bims-traimu Biomed News
on Trained immunity
Issue of 2022‒08‒28
ten papers selected by
Yantong Wan
Southern Medical University

  1. Antioxid Redox Signal. 2022 Aug 26.
      SIGNIFICANCE: Cigarette smoke (CS) is a prominent cause of morbidity and death and poses a serious challenge to the current healthcare system worldwide. Its multifaceted roles have led to cardiovascular, respiratory, immunological, and neoplastic diseases.RECENT ADVANCES: CS influences both innate and adaptive immunity and regulates immune responses by exacerbating pathogenic immunological responses and/or suppressing defense immunity. There is substantial evidence pointing toward a critical role of CS in vascular immunopathology, but a comprehensive and up-to-date review is lacking.
    CRITICAL ISSUES: This review aims to synthesize novel conceptual advances on the immunomodulatory action of CS with a focus on the cardiovascular system from the following perspectives: (1) the signaling of danger-associated molecular pattern (DAMPs) receptors contributes to CS modulation of inflammation and immunity; (2) CS reprograms immunometabolism and trained immunity-related metabolic pathways in innate immune cells and T cells, which can be sensed by the cytoplasmic (cytosolic and non-nuclear organelles) reactive oxygen species (ROS) system in vascular cells; (3) how nuclear ROS drive CS-promoted DNA damage and cell death pathways, thereby amplifying inflammation and immune responses; and (4) CS induces endothelial cell (EC) dysfunction and vascular inflammation to promote cardiovascular diseases.
    FUTURE DIRECTIONS: Despite significant progress in understanding the cellular and molecular mechanisms linking CS to immunity. Further investigations are warranted to elucidate novel mechanisms responsible for CS-mediated immunopathology of cardiovascular diseases; in particular, the research in redox regulation of immune functions of ECs and their fate affected by CS is still in its infancy.
  2. Front Immunol. 2022 ;13 857707
      Current studies have demonstrated that innate immunity possesses memory characteristics. Although the molecular mechanisms underlying innate immune memory have been addressed by numerous studies, genetic variations in innate immune memory and the associated genes remain unclear. Here, we explored innate immune memory in 163 lines of Drosophila melanogaster from the Drosophila Synthetic Population Resource. In our assay system, prior training with low pathogenic bacteria (Micrococcus luteus) increased the survival rate of flies after subsequent challenge with highly pathogenic bacteria (Staphylococcus aureus). This positive training effect was observed in most lines, but some lines exhibited negative training effects. Survival rates under training and control conditions were poorly correlated, suggesting that distinct genetic factors regulate training effects and normal immune responses. Subsequent quantitative trait loci analysis suggested that four loci containing 80 genes may be involved in regulating innate immune memory. Among them, Adgf-A, which encodes an extracellular adenosine deaminase-related growth factor, was shown to be associated with training effects. Our study findings help to elucidate the genetic architecture of innate immune memory in Drosophila and may provide insight for new therapeutic treatments aimed at boosting immunity.
    Keywords:  Adgf-A; Drosophila; Drosophila synthetic population resource (DSPR); innate immune memory; quantitative trait loci (QTL)
  3. Clin Exp Immunol. 2022 Aug 24. pii: uxac073. [Epub ahead of print]
      Previous studies have shown that monocytes can be 'trained' or tolerized by certain stimuli to respond stronger or weaker to a secondary stimulation. Rewiring of glucose metabolism was found to be important in inducing this phenotype. As we previously found that Borrelia burgdorferi (B. burgdorferi), the causative agent of Lyme borreliosis (LB), alters glucose metabolism in monocytes, we hypothesized that this may also induce long-term changes in innate immune responses. We found that exposure to B. burgdorferi decreased cytokine production in response to the TLR4-ligand lipopolysaccharide (LPS). In addition, B. burgdorferi exposure decreased baseline levels of glycolysis, as assessed by lactate production. Using GWAS analysis, we identified a gene, microfibril-associated protein 3-like (MFAP3L) as a factor influencing lactate production after B. burgdorferi exposure. Validation experiments proved that MFAP3L affects lactate- and cytokine production following B. burgdorferi ​stimulation. This is mediated by functions of MFAP3L, which includes activating ERK2 and through activation of platelet degranulation. Moreover, we showed that platelets and platelet-derived factors play important roles in B. burgdorferi-induced cytokine production. Certain platelet-derived factors, such Chemokine C-X-C motif ligand 7 (CXCL7) and (C-C motif) ligand 5 (CCL5), were elevated in the circulation of LB patients in comparison to healthy individuals.
    Keywords:   Borrelia burgdorferi ; CXCL7; Lyme disease; metabolism; platelets; trained immunity
  4. FEBS Lett. 2022 Aug 23.
      Regulation of cellular catabolic metabolism in immune cells has recently become a major concept for resolution of inflammation. Nuclear receptors (NRs), including peroxisome proliferator activator receptors (PPARs), 1,25-dihydroxyvitamin D(3) receptor (VDR), liver X receptors (LXRs), glucocorticoid receptors (GRs), estrogen-related receptor α (ERRα) and Nur77, have been identified as major modulators of inflammation, affecting innate immune cells, such as macrophages. Evidence emerges on how NRs regulate cellular metabolism in macrophages during inflammatory processes and contribute to the resolution of inflammation. This could have new implications for our understanding of how NRs shape immune responses and inform anti-inflammatory drug design. This review will highlight the recent developments about NRs and their role in cellular metabolism in macrophages.
