal, Premlata Kumari, Bhabasha Gyanadeep Utakalaja, Shraddheya Kumar Patel, Narottam Acharya.

  Disseminated fungal infections account for ~1.5 million deaths per year worldwide, and mortality may increase further due to a rise in the number of immunocompromised individuals and drug-resistance fungal species. Since an approved antifungal vaccine is yet to be available, this study explored the immunogenicity and vaccine efficacy of a DNA polymerase mutant strain of Candida albicans. CNA25 is a pol32ΔΔ strain that exhibits growth defects and does not cause systemic candidiasis in mice. Immunized mice with live CNA25 were fully protected against C. albicans and C. parapsilosis but partially against C. tropicalis and C. glabrata infections. CNA25 induced steady expression of TLR2 and Dectin-1 receptors leading to a faster recognition and clearance by the immune system associated with the activation of protective immune responses mostly mediated by neutrophils, macrophages, NK cells, B cells, and CD4+ and CD8+ T cells. Molecular blockade of Dectin-1, IL-17, IFNγ, and TNFα abolished resistance to reinfection. Altogether, this study suggested that CNA25 collectively activates innate, adaptive, and trained immunity to be a promising live whole-cell vaccine against systemic candidiasis.

Keywords:  Antifungal Vaccine; Cytokines; Dectin-1; Neutrophils; Trained Immunity

DOI:  https://doi.org/10.1038/s44321-024-00080-8
J Immunol Res. 2024 ;2024 2765001

β-Glucan Subverts the Function of Myeloid Cells in Neonates.

Yingying Chen, Hui Li, Lin Zhu, Quan Yang, Jie Zhou.

β-Glucan is the main component of the cell wall of pathogen-associated molecular patterns (PAMPs) including various yeast, fungi, or certain bacteria. Previous reports demonstrated that β-glucan was widely investigated as a potent immunomodulators to stimulate innate and adaptive immune responses, which indicated that it could be recommended as an effective adjuvant in immunotherapy. However, the detailed effects of β-glucan on neonatal immunity are still largely unknown. Here, we found that β-glucan did not affect the frequencies and numbers of myeloid cells in the spleen and bone marrow from neonates. Functional assay revealed that β-glucan from neonates compromised the immunosuppressive function of immature myeloid cells, which were myeloid-derived suppressor cells (MDSCs). Flow cytometry or gene expression analysis revealed that β-glucan-derived polymorphonuclear (PMN)-MDSCs produced lower level of reactive oxygen species (ROS) and arginase-1 (Arg1) in neonatal mice. Furthermore, β-glucan administration significantly decreased the frequency and ROS level of PMN-MDSCs in vitro. These observations suggest that β-glucan facilitates the maturation of myeloid cells in early life, which may contribute to its beneficial effects against immune disorders later in life.

DOI: https://doi.org/10.1155/2024/2765001
Curr Res Insect Sci. 2024 ;5 100085

Generation of specific immune memory by bacterial exposure in the major malaria vector Anopheles arabiensis (Diptera: Culicidae).

Nashrin F Patel, Shüné V Oliver.

  There is a growing body of evidence that invertebrates can generate improved secondary responses after a primary challenge. This immunological memory can be primed by a range of pathogens, including bacteria. The generation of immunological memory has been demonstrated in mosquitoes, with the memory primed by a range of initial stimuli. This study aimed to examine whether insecticide resistance affects the capacity to generate immunological memory. The primary hypothesis was tested by examining the capacity of genetically related laboratory-reared Anopheles arabiensis strains that differ by insecticide resistant phenotype to generate immunological memory. The competing hypothesis tested was that the bacterial virulence was the key determinant in generating immunological memory. Immune memory was generated in F1 females but not males. Immunological memory was demonstrated in both laboratory strains, but the efficacy differed by the insecticide resistant phenotype of the strain. An initial oral challenge provided by a blood meal resulted generated better memory than an oral challenge by sugar. The efficacy of memory generation between the two bacterial strains differed between the two mosquito strains. Regardless of the challenge, the two strains differed in their capacity to generate memory. This study therefore demonstrated that insecticide resistant phenotype affected the capacity of the two strains to generate immunological memory. Although this study needs to be replicated with wild mosquitoes, it does suggest that a potential role for insecticide resistance in the functioning of the immune system and memory generation of An. arabiensis.

Keywords:  Immune memory; Insecticide resistance; Priming; Transgenerational

DOI:  https://doi.org/10.1016/j.cris.2024.100085
Cell Death Discov. 2024 May 24. 10(1): 253

Melatonin alleviates septic ARDS by inhibiting NCOA4-mediated ferritinophagy in alveolar macrophages.

Wenting Xu, Yutong Wu, Sheng Wang, Song Hu, Yu Wang, Wenyu Zhou, Yuanli Chen, Quanfu Li, Lina Zhu, Hao Yang, Xin Lv.

