bims-traimu 2024-08-04 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2024‒08‒04
twelve papers selected by
Yantong Wan, Southern Medical University

Trained immunity inducers in cancer immunotherapy.
Repetitive Administration of Low-Dose Lipopolysaccharide Improves Repeated Social Defeat Stress-Induced Behavioral Abnormalities and Aberrant Immune Response.
Macrophage plasticity: signaling pathways, tissue repair, and regeneration.
Functional and epigenetic changes in monocytes from adults immunized with an AS01-adjuvanted vaccine.
A viral vaccine design harnessing prior BCG immunization confers protection against Ebola virus.
NKT cells promote Th1 immune bias to dengue virus that governs long term protective antibody dynamics.
Phosphorylation of PFKL regulates metabolic reprogramming in macrophages following pattern recognition receptor activation.
Endogenously produced itaconate negatively regulates innate-driven cytokine production and drives global ubiquitination in human macrophages.
TAX1BP1/A20 inhibited TLR2-NF-κB activation to induce tolerant expression of IL-6 in endothelial cells.
Adenosine triggers early astrocyte reactivity that provokes microglial responses and drives the pathogenesis of sepsis-associated encephalopathy in mice.
Multi-omic profiling of pathogen-stimulated primary immune cells.
Glycolytic enzyme PGK1 promotes M1 macrophage polarization and induces pyroptosis of acute lung injury via regulation of NLRP3.

Front Immunol. 2024 ;15 1427443

Trained immunity inducers in cancer immunotherapy.

Yongjun Sui, Jay A Berzofsky.

  While most of the cancer immunotherapy strategies engage adaptive immunity, especially tumor-associated T cells, the small fraction of responding patients and types of cancers amenable, and the possibility of severe adverse effects limit its usage. More effective and general interventions are urgently needed. Recently, a de facto innate immune memory, termed 'trained immunity', has become a new research focal point, and promises to be a powerful tool for achieving long-term therapeutic benefits against cancers. Trained immunity-inducing agents such as BCG and fungal glucan have been shown to be able to avert the suppressive tumor microenvironment (TME), enhance T cell responses, and eventually lead to tumor regression. Here, we review the current understating of trained immunity induction and highlight the critical roles of emergency granulopoiesis, interferon γ and tissue-specific induction. Preclinical and clinical studies that have exploited trained immunity inducers for cancer immunotherapy are summarized, and repurposed trained immunity inducers from other fields are proposed. We also outline the challenges and opportunities for trained immunity in future cancer immunotherapies. We envisage that more effective cancer vaccines will combine the induction of trained immunity with T cell therapies.

Keywords:  T cell responses; cancer immunotherapy; interferon γ; trained immunity; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1427443
J Neuroimmune Pharmacol. 2024 Jul 27. 19(1): 38

Repetitive Administration of Low-Dose Lipopolysaccharide Improves Repeated Social Defeat Stress-Induced Behavioral Abnormalities and Aberrant Immune Response.

Vichuda Charoensaensuk, Wei-Lan Yeh, Bor-Ren Huang, Tsung-Che Hsu, Sheng-Yun Xie, Chao-Wei Chen, Yu-Wen Wang, Liang-Yo Yang, Cheng-Fang Tsai, Dah-Yuu Lu.

