bims-traimu 2024-09-08 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2024–09–08
thirteen papers selected by
Yantong Wan, Southern Medical University

"Glycans in Trained Immunity: Educators of innate immune memory in homeostasis and disease".
Trained immunity across organs.
The role of trained immunity in sepsis.
Potential Contributions of Human Endogenous Retroviruses in Innate Immune Memory.
BCG immunization induced KLRG1+ NK cells show memory-like responses to mycobacterial and HIV antigens.
Trained and ready - the case for an inflammatory memory for hematopoietic stem and progenitor cells in the AML niche.
Weight loss-induced adipose macrophage memory improves local Staphylococcus aureus clearance in male mice.
Monocytes Reprogrammed by 4-PBA Potently Contribute to the Resolution of Inflammation and Atherosclerosis.
Efficacy and outcomes of BCG re-vaccination in COVID-19: a systematic review, meta-analysis, and meta-regression of randomized controlled trials.
Early life psychosocial stress increases binge-like ethanol consumption and CSF1R inhibition prevents stress-induced alterations in microglia and brain macrophage population density.
Inhibition of colorectal cancer in Alzheimer's disease is mediated by gut microbiota via induction of inflammatory tolerance.
Activation of Toll-like receptor 2 promotes mesenchymal stem/stromal cell-mediated immunoregulation and angiostasis through AKR1C1.
ABHD8 antagonizes inflammation by facilitating chaperone-mediated autophagy-mediated degradation of NLRP3.

Carbohydr Res. 2024 Aug 20. pii: S0008-6215(24)00224-6. [Epub ahead of print]544 109245

"Glycans in Trained Immunity: Educators of innate immune memory in homeostasis and disease".

Pedro Almeida, Ângela Fernandes, Inês Alves, Salomé S Pinho.

  Trained Immunity is defined as a biological process normally induced by exogenous or endogenous insults that triggers epigenetic and metabolic reprogramming events associated with long-term adaptation of innate immune cells. This trained phenotype confers enhanced responsiveness to subsequent triggers, resulting in an innate immune "memory" effect. Trained Immunity, in the past decade, has revealed important benefits for host defense and homeostasis, but can also induce potentially harmful outcomes associated with chronic inflammatory disorders or autoimmune diseases. Interestingly, evidence suggest that the "trainers" prompting trained immunity are frequently glycans structures. In fact, the exposure of different types of glycans at the surface of pathogens is a key driver of the training phenotype, leading to the reprogramming of innate immune cells through the recognition of those glycan-triggers by a variety of glycan-binding proteins (GBPs) expressed by the immune cells. β-glucan or mannose-enriched structures in Candida albicans are some of the examples that highlight the potential of glycans in trained immunity, both in homeostasis and in disease. In this review, we will discuss the relevance of glycans exposed by pathogens in establishing key immunological hubs with glycan-recognizing receptors expressed in immune cells, highlighting how this glycan-GBP network can impact trained immunity. Finally, we discuss the power of glycans and GBPs as potential targets in trained immunity, envisioning potential therapeutic applications.

Keywords:  BCG; Candida albicans; Glycan-binding proteins; Glycans; Tolerance; Trained immunity

DOI:  https://doi.org/10.1016/j.carres.2024.109245
Nat Immunol. 2024 Sep;25(9): 1509

Trained immunity across organs.

Paula Jauregui.

DOI: https://doi.org/10.1038/s41590-024-01958-y
Front Immunol. 2024 ;15 1449986

The role of trained immunity in sepsis.

Wenjuan Wang, Lisi Ma, Bin Liu, Liangliang Ouyang.

  Sepsis is defined as a life-threatening organ dysfunction syndrome caused by dysregulated host response to infection, characterized by a systemic inflammatory response to infection. The use of antibiotics, fluid resuscitation, and organ support therapy has limited prognostic benefit in patients with sepsis, and its incidence is not diminishing, which is attracting increased attention in medicine. Sepsis remains one of the most debilitating and expensive illnesses. One of the main reasons of septic mortality is now understood to be disruption of immune homeostasis. Immunotherapy is revolutionizing the treatment of illnesses in which dysregulated immune responses play a significant role. This "trained immunity", which is a potent defense against infection regardless of the type of bacteria, fungus, or virus, is attributed to the discovery that the innate immune cells possess immune memory via metabolic and epigenetic reprogramming. Here we reviewed the immunotherapy of innate immune cells in sepsis, the features of trained immunity, and the relationship between trained immunity and sepsis.