Ferroptosis is a novel form of programmed cell death which can exacerbate lung injury in septic acute respiratory distress syndrome (ARDS). Alveolar macrophages, crucial innate immune cells, play a pivotal role in the pathogenesis of ARDS. Ferritinophagy is a process of ferritin degradation mediated by nuclear receptor coactivator 4 (NCOA4) which releases large amounts of iron ions thus promoting ferroptosis. Recent evidence revealed that inhibiting macrophage ferroptosis can effectively attenuate pulmonary inflammatory injury. Melatonin (MT), an endogenous neurohormone, has antioxidant and anti-inflammatory effects and can reduce septic ARDS. However, it is not clear whether MT's pulmonary protective effect is related to the inhibition of macrophage ferritinophagy. Our in vitro experiments demonstrated that MT decreased intracellular malondialdehyde (MDA), Fe2+, and lipid peroxidation levels, increased glutathione (GSH) levels and cell proliferation, and upregulated glutathione peroxidase 4 (GPX4) and ferritin heavy chain 1 (FTH1) protein levels in LPS-treated macrophages. Mechanistically, the antiferroptotic effect of MT on LPS-treated macrophages was significantly compromised by the overexpression of NCOA4. Our in vivo experiments revealed that MT alleviated the protein expression of NCOA4 and FTH1 in the alveolar macrophages of septic mice. Furthermore, MT improved lipid peroxidation and mitigated damage in alveolar macrophages and lung tissue, ultimately increasing the survival rates of septic mice. These findings indicate that MT can inhibit ferroptosis in an NCOA4-mediated ferritinophagy manner, thereby ameliorating septic ARDS.

DOI: https://doi.org/10.1038/s41420-024-01991-8
Nat Commun. 2024 May 21. 15(1): 4340

Disruption of TIGAR-TAK1 alleviates immunopathology in a murine model of sepsis.

Dongdong Wang, Yanxia Li, Hao Yang, Xiaoqi Shen, Xiaolin Shi, Chenyu Li, Yongjing Zhang, Xiaoyu Liu, Bin Jiang, Xudong Zhu, Hanwen Zhang, Xiaoyu Li, Hui Bai, Qing Yang, Wei Gao, Fang Bai, Yong Ji, Qi Chen, Jingjing Ben.

Macrophage-orchestrated inflammation contributes to multiple diseases including sepsis. However, the underlying mechanisms remain to be defined clearly. Here, we show that macrophage TP53-induced glycolysis and apoptosis regulator (TIGAR) is up-regulated in murine sepsis models. When myeloid Tigar is ablated, sepsis induced by either lipopolysaccharide treatment or cecal ligation puncture in male mice is attenuated via inflammation inhibition. Mechanistic characterizations indicate that TIGAR directly binds to transforming growth factor β-activated kinase (TAK1) and promotes tumor necrosis factor receptor-associated factor 6-mediated ubiquitination and auto-phosphorylation of TAK1, in which residues 152-161 of TIGAR constitute crucial motif independent of its phosphatase activity. Interference with the binding of TIGAR to TAK1 by 5Z-7-oxozeaenol exhibits therapeutic effects in male murine model of sepsis. These findings demonstrate a non-canonical function of macrophage TIGAR in promoting inflammation, and confer a potential therapeutic target for sepsis by disruption of TIGAR-TAK1 interaction.

DOI: https://doi.org/10.1038/s41467-024-48708-0
J Inflamm (Lond). 2024 May 24. 21(1): 17

Lipopolysaccharide pretreatment increases the sensitivity of the TRPV1 channel and promotes an anti-inflammatory phenotype of capsaicin-activated macrophages.

Daniel Vašek, Natálie Fikarová, Vendula Nagy Marková, Ondřej Honc, Lenka Pacáková, Bianka Porubská, Veronika Somova, Jiří Novotný, Barbora Melkes, Magdaléna Krulová.

   BACKGROUND: The transient receptor potential vanilloid 1 (TRPV1) is well-established in neuronal function, yet its role in immune reactions remains enigmatic. The conflicting data on its inflammatory role, suggesting both pro-inflammatory and anti-inflammatory effects upon TRPV1 stimulation in immune cells, adds complexity. To unravel TRPV1 immunomodulatory mechanisms, we investigated how the TRPV1 agonist capsaicin influences lipopolysaccharide (LPS)-induced pro-inflammatory macrophage phenotypes.
RESULTS: Changes in the surface molecules, cytokine production, and signaling cascades linked to the phenotype of M1 or M2 macrophages of the J774 macrophage cell line and bone marrow-derived macrophages, treated with capsaicin before or after the LPS-induced inflammatory reaction were determined. The functional capacity of macrophages was also assessed by infecting the stimulated macrophages with the intracellular parasite Leishmania mexicana.
CONCLUSION: Our findings reveal that TRPV1 activation yields distinct macrophage responses influenced by the inflammatory context. LPS pre-treatment followed by capsaicin activation prompted increased calcium influx, accompanied by a shift toward an anti-inflammatory M2b-like polarization state.

Keywords:  Capsaicin; Inflammation; Macrophages; TRPV1

DOI:  https://doi.org/10.1186/s12950-024-00391-0
Int Immunopharmacol. 2024 May 22. pii: S1567-5769(24)00797-5. [Epub ahead of print]135 112277

IRG1/itaconate alleviates acute liver injury in septic mice by suppressing NLRP3 expression and its mediated macrophage pyroptosis via regulation of the Nrf2 pathway.