  Repetitive exposure of innate immune cells to a subthreshold dosage of endotoxin components may modulate inflammatory responses. However, the regulatory mechanisms in the interactions between the central nervous system (CNS) and the immune system remain unclear. This study aimed to investigate the effects of lipopolysaccharide (LPS) preconditioning in repeated social defeat stress (RSDS)-induced abnormal immune responses and behavioral impairments. This study aimed to elucidate the mechanisms that underlie the protective effects of repeated administration of a subthreshold dose LPS on behavioral impairments using the RSDS paradigm. LPS preconditioning improved abnormal behaviors in RSDS-defeated mice, accompanied by decreased monoamine oxidases and increased glucocorticoid receptor expression in the hippocampus. In addition, pre-treated with LPS significantly decreased the recruited peripheral myeloid cells (CD11b+CD45hi), mainly circulating inflammatory monocytes (CD11b+CD45hiLy6ChiCCR2+) into the brain in response to RSDS challenge. Importantly, we found that LPS preconditioning exerts its protective properties by regulating lipocalin-2 (LCN2) expression in microglia, which subsequently induces expressions of chemokine CCL2 and pro-inflammatory cytokine. Subsequently, LPS-preconditioning lessened the resident microglia population (CD11b+CD45intCCL2+) in the brains of the RSDS-defeated mice. Moreover, RSDS-associated expressions of leukocytes (CD11b+CD45+CCR2+) and neutrophils (CD11b+CD45+Ly6G+) in the bone marrow, spleen, and blood were also attenuated by LPS-preconditioning. In particular, LPS preconditioning also promoted the expression of endogenous antioxidants and anti-inflammatory proteins in the hippocampus. Our results demonstrate that LPS preconditioning ameliorates lipocalin 2-associated microglial activation and aberrant immune response and promotes the expression of endogenous antioxidants and anti-inflammatory protein, thereby maintaining the homeostasis of pro-inflammation/anti-inflammation in both the brain and immune system, ultimately protecting the mice from RSDS-induced aberrant immune response and behavioral changes.

Keywords:  Chemokine; LPS tolerance; Lipocalin-2; Microglia; RSDS

DOI:  https://doi.org/10.1007/s11481-024-10141-x
MedComm (2020). 2024 Aug;5(8): e658

Macrophage plasticity: signaling pathways, tissue repair, and regeneration.

Lingfeng Yan, Jue Wang, Xin Cai, Yih-Cherng Liou, Han-Ming Shen, Jianlei Hao, Canhua Huang, Gaoxing Luo, Weifeng He.

  Macrophages are versatile immune cells with remarkable plasticity, enabling them to adapt to diverse tissue microenvironments and perform various functions. Traditionally categorized into classically activated (M1) and alternatively activated (M2) phenotypes, recent advances have revealed a spectrum of macrophage activation states that extend beyond this dichotomy. The complex interplay of signaling pathways, transcriptional regulators, and epigenetic modifications orchestrates macrophage polarization, allowing them to respond to various stimuli dynamically. Here, we provide a comprehensive overview of the signaling cascades governing macrophage plasticity, focusing on the roles of Toll-like receptors, signal transducer and activator of transcription proteins, nuclear receptors, and microRNAs. We also discuss the emerging concepts of macrophage metabolic reprogramming and trained immunity, contributing to their functional adaptability. Macrophage plasticity plays a pivotal role in tissue repair and regeneration, with macrophages coordinating inflammation, angiogenesis, and matrix remodeling to restore tissue homeostasis. By harnessing the potential of macrophage plasticity, novel therapeutic strategies targeting macrophage polarization could be developed for various diseases, including chronic wounds, fibrotic disorders, and inflammatory conditions. Ultimately, a deeper understanding of the molecular mechanisms underpinning macrophage plasticity will pave the way for innovative regenerative medicine and tissue engineering approaches.

Keywords:  epigenetic regulation; macrophages; plasticity; signaling pathways; tissue repair

DOI:  https://doi.org/10.1002/mco2.658
Sci Transl Med. 2024 Jul 31. 16(758): eadl3381

Functional and epigenetic changes in monocytes from adults immunized with an AS01-adjuvanted vaccine.

Viviane Bechtold, Kinga K Smolen, Wivine Burny, Simone P de Angelis, Simon Delandre, Ahmed Essaghir, Arnaud Marchant, Cheikh Ndour, Martin Taton, Robbert van der Most, Fabienne Willems, Arnaud M Didierlaurent.