Keywords:  immunotherapy; innate immune cells; reprogramming; sepsis; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2024.1449986
J Immunol. 2024 Sep 04. pii: ji2300411. [Epub ahead of print]

Potential Contributions of Human Endogenous Retroviruses in Innate Immune Memory.

Pengcheng Du, Jiarui Li, Mingxi Hua, Liuluan Zhu, Chen Chen, Hui Zeng.

The phenomenon wherein innate immune cells adopt long-term inflammatory phenotypes following the first stimuli is named trained immunity and can improve host defense against infections. Transcriptional and epigenetic reprogramming are critical mechanisms of trained immunity; however, the regulatory networks are not entirely clear at present. The human endogenous retroviruses (HERVs) provide large amounts of transcriptional regulators in the regulatory pathways. In this study, we analyzed published large omics data to explore the roles of such "dark matter" of the human genome in trained and tolerant macrophages. We collected 80 RNA sequencing data and 62 sequencing data to detect histone modifications and active regulatory regions from nine published studies on trained and tolerant macrophages. By analyzing the characteristics of transcription and epigenetic modification of HERVs, as well as their association with gene expression, we found that 15.3% of HERVs were transcribed nonrandomly from noncoding regions and enriched in specific HERV families and specific chromosomes, such as chromosomes 11, 15, 17, and 19, and they were highly related with the expression of adjacent genes. We found that 295 differentially expressed HERVs are located in 50-kbp flanking regions of 142 differentially expressed genes. We found epigenetic changes of these HERVs and that overlap with predicted enhancers and identified 35 enhancer-like HERVs. The related genes were highly involved in the activation and inflammatory responses, such as the TLR pathway. Other pathways including phosphoinositide signaling and transport of folate and K+ might be also related with trained immunity, which require further study. These results demonstrated that HERVs might play important roles in trained immunity.

DOI: https://doi.org/10.4049/jimmunol.2300411
Cell Immunol. 2024 Sep 02. pii: S0008-8749(24)00068-6. [Epub ahead of print]403-404 104865

BCG immunization induced KLRG1+ NK cells show memory-like responses to mycobacterial and HIV antigens.

Manuja Gunasena, Mario Alles, Thorsten Demberg, Will Mulhern, Namal P M Liyanage.

  Bacille-Calmette-Guérin (BCG) is the only approved vaccine against Mycobacterium tuberculosis (MTB), offering protection not only against tuberculosis (TB) but also non-related infections. 'Trained immunity' of innate immune cells is considered one of the mechanisms of this broad protection derived through BCG. Here, we investigated the effect of BCG on Natural Killer (NK) cells, a key innate immune cell type, and their subsequent responses to mycobacterial and HIV antigens. We found that BCG-induced KLRG1+ NK cells exhibit significantly higher production of IFNγ, compared to KLRG1- cells, indicating their memory-like responses upon exposure to these antigens (p < 0.05). These findings may be important in regions of high burden of HIV and TB where BCG is routinely administered.

Keywords:  BCG; HIV; Natural killer cells; Trained immunity

DOI:  https://doi.org/10.1016/j.cellimm.2024.104865
Oncotarget. 2024 Sep 04. 15 609-613

Trained and ready - the case for an inflammatory memory for hematopoietic stem and progenitor cells in the AML niche.

Ding-Wen Chen, Eric K Wafula, Peter Kurre.

  Lifelong hematopoiesis is sustained by crosstalk between hematopoietic stem and progenitor cells (HSPCs) and specialized bone marrow niches. Acute myeloid leukemia (AML) upends that balance, as leukemic blasts secrete factors that remodel the bone marrow into a self-reinforcing leukemic niche. The inflammatory secretome behind this compartmental adaptation accounts for a progressive decline in hematopoietic function that leads to diagnosis and persists through early treatment. Not surprisingly, the mediators of an acute inflammatory injury and HSPC suppression have attracted much attention in an effort to alleviate morbidity and improve outcomes. HSPCs typically recover during disease remission and re-expand in the bone marrow (BM), but little is known about potentially lasting consequences for stem cells and progenitors. We recently showed that AML-experienced HSPCs actively participate in the inflammatory process during leukemic progression. HSPCs are constituent components of the innate immune system, and elegant studies of infection and experimental inflammation over the past decade have described the generation of an adoptively transferable, innate immune memory. Building on this paradigm, we discuss the potential translational relevance of a durable legacy in AML-experienced HSPC.