Pei Zhou, Lei Yang, Ruidong Li, Yuping Yin, Gengchen Xie, Xinghua Liu, Liang Shi, Kaixiong Tao, Peng Zhang.

  Sepsis, a systemic inflammatory response triggered by infection, has a considerably high mortality rate. However, effective prevention and intervention measures against sepsis remain insufficient. Therefore, this study aimed to investigate the mechanisms underlying the protective properties of immune response gene-1 (IRG1) and 4-Octyl itaconate (OI) during acute liver damage in mice with sepsis. A sepsis mouse model was established to compare wild-type and IRG1-/- groups. The impact of IRG1/Itaconate on pro- and anti-inflammatory cytokines was evaluated using J774A.1 cells. IRG1/Itaconate substantially reduced pro-inflammatory cytokines and increased the release of anti-inflammatory cytokines. It reduced pathological damage to liver tissues, preserved normal liver function, decreased the release of reactive oxygen species (ROS) and LDH, and enhanced the GSH/GSSG ratio. Moreover, IRG1 and itaconic acid activated the Nrf2 signaling pathway, regulating the expression of its downstream antioxidative stress-related proteins. Additionally, they inhibited the activity of NLRP3 inflammatory vesicles to suppress the expression of macrophage-associated pyroptosis signaling molecules. Our findings demonstrate that IRG1/OI inhibits NLRP3 inflammatory vesicle activation and macrophage pyroptosis by modulating the Nrf2 signaling pathway, thereby attenuating acute liver injury in mice with sepsis. These findings could facilitate the clinical application of IRG1/Itaconate to prevent sepsis-induced acute liver injury.

Keywords:  Acute liver injury; IRG1; NLRP3; Nrf2; Pyroptosis; Sepsis

DOI:  https://doi.org/10.1016/j.intimp.2024.112277
Int Immunopharmacol. 2024 May 20. pii: S1567-5769(24)00803-8. [Epub ahead of print]135 112283

LPS exposure alleviates multiple tissues damage by facilitating macrophage efferocytosis.

Yuwen Han, Jiukun Hu, Jinlin Pan, Xueyan Song, Yuanshuai Zhou, Jun Zhang, Yue Yang, Xiaohua Shi, Minxuan Sun, Jiao Yang.

  Toll-like receptors (TLRs) play a crucial role in mediating immune responses by recognizing pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), as well as facilitating apoptotic cell (ACs) clearance (efferocytosis), thus contributing significantly to maintaining homeostasis and promoting tissue resolution. In this study, we investigate the impact of TLR agonists on macrophage efferocytosis. Our findings demonstrate that pretreatment with the TLR agonist lipopolysaccharide (LPS) significantly enhances macrophage phagocytic ability, thereby promoting efferocytosis both in vitro and in vivo. Moreover, LPS pretreatment confers tissue protection against damage by augmenting macrophage efferocytic capacity in murine models. Further examination reveals that LPS modulates efferocytosis by upregulating the expression of Tim4.These results underscore the pivotal role of TLR agonists in regulating the efferocytosis process and suggest potential therapeutic avenues for addressing inflammatory diseases. Overall, our study highlights the intricate interplay between LPS pretreatment and efferocytosis in maintaining tissue homeostasis and resolving inflammation.

Keywords:  Efferocytosis; Inflammation; LPS; Macrophage; Tissue resolution

DOI:  https://doi.org/10.1016/j.intimp.2024.112283
Mol Cell. 2024 May 10. pii: S1097-2765(24)00388-5. [Epub ahead of print]

Pathways for macrophage uptake of cell-free circular RNAs.

Laura Amaya, Brian Abe, Jie Liu, Feifei Zhao, Wenyan Lucy Zhang, Robert Chen, Rui Li, Steven Wang, Roarke A Kamber, Miao-Chih Tsai, Michael C Bassik, Ravindra Majeti, Howard Y Chang.

  Circular RNAs (circRNAs) are stable RNAs present in cell-free RNA, which may comprise cellular debris and pathogen genomes. Here, we investigate the phenomenon and mechanism of cellular uptake and intracellular fate of exogenous circRNAs. Human myeloid cells and B cells selectively internalize extracellular circRNAs. Macrophage uptake of circRNA is rapid, energy dependent, and saturable. CircRNA uptake can lead to translation of encoded sequences and antigen presentation. The route of internalization influences immune activation after circRNA uptake, with distinct gene expression programs depending on the route of RNA delivery. Genome-scale CRISPR screens and chemical inhibitor studies nominate macrophage scavenger receptor MSR1, Toll-like receptors, and mTOR signaling as key regulators of receptor-mediated phagocytosis of circRNAs, a dominant pathway to internalize circRNAs in parallel to macropinocytosis. These results suggest that cell-free circRNA serves as an "eat me" signal and danger-associated molecular pattern, indicating orderly pathways of recognition and disposal.

Keywords:  MSR1; RNA uptake; circRNA; innate immunity; macropinocytosis; phagocytosis

DOI:  https://doi.org/10.1016/j.molcel.2024.04.022