The adjuvant AS01 plays a key role in the immunogenicity of several approved human vaccines with demonstrated high efficacy. Its adjuvant effect relies on activation of the innate immune system. However, specific effects of AS01-adjuvanted vaccines on innate cell function and epigenetic remodeling, as described for Bacille Calmette-Guérin (BCG) and influenza vaccines, are still unknown. We assessed the long-term functional and epigenetic changes in circulating monocytes and dendritic cells induced by a model vaccine containing hepatitis B surface antigen and AS01 in healthy adults (NCT01777295). The AS01-adjuvanted vaccine, but not an Alum-adjuvanted vaccine, increased the number of circulating monocytes and their expression of human leukocyte antigen (HLA)-DR, which correlated with the magnitude of the memory CD4+ T cell response. Single-cell analyses revealed epigenetic alterations in monocyte and dendritic cell subsets, affecting accessibility of transcription factors involved in cell functions including activator protein-1 (AP-1), GATA, C/EBP, and interferon regulatory factor. The functional changes were characterized by a reduced proinflammatory response to Toll-like receptor activation and an improved response to interferon-γ, a cytokine critical for the adjuvant's mode of action. Epigenetic changes were most evident shortly after the second vaccine dose in CD14+ monocytes, for which accessibility differences of some transcription factors could persist for up to 6 months postvaccination. Together, we show that reprogramming of monocyte subsets occurs after vaccination with an AS01-adjuvanted vaccine, an effect that may contribute to the impact of vaccination beyond antigen-specific protection.

DOI: https://doi.org/10.1126/scitranslmed.adl3381
Front Immunol. 2024 ;15 1429909

A viral vaccine design harnessing prior BCG immunization confers protection against Ebola virus.

Tony W Ng, Wakako Furuyama, Ariel S Wirchnianski, Noemí A Saavedra-Ávila, Christopher T Johndrow, Kartik Chandran, William R Jacobs, Andrea Marzi, Steven A Porcelli.

  Previous studies have demonstrated the efficacy and feasibility of an anti-viral vaccine strategy that takes advantage of pre-existing CD4+ helper T (Th) cells induced by Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccination. This strategy uses immunization with recombinant fusion proteins comprised of a cell surface expressed viral antigen, such as a viral envelope glycoprotein, engineered to contain well-defined BCG Th cell epitopes, thus rapidly recruiting Th cells induced by prior BCG vaccination to provide intrastructural help to virus-specific B cells. In the current study, we show that Th cells induced by BCG were localized predominantly outside of germinal centers and promoted antibody class switching to isotypes characterized by strong Fc receptor interactions and effector functions. Furthermore, BCG vaccination also upregulated FcγR expression to potentially maximize antibody-dependent effector activities. Using a mouse model of Ebola virus (EBOV) infection, this vaccine strategy provided sustained antibody levels with strong IgG2c bias and protection against lethal challenge. This general approach can be easily adapted to other viruses, and may be a rapid and effective method of immunization against emerging pandemics in populations that routinely receive BCG vaccination.

Keywords:  CD4+ T cells; Ebola virus; Fc receptors; Mycobacterium bovis BCG; antibodies; intrastructural help; vaccines

DOI:  https://doi.org/10.3389/fimmu.2024.1429909
J Clin Invest. 2024 Aug 01. pii: e169251. [Epub ahead of print]

NKT cells promote Th1 immune bias to dengue virus that governs long term protective antibody dynamics.

Youngjoo Choi, Wilfried Aa Saron, Aled O'Neill, Manouri Senanayake, Annelies Wilder-Smith, Abhay Ps Rathore, Ashley L St John.

  NKT cells are innate-like T cells, recruited to the skin during viral infection, yet their contributions to long-term immune memory to viruses are unclear. We identified granzyme K, a product made by cytotoxic cells including NKT cells, is linked to induction of Th1-associated antibodies during primary dengue virus (DENV) infection in humans. We examined the role of NKT cells in vivo using DENV-infected mice lacking CD1d-dependent (CD1ddep) NKT cells. In CD1d-KO mice, Th1-polarized immunity and infection resolution were impaired, which was dependent on intrinsic NKT cell production of IFN-γ, since it was restored by adoptive transfer of WT but not IFN-γ-KO NKT cells. Furthermore, NKT cell deficiency triggered immune bias, resulting in higher levels of Th2-associated IgG1 than Th1-associated IgG2a, which failed to protect against a homologous DENV re-challenge and promoted antibody-dependent enhanced disease during secondary heterologous infections. Similarly, Th2-immunity, typified by a higher IgG4:IgG3 ratio, was associated with worsened human disease severity during secondary infections. Thus, CD1ddep NKT cells establish Th1 polarity during the early innate response to DENV, which promotes infection resolution, memory formation and long-term protection from secondary homologous and heterologous infections. These observations illustrate how early innate immune responses during primary infections can influence secondary infection outcomes.