Keywords:  acute myeloid leukemia; hematopoietic stem and progenitor cells; inflammation; innate immune reprogramming; trained immunity

DOI:  https://doi.org/10.18632/oncotarget.28642
bioRxiv. 2024 Aug 04. pii: 2024.08.03.606494. [Epub ahead of print]

Weight loss-induced adipose macrophage memory improves local Staphylococcus aureus clearance in male mice.

McArthur Bolden, Xenia D Davis, Edward R Sherwood, Julia K Bohannon, Heather L Caslin.

Different stimuli can induce innate immune memory to improve pathogen defense or worsen cardiometabolic disease. However, it is less clear if the same stimuli can induce both the protective and detrimental effects of innate immune memory. We previously showed that weight loss induces innate immune memory in adipose macrophages that correlates with worsened diabetes risk after weight regain. In this study, we investigated the effect of weight loss on macrophage cytokine production and overall survival in a mouse model of infection. Male C57Bl/6J mice were put on high-fat or low-fat diets over 18 weeks to induce weight gain or weight loss. Lean mice served as controls. All mice were then infected IV with 2.5×10^6 CFU Staphylococcus aureus . Tissues were collected from 10 mice/group at day 3 and the remaining animals were followed for survival. Weight gain mice had the highest blood neutrophils and the highest bacterial burden in the kidney. However, there was no significant difference in survival. The weight loss group had the highest plasma TNF-α and a significant reduction in bacterial burden in the adipose tissue that correlated with increased adipose macrophage cytokine production. Thus, weight loss-induced adipose macrophage memory may both improve local S.aureus clearance and worsen diabetes risk upon weight regain. Collectively, these findings support the notion that innate immune memory is an evolutionarily protective mechanism that also contributes to the development of cardiometabolic diseases.

DOI: https://doi.org/10.1101/2024.08.03.606494
Circ Res. 2024 Sep 03.

Monocytes Reprogrammed by 4-PBA Potently Contribute to the Resolution of Inflammation and Atherosclerosis.

Shuo Geng, Ran Lu, Yao Zhang, Yajun Wu, Ling Xie, Blake Caldwell, Kisha Pradhan, Ziyue Yi, Jacqueline Hou, Feng Xu, Xian Chen, Liwu Li.

   BACKGROUND: Chronic inflammation initiated by inflammatory monocytes underlies the pathogenesis of atherosclerosis. However, approaches that can effectively resolve chronic low-grade inflammation targeting monocytes are not readily available. The small chemical compound 4-phenylbutyric acid (4-PBA) exhibits broad anti-inflammatory effects in reducing atherosclerosis. Selective delivery of 4-PBA reprogrammed monocytes may hold novel potential in providing targeted and precision therapeutics for the treatment of atherosclerosis.
METHODS: Systems analyses integrating single-cell RNA sequencing and complementary immunologic approaches characterized key resolving characteristics as well as defining markers of reprogrammed monocytes trained by 4-PBA. Molecular mechanisms responsible for monocyte reprogramming were assessed by integrated biochemical and genetic approaches. The intercellular propagation of homeostasis resolution was evaluated by coculture assays with donor monocytes trained by 4-PBA and recipient naive monocytes. The in vivo effects of monocyte resolution and atherosclerosis prevention by 4-PBA were assessed with the high-fat diet-fed ApoE-/- mouse model with IP 4-PBA administration. Furthermore, the selective efficacy of 4-PBA-trained monocytes was examined by IV transfusion of ex vivo trained monocytes by 4-PBA into recipient high-fat diet-fed ApoE-/- mice.
RESULTS: In this study, we found that monocytes can be potently reprogrammed by 4-PBA into an immune-resolving state characterized by reduced adhesion and enhanced expression of anti-inflammatory mediator CD24. Mechanistically, 4-PBA reduced the expression of ICAM-1 (intercellular adhesion molecule 1) via reducing peroxisome stress and attenuating SYK (spleen tyrosine kinase)-mTOR (mammalian target of rapamycin) signaling. Concurrently, 4-PBA enhanced the expression of resolving mediator CD24 through promoting PPARγ (peroxisome proliferator-activated receptor γ) neddylation mediated by TOLLIP (toll-interacting protein). 4-PBA-trained monocytes can effectively propagate anti-inflammation activity to neighboring monocytes through CD24. Our data further demonstrated that 4-PBA-trained monocytes effectively reduce atherosclerosis pathogenesis when administered in vivo.
CONCLUSIONS: Our study describes a robust and effective approach to generate resolving monocytes, characterizes novel mechanisms for targeted monocyte reprogramming, and offers a precision therapeutics for atherosclerosis based on delivering reprogrammed resolving monocytes.