    Keywords:  Cellular Metabolism; ERRα; GR; Immunometabolism; Inflammation; LXR; Macrophages; Nuclear Receptors; Nur77; PPAR; VDR
  5. Adv Healthc Mater. 2022 Aug 26. e2201085
      Microcarrier-based Mesenchymal stem cells (MSCs) delivery have attracted increasing attention in acute liver failure (ALF) therapy, while there is still room for improvement in terms of improving cell loading efficiency, enhancing anti-inflammatory features, and controlling cell release. Here, we present novel lipopolysaccharide (LPS)-composited magnetic-thermal responsive inverse opal particles (MIOPs) for the delivery of MSCs. The MIOPs are composed of a chitosan inverse opal skeleton filled with a hydrogel containing LPS, poly(N-isopropylacrylamide) (PNIPAM), and Fe3 O4 nanoparticles. Benefitting from the biocompatible chitosan component and the huge specific surface area, the resultant MIOPs could capture MSCs in a non-destructive way. Besides, LPS could be released from the MIOPs under the stimulation of an alternating magnetic field (AMF), by which the MSCs are activated to gain the feature of "trained immunity". Moreover, this process could be monitored in real-time by the structural color change of the MIOPs. With that, the MSCs-laden MIOPs are employed in rats with ALF, and they exhibited obvious anti-inflammatory and therapeutic efficacy superior to untrained MSCs. These performances make the MIOPs a distinctive cell delivery platform for clinical tissue recovery applications. This article is protected by copyright. All rights reserved.
    Keywords:  acute liver failure; inverse opal; microcarrier; structural color; trained immunity
  6. Commun Biol. 2022 Aug 26. 5(1): 878
      Translocated lipopolysaccharide (LPS) activates monocytes via TLR4 and is hypothesized to increase cardiovascular disease risk in persons living with HIV. We tested whether mTOR activity supports LPS-stimulated monocyte production of pro-inflammatory cytokines and tissue factor (TF), as it propels the inflammatory response in several immune cell types besides monocytes. However, multi-omics analyses here demonstrate that mTOR activates a metabolic pathway that limits abundance of these gene products in monocytes. Treatment of primary human monocytes with catalytic mTOR inhibitors (mTORi) increased LPS-induced polyfunctional responses, including production of IL-1β, IL-6, and the pro-coagulant, TF. NF-κB-driven transcriptional activity is enhanced with LPS stimulation after mTORi treatment to increase expression of F3 (TF). Moreover, intracellular NAD+ availability is restricted due to decreased salvage pathway synthesis. These results document mTOR-mediated restraint of the LPS-induced transcriptional response in monocytes and a metabolic mechanism informing strategies to reverse enhanced risk of coagulopathy in pro-inflammatory states.
  7. Cell Death Dis. 2022 Aug 24. 13(8): 731
      Host organisms use different innate immune mechanisms to defend against pathogenic infections, while tight control of innate immunity is essential for proper immune induction and balance. Here, we reported that apoptotic induction or caspase-3 overexpression caused dramatic reduction of differently triggered cytokine signalings in human cells, murine primary cells and mouse model, while the loss of caspase-3 or inhibiting apoptosis markedly enhances these immune signalings. Furthermore, caspase-3 can mediate the cleavage of NF-κB members p65/RelA, RelB, and c-Rel via its protease activity. And the caspase-3-resistant p65/RelA, RelB, or c-Rel mutant mostly restored the caspase-3-induced suppression of cytokine production. Interestingly, we further uncovered that apoptotic induction also dramatically inhibited Toll immune signaling in Drosophila, and the Drosophila effector caspases, drICE and DCP-1, also mediated the degradation of DIF, the NF-κB of Toll signaling. Together, our findings demonstrate apoptotic effector caspases, including mammalian caspase-3 and fly drICE/DCP-1, can function as repressors of NF-κB-mediated innate immune signalings.
  8. Shock. 2022 Aug 17.
      OBJECTIVES: Nosocomial pneumonia is a common complication in critically ill patients. The goal of this study was to examine the efficacy of the toll-like receptor 4 (TLR4) agonist 3-deacyl phosphorylated hexacyl disaccharide (3D PHAD), in a clinically relevant murine model of pneumonia and assess the cellular mechanisms that mediate the protective response.DESIGN: Mice received intrapulmonary 3D PHAD (20 μg) or vehicle for 2 consecutive days prior to challenge with intrapulmonary Klebsiella pneumoniae (2.3x103 colony forming units (CFU)). Mice were followed for 14-day survival, pulmonary K. pneumoniae burden, lung leukocyte profile, leukocyte phagocytic capacity and cytokine production. Pneumonia severity and leukocyte recruitment were further assessed by histological evaluation.