Keywords:  Cellular immune response; Immunoglobulins; Immunology; Infectious disease; NKT cells

DOI:  https://doi.org/10.1172/JCI169251
Nat Commun. 2024 Jul 31. 15(1): 6438

Phosphorylation of PFKL regulates metabolic reprogramming in macrophages following pattern recognition receptor activation.

Meiyue Wang, Heinrich Flaswinkel, Abhinav Joshi, Matteo Napoli, Sergi Masgrau-Alsina, Julia M Kamper, Antonia Henne, Alexander Heinz, Marleen Berouti, Niklas A Schmacke, Karsten Hiller, Elisabeth Kremmer, Benedikt Wefers, Wolfgang Wurst, Markus Sperandio, Jürgen Ruland, Thomas Fröhlich, Veit Hornung.

Innate immune responses are linked to key metabolic pathways, yet the proximal signaling events that connect these systems remain poorly understood. Here we show that phosphofructokinase 1, liver type (PFKL), a rate-limiting enzyme of glycolysis, is phosphorylated at Ser775 in macrophages following several innate stimuli. This phosphorylation increases the catalytic activity of PFKL, as shown by biochemical assays and glycolysis monitoring in cells expressing phosphorylation-defective PFKL variants. Using a genetic mouse model in which PFKL Ser775 phosphorylation cannot take place, we observe that upon activation, glycolysis in macrophages is lower than in the same cell population of wild-type animals. Consistent with their higher glycolytic activity, wild-type cells have higher levels of HIF1α and IL-1β than PfklS775A/S775A after LPS treatment. In an in vivo inflammation model, PfklS775A/S775A mice show reduced levels of MCP-1 and IL-1β. Our study thus identifies a molecular link between innate immune activation and early induction of glycolysis.

DOI: https://doi.org/10.1038/s41467-024-50104-7
Cell Rep. 2024 Aug 01. pii: S2211-1247(24)00899-4. [Epub ahead of print]43(8): 114570

Endogenously produced itaconate negatively regulates innate-driven cytokine production and drives global ubiquitination in human macrophages.

Luke A Bourner, Linda A Chung, Haiyan Long, Anne F McGettrick, Junpeng Xiao, Kenneth Roth, Jade D Bailey, Marie Strickland, Bo Tan, Jason Cunningham, Barry Lutzke, James McGee, Francella J Otero, David C Gemperline, Lin Zhang, Ying C Wang, Michael J Chalmers, Chiao-Wen Yang, Jesus A Gutierrez, Luke A J O'Neill, Frank C Dorsey.

  A wide variety of electrophilic derivatives of itaconate, the Kreb's cycle-derived metabolite, are immunomodulatory, yet these derivatives have overlapping and sometimes contradictory activities. Therefore, we generated a genetic system to interrogate the immunomodulatory functions of endogenously produced itaconate in human macrophages. Endogenous itaconate is driven by multiple innate signals restraining inflammatory cytokine production. Endogenous itaconate directly targets cysteine 13 in IRAK4 (disrupting IRAK4 autophosphorylation and activation), drives the degradation of nuclear factor κB, and modulates global ubiquitination patterns. As a result, cells unable to make itaconate overproduce inflammatory cytokines such as tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), and IL-1β in response to these innate activators. In contrast, the production of interferon (IFN)β, downstream of LPS, requires the production of itaconate. These data demonstrate that itaconate is a critical arbiter of inflammatory cytokine production downstream of multiple innate signaling pathways, laying the groundwork for the development of itaconate mimetics for the treatment of autoimmunity.