Keywords:  atherosclerosis; inflammation resolution; monocyte; systems dynamics; therapeutics

DOI:  https://doi.org/10.1161/CIRCRESAHA.124.325023
Ann Med Surg (Lond). 2024 Sep;86(9): 5439-5446

Efficacy and outcomes of BCG re-vaccination in COVID-19: a systematic review, meta-analysis, and meta-regression of randomized controlled trials.

Hritvik Jain, Ramez M Odat, Ayham Mohammad Hussein, Debankur Dey, Mushood Ahmed, Jyoti Jain, Aman Goyal, Tanya Ratnani, Muhammad Idrees, Priyadarshi Prajjwal, Siddhant Passey, Rukesh Yadav.

   Introduction: The Bacillus Calmette-Guerin (BCG) vaccine has a beneficial "off-target" effect that offers heterologous protection against respiratory tract infections by inducing trained immunity. The need for producing antigen-specific COVID-19 vaccines leads to delays in vaccine administration. Current randomized controlled trials (RCTs) report conflicting data on BCG's efficacy in COVID-19 infection.
Methods: A comprehensive literature search was conducted using major bibliographic databases to identify RCTs evaluating the outcomes of BCG re-vaccination in COVID-19. For dichotomous outcomes, odds ratios (ORs) with 95% CIs were pooled using the DerSimonian-Laird random-effects model. Statistical significance was set at P less than 0.05.
Results: Thirteen RCTs with 13 939 participants (7004 in the BCG re-vaccination group and 6935 in the placebo group) were included. BCG re-vaccination did not lead to a statistically significant difference in the incidence of COVID-19 infection [OR: 1.04; 95% CI: 0.91, 1.19; P=0.56], COVID-19-related hospitalizations [OR: 0.81; 95% CI: 0.38, 1.72; P=0.58), ICU admissions [OR: 0.43; 95% CI: 0.13, 1.46; P=0.18], or mortality [OR: 0.67; 95% CI 0.15, 3.04; P=0.60]. For safety outcomes, BCG re-vaccination led to a significant increase in the local injection site complications [OR: 99.79; 95% CI: 31.04, 320.80; P<0.00001], however, the risk of serious adverse events was similar [OR: 1.19; 95% CI: 0.84, 1.67; P=0.33].
Conclusions: BCG re-vaccination does not decrease the incidence of COVID-19 infection, COVID-19-related hospitalizations, ICU admissions, COVID-19-related mortality, and serious adverse events; however, it leads to a rise in local injection site complications. Caution should be exercised when overstating BCG's efficacy in COVID-19 prevention.

Keywords:  BCG vaccine; COVID-19; SARS-CoV-2; coronavirus; vaccine

DOI:  https://doi.org/10.1097/MS9.0000000000002370
bioRxiv. 2024 Aug 12. pii: 2024.07.27.605403. [Epub ahead of print]

Early life psychosocial stress increases binge-like ethanol consumption and CSF1R inhibition prevents stress-induced alterations in microglia and brain macrophage population density.

Stephen C Gironda, Samuel W Centanni, Jeffrey L Weiner.