    SETTING: Research laboratory.
    SUBJECTS: Wild type, male C57BL/6 J mice.
    INTERVENTIONS: Intrapulmonary treatment with 20 μg 3D PHAD for 2 consecutive days.
    MEASUREMENTS AND MAIN RESULTS: Intrapulmonary treatment with 3D PHAD decreased lung K. pneumoniae CFU and pneumonia severity with an associated improvement in survival compared to mice treated with vehicle. The numbers of neutrophils, monocytes and macrophages in the lungs of 3D PHAD-treated mice were higher than in vehicle-treated mice prior to infection, but were not significantly different from vehicle-treated mice at 48 hours after K. pneumoniae challenge. Lung innate leukocytes from 3D PHAD-treated mice had increased phagocytic capacity. Treatment with 3D PHAD alone increased cytokines in the lungs, but decreased cytokines in plasma during K. pneumoniae pneumonia as compared to control.
    CONCLUSIONS: Intrapulmonary treatment with 3D PHAD augments innate immunity in the lung and facilitates resistance to K. pneumoniae pneumonia.
  9. Sci Transl Med. 2022 Aug 24. 14(659): eabo2028
      Sepsis is a challenging clinical syndrome caused by a dysregulated host response to infection. Here, we identified an unexpected proseptic activity of aconitate decarboxylase 1 (ACOD1) in monocytes and macrophages. Previous studies have suggested that ACOD1, also known as immune-responsive gene 1, is an immunometabolic regulator that favors itaconate production to inhibit bacterial lipopolysaccharide-induced innate immunity. We used next-generation sequencing of lipopolysaccharide-activated THP1 cells to demonstrate that ACOD1 accumulation confers a robust proinflammation response by activating a cytokine storm, predominantly through the tumor necrosis factor signaling pathway. We further revealed that the phosphorylation of cyclin-dependent kinase 2 (CDK2) on threonine-160 mediates the activation of mitogen-activated protein kinase 8 through receptor for activated C kinase 1, leading to JUN-dependent transcription of ACOD1 in human and mouse macrophages or monocytes. Genetic deletion of CDK2 or ACOD1 in myeloid cells, or the administration of the CDK inhibitor dinaciclib, protected mice against polymicrobial sepsis and was associated with improved survival and decreased cytokine storm. The expression of the CDK2-ACOD1 axis also correlated with severity of illness in a cohort of 40 patients with bacterial sepsis. Thus, our findings provide evidence for a previously unrecognized function of ACOD1 in innate immunity and suggest it as a potential therapeutic target for the treatment of sepsis.
  10. Front Immunol. 2022 ;13 938944
      Initial lipopolysaccharide (LPS) exposure leads to a hypo-responsive state by macrophages to a secondary stimulation of LPS, known as endotoxin tolerance. However, recent findings show that functions of endotoxin-tolerant macrophages are not completely suppressed, whereas they undergo a functional re-programming process with upregulation of a panel of molecules leading to enhanced protective functions including antimicrobial and tissue-remodeling activities. However, the underlying molecular mechanisms are still elusive. Erythropoietin (EPO), a glycoprotein regulated by hypoxia-inducible factor 1α (HIF-1α), exerts anti-inflammatory and tissue-protective activities. Nevertheless, the potential effects of EPO on functional re-programming of endotoxin-tolerant macrophages have not been investigated yet. Here, we found that initial LPS exposure led to upregulation of HIF-1α/EPO in macrophages and that EPO enhanced tolerance in tolerized macrophages and mice as demonstrated by suppressed proinflammatory genes such as Il1b, Il6, and Tnfa after secondary LPS stimulation. Moreover, we showed that EPO improved host protective genes in endotoxin-tolerant macrophages and mice, such as the anti-bacterial genes coding for cathelicidin-related antimicrobial peptide (Cnlp) and macrophage receptor with collagenous structure (Marco), and the tissue-repairing gene vascular endothelial growth factor C (Vegfc). Therefore, our findings indicate that EPO mediates the functional re-programming of endotoxin-tolerant macrophages. Mechanistically, we found that PI3K/AKT signaling contributed to EPO-mediated re-programming through upregulation of Irak3 and Wdr5 expression. Specifically, IL-1 receptor-associated kinase 3 (IRAK3) was responsible for inhibiting proinflammatory genes Il1b, Il6, and Tnfa in tolerized macrophages after LPS rechallenge, whereas WDR5 contributed to the upregulation of host beneficial genes including Cnlp, Marco, and Vegfc. In a septic model of mice, EPO pretreatment significantly promoted endotoxin-tolerant re-programming, alleviated lung injury, enhanced bacterial clearance, and decreased mortality in LPS-tolerized mice after secondary infection of Escherichia coli. Collectively, our results reveal a novel role for EPO in mediating functional re-programming of endotoxin-tolerant macrophages; thus, targeting EPO appears to be a new therapeutic option in sepsis and other inflammatory disorders.
    Keywords:  HIF-1α; endotoxin tolerance; erythropoietin; macrophages; sepsis