Keywords:  ACOD1; CP: Immunology; IRAK4; IRG1; MYC; immunometabolism; itaconate; macrophage

DOI:  https://doi.org/10.1016/j.celrep.2024.114570
Int Immunopharmacol. 2024 Jul 29. pii: S1567-5769(24)01310-9. [Epub ahead of print]139 112789

TAX1BP1/A20 inhibited TLR2-NF-κB activation to induce tolerant expression of IL-6 in endothelial cells.

Mei Yang, Xueting Liu, Manli Jiang, Jinyue Hu, Zhilin Xiao.

  The inflammatory cascadedriven by interleukin-6 (IL-6) plays a crucial role in the initiation and progression of chronic inflammatory conditions such as atherosclerosis. Research has demonstrated that prolonged exposure to inflammatory stimuli leads to the development of "immune tolerance" in specialized immune cells such as monocytes and macrophages, serving as a mechanism to prevent tissue damage and curb the inflammatory cascade. However, our recent investigation revealed that immune tolerance did not effectively regulate the production of IL-6 in human umbilical vein endothelial cells (HUVECs) when stimulated by a Toll-like receptor 2 (TLR2) ligand Pam3CSK4, which is a potent activator of the pro-inflammatory transcription factor NF-κB. Furthermore, the negative regulator of NF-κB signaling, A20, was ineffective in suppressing TLR2-induced IL-6 synthesis in this context. Notably, all A20 auxiliary molecules, with the exception of TAX1BP1, were found to be significantly expressed in HUVECs. DNA methylation in TAX1BP1 was confirmed in GEO database. According to the information provided, it is hypothesized that altered DNA methylation in HUVECs could potentially lead to decreased expression of TAX1BP1, thereby impeding A20's capacity to modulate continuous activation of the TLR2-NF-κB pathway. This may consequently lead to unregulated production of IL-6, evading immune tolerance mechanisms. Subsequent investigations suggested that demethylating TAX1BP1 could enhance its expression, potentially reducing the endogenous IL-6 levels induced by repeated TLR2 stimulation and restoring A20's inhibitory role in NF-κB signaling. Additionally, over-expression of TAX1BP1 coulddecrease the production of atherosclerosis-associated cytokines like IL-6, MCP-1, ICAM-1, and VCAM-1, while increasing NO release following repeated Pam3cks4 stimulation, along with enhanced co-localization of TAX1BP1 and A20. These findings indicate that inducing immune tolerance in endothelial cells may effectively suppress endogenous IL-6 production and halt the IL-6-mediated inflammatory cascade, with TAX1BP1/A20 identified as crucial components in this process.These insights provide novel perspectives and potential targets for therapeutic strategies in inflammatoryimmunological disorders involving the overproduction of IL-6.

Keywords:  Endothelial cells; Immune-tolerance; Interleukin-6; NF-κB signaling; Tax1-binding protein 1/A20

DOI:  https://doi.org/10.1016/j.intimp.2024.112789
Nat Commun. 2024 Jul 27. 15(1): 6340

Adenosine triggers early astrocyte reactivity that provokes microglial responses and drives the pathogenesis of sepsis-associated encephalopathy in mice.

Qilin Guo, Davide Gobbo, Na Zhao, Hong Zhang, Nana-Oye Awuku, Qing Liu, Li-Pao Fang, Tanja M Gampfer, Markus R Meyer, Renping Zhao, Xianshu Bai, Shan Bian, Anja Scheller, Frank Kirchhoff, Wenhui Huang.

Molecular pathways mediating systemic inflammation entering the brain parenchyma to induce sepsis-associated encephalopathy (SAE) remain elusive. Here, we report that in mice during the first 6 hours of peripheral lipopolysaccharide (LPS)-evoked systemic inflammation (6 hpi), the plasma level of adenosine quickly increased and enhanced the tone of central extracellular adenosine which then provoked neuroinflammation by triggering early astrocyte reactivity. Specific ablation of astrocytic Gi protein-coupled A1 adenosine receptors (A1ARs) prevented this early reactivity and reduced the levels of inflammatory factors (e.g., CCL2, CCL5, and CXCL1) in astrocytes, thereby alleviating microglial reaction, ameliorating blood-brain barrier disruption, peripheral immune cell infiltration, neuronal dysfunction, and depression-like behaviour in the mice. Chemogenetic stimulation of Gi signaling in A1AR-deficent astrocytes at 2 and 4 hpi of LPS injection could restore neuroinflammation and depression-like behaviour, highlighting astrocytes rather than microglia as early drivers of neuroinflammation. Our results identify early astrocyte reactivity towards peripheral and central levels of adenosine as an important pathway driving SAE and highlight the potential of targeting A1ARs for therapeutic intervention.