Early life stress (ELS) has lasting consequences on microglia and brain macrophage function. During ELS, microglia and brain macrophages alter their engagement with synapses leading to changes in neuronal excitability. Further, ELS can induce innate immune memory formation in microglia and brain macrophages resulting in altered responsivity to future environmental stimuli. These alterations can result in lasting adaptations in circuit function and may mediate the relationship between ELS and the risk to develop alcohol use disorder (AUD). Whether microglia and brain macrophages truly mediate this relationship remains elusive. Here, we report: 1) an ELS model, psychosocial stress (PSS), increases binge-like ethanol consumption in early adulthood. 2) Repeated binge-like ethanol consumption increases microglia and brain macrophage population densities across the brain. 3) PSS may elicit innate immune memory formation in microglia and brain macrophages leading to altered population densities following repeated binge-like ethanol consumption. 4) Microglia and brain macrophage inhibition trended towards preventing PSS-evoked changes in binge-like ethanol consumption and normalized microglia and brain macrophage population densities. Therefore, our study suggests that acutely inhibiting microglia and brain macrophage function during periods of early life PSS may prevent innate immune memory formation and assist in reducing the risk to develop AUD.
Highlights: An early life psychosocial stress (PSS) exposure increases ethanol consumptionMicroglial inhibition during PSS trends towards reducing ethanol consumptionBinge ethanol consumption increases microglial count and alters cell proximityEarly life PSS alters microglial responsivity to binge ethanol consumptionMicroglial inhibition may prevent microglial innate immune memory formation.

DOI: https://doi.org/10.1101/2024.07.27.605403
Proc Natl Acad Sci U S A. 2024 Sep 10. 121(37): e2314337121

Inhibition of colorectal cancer in Alzheimer's disease is mediated by gut microbiota via induction of inflammatory tolerance.

Nan Zhang, Rui Zhang, Lei Jiang, Zhaoyu Gao, Wenzhen Xia, Xiaoying Ma, Yushi Qin, Di Zhang, Jiazheng Li, Pei Tian, Qi Zhang, Wanchang Wang, Kaixia Zhang, Shan Xu, Na Zhao, Shunjiang Xu.

  Epidemiological studies have revealed an inverse relationship between the incidence of Alzheimer's disease (AD) and various cancers, including colorectal cancer (CRC). We aimed to determine whether the incidence of CRC is reduced in AD-like mice and whether gut microbiota confers resistance to tumorigenesis through inducing inflammatory tolerance using 16S ribosomal RNA gene sequencing and fecal microbiota transplantation (FMT). AD-like mice experienced a significantly decreased incidence of CRC tumorigenesis induced by azoxymethane-dextran sodium sulfate as evidenced by suppressed intestinal inflammation compared with control mice. However, FMT from age-matched control mice reversed the inhibitory effects on the tumorigenesis of CRC and inflammatory response in AD-like mice. The key bacterial genera in gut microbiota, including Prevotella, were increased in both the AD-like mice and in patients with amnestic mild cognitive impairment (aMCI) but were decreased in patients with CRC. Pretreatment with low-dose Prevotella-derived lipopolysaccharides (LPS) induced inflammatory tolerance both in vivo and in vitro and inhibited CRC tumorigenesis in mice. Imbalanced gut microbiota increased intestinal barrier permeability, which facilitated LPS absorption from the gut into the blood, causing cognitive decline in AD-like mice and patients with aMCI. These data reveal that intestinal Prevotella-derived LPS exerts a resistant effect to CRC tumorigenesis via inducing inflammatory tolerance in the presence of AD. These findings provide biological evidence demonstrating the inverse relationship between the incidence of AD and CRC.

Keywords:  Alzheimer’s disease (AD); LPS; colorectal cancer (CRC); gut microbiota; inflammatory tolerance

DOI:  https://doi.org/10.1073/pnas.2314337121
Theranostics. 2024 ;14(12): 4713-4729

Activation of Toll-like receptor 2 promotes mesenchymal stem/stromal cell-mediated immunoregulation and angiostasis through AKR1C1.

Jung Hwa Ko, Hyun Ju Lee, Chang Ho Yoon, Yoo Rim Choi, Jin Suk Ryu, Joo Youn Oh.

  Background: Mesenchymal stem/stromal cells (MSCs) maintain tissue homeostasis in response to microenvironmental perturbations. Toll-like receptors (TLRs) are key sensors for exogenous and endogenous signals produced during injury. In this study, we aimed to investigate whether TLRs affect the homeostatic functions of MSCs after injury. Methods: We examined the expression of TLR2, TLR3 and TLR4 in MSCs, and analyzed the functional significance of TLR2 activation using single-cell RNA sequencing. Additionally, we investigated the effects and mechanisms of TLR2 and its downstream activation in MSCs on the MSCs themselves, on monocytes/macrophages, and in a mouse model of sterile injury-induced inflammatory corneal angiogenesis. Results: MSCs expressed TLR2, which was upregulated by monocytes/macrophages. Activation of TLR2 in MSCs promoted their immunoregulatory and angiostatic functions in monocytes/macrophages and in mice with inflammatory corneal angiogenesis, whereas TLR2 inhibition attenuated these functions. Single-cell RNA sequencing revealed AKR1C1, a gene encoding aldo-keto reductase family 1 member C1, as the most significantly inducible gene in MSCs upon TLR2 stimulation, though its stimulation did not affect cell compositions. AKR1C1 protected MSCs against ferroptosis, increased secretion of anti-inflammatory cytokines, and enhanced their ability to drive monocytes/macrophages towards immunoregulatory phenotypes, leading to the amelioration of inflammatory corneal neovascularization in mice. Conclusion: Our findings suggest that activation of TLR2-AKR1C1 signaling in MSCs serves as an important pathway for the survival and homeostatic activities of MSCs during injury.

Keywords:  Ado-keto reductase family 1 member C1; Cornea; Mesenchymal stem/stromal cell; Monocyte/macrophage; Toll-like receptor 2

DOI:  https://doi.org/10.7150/thno.100327
Autophagy. 2024 Sep 03. 1-14

ABHD8 antagonizes inflammation by facilitating chaperone-mediated autophagy-mediated degradation of NLRP3.

Shuai Yang, Mengqiu Li, Guangyu Lian, Yaoxing Wu, Jun Cui, Liqiu Wang.

  The NLRP3 inflammasome is a multiprotein complex that plays a vital role in the innate immune system in response to microbial infections and endogenous danger signals. Aberrant activation of the NLRP3 inflammasome is implicated in a spectrum of inflammatory and autoimmune diseases, emphasizing the necessity for precise regulation of the NLRP3 inflammasome to maintain immune homeostasis. The protein level of NLRP3 is a limiting step for inflammasome activation, which must be tightly controlled to avoid detrimental consequences. Here, we demonstrate that ABHD8, a member of the α/β-hydrolase domain-containing (ABHD) family, interacts with NLRP3 and promotes its degradation through the chaperone-mediated autophagy (CMA) pathway. ABHD8 acts as a scaffold to recruit palmitoyltransferase ZDHHC12 to NLRP3 for its palmitoylation as well as subsequent CMA-mediated degradation. Notably, ABHD8 deficiency results in the stabilization of NLRP3 protein and promotes NLRP3 inflammasome activation. We further confirm that ABHD8 overexpression ameliorates LPS- or alum-triggered NLRP3 inflammasome activation in vivo. Interestingly, the nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impairs the ABHD8-NLRP3 association, resulting in an elevation in NLRP3 protein level and excessive inflammasome activation. These findings demonstrate that ABHD8 May represent a potential therapeutic target in conditions associated with NLRP3 inflammasome dysregulation.Abbreviations: 3-MA: 3-methyladenine; ABHD: α/β-hydrolase domain-containing; BMDMs: Bone marrow-derived macrophages; CFZ: carfilzomib; CHX: cycloheximide; CMA: chaperone-mediated autophagy; CQ: chloroquine; DAMPs: danger/damage-associated molecular patterns; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; LAMP2A: lysosomal associated membrane protein 2A; NH4Cl: ammonium chloride; NLRP3: NLR family pyrin domain containing 3; PAMPs: pathogen-associated molecular patterns; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.

Keywords:  ABHD8; CMA; NLRP3; inflammasome; palmitoylation

DOI:  https://doi.org/10.1080/15548627.2024.2395158