DOI: https://doi.org/10.1038/s41467-024-50466-y
iScience. 2024 Aug 16. 27(8): 110471

Multi-omic profiling of pathogen-stimulated primary immune cells.

Renee Salz, Emil E Vorsteveld, Caspar I van der Made, Simone Kersten, Merel Stemerdink, Tabea V Riepe, Tsung-Han Hsieh, Musa Mhlanga, Mihai G Netea, Pieter-Jan Volders, Alexander Hoischen, Peter A C 't Hoen.

  We performed long-read transcriptome and proteome profiling of pathogen-stimulated peripheral blood mononuclear cells (PBMCs) from healthy donors to discover new transcript and protein isoforms expressed during immune responses to diverse pathogens. Long-read transcriptome profiling reveals novel sequences and isoform switching induced upon pathogen stimulation, including transcripts that are difficult to detect using traditional short-read sequencing. Widespread loss of intron retention occurs as a common result of all pathogen stimulations. We highlight novel transcripts of NFKB1 and CASP1 that may indicate novel immunological mechanisms. RNA expression differences did not result in differences in the amounts of secreted proteins. Clustering analysis of secreted proteins revealed a correlation between chemokine (receptor) expression on the RNA and protein levels in C. albicans- and poly(I:C)-stimulated PBMCs. Isoform aware long-read sequencing of pathogen-stimulated immune cells highlights the potential of these methods to identify novel transcripts, revealing a more complex transcriptome landscape than previously appreciated.

Keywords:  Immunology; Proteomics; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2024.110471
Respir Res. 2024 Jul 30. 25(1): 291

Glycolytic enzyme PGK1 promotes M1 macrophage polarization and induces pyroptosis of acute lung injury via regulation of NLRP3.

Guiyin Zhu, Haiyang Yu, Tian Peng, Kun Yang, Xue Xu, Wen Gu.

  Acute lung injury (ALI) is characterized by an unregulated inflammatory reaction, often leading to severe morbidity and ultimately death. Excessive inflammation caused by M1 macrophage polarization and pyroptosis has been revealed to have a critical role in ALI. Recent study suggests that glycolytic reprogramming is important in the regulation of macrophage polarization and pyroptosis. However, the particular processes underlying ALI have yet to be identified. In this study, we established a Lipopolysaccharide(LPS)-induced ALI model and demonstrated that blocking glycolysis by using 2-Deoxy-D-glucose(2-DG) significantly downregulated the expression of M1 macrophage markers and pyroptosis-related genes, which was consistent with the in vitro results. Furthermore, our research has revealed that Phosphoglycerate Kinase 1(PGK1), an essential enzyme in the glycolysis pathway, interacts with NOD-, LRR- and pyrin domain-containing protein 3(NLRP3). We discovered that LPS stimulation improves the combination of PGK1 and NLRP3 both in vivo and in vitro. Interestingly, the absence of PGK1 reduces the phosphorylation level of NLRP3. Based on in vitro studies with mice bone marrow-derived macrophages (BMDMs), we further confirmed that siPGK1 plays a protective role by inhibiting macrophage pyroptosis and M1 macrophage polarization. The PGK1 inhibitor NG52 suppresses the occurrence of excessive inflammation in ALI. In general, it is plausible to consider a therapeutic strategy that focuses on modulating the relationship between PGK1 and NLRP3 as a means to mitigate the activation of inflammatory macrophages in ALI.

Keywords:  Acute lung injury; Glycolytic reprogramming; Macrophage polarization; Pyroptosis

DOI:  https://doi.org/10.1186/s12931-024-02926-8