bims-traimu 2024-11-03 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2024–11–03
eleven papers selected by
Yantong Wan, Southern Medical University

Is There a Role for Immunostimulant Bacterial Lysates in the Management of Respiratory Tract Infection?
Innate memory against viruses.
Alternations in inflammatory macrophage niche drive phenotypic and functional plasticity of Kupffer cells.
Mechanism of lactic acidemia-promoted pulmonary endothelial cells death in sepsis: role for CIRP-ZBP1-PANoptosis pathway.
Local Controlled Delivery of IL-4 Decreases Inflammatory Bone Loss in a Murine Model of Periodontal Disease.
TLR Agonist Nano Immune Therapy Clears Peritoneal and Systemic Ovarian Cancer.
Kupffer cell reverse migration into the liver sinusoids mitigates neonatal sepsis and meningitis.
Sepsis-induced changes in pyruvate metabolism: insights and potential therapeutic approaches.
E2F2 Reprograms Macrophage Function By Modulating Material and Energy Metabolism in the Progression of Metabolic Dysfunction-Associated Steatohepatitis.
Intranasal immunization with poly I:C and CpG ODN adjuvants enhances the protective efficacy against Helicobacter pylori infection in mice.
Dexmedetomidine Ameliorates Myocardial Ischemia-Reperfusion Injury by Inhibiting MDH2 Lactylation via Regulating Metabolic Reprogramming.

Biomolecules. 2024 Oct 02. pii: 1249. [Epub ahead of print]14(10):

Is There a Role for Immunostimulant Bacterial Lysates in the Management of Respiratory Tract Infection?

Mario Di Gioacchino, Francesca Santilli, Andrea Pession.

  Bacterial Lysates are immunostimulants clinically prescribed for the prevention of respiratory tract infections (RTIs). It has been shown that Bacterial Lysates upregulate the immune system, acting both on innate and adaptive reactions. In fact, there are demonstrations of their efficacy in restoring the integrity and immune function of epithelial barriers, activating ILC3 and dendritic cells with an enhanced Th1 response, and producing serum IgG and serum and salivary IgA specific to the administered bacterial antigens. The activated immune system also protects against other bacteria and viruses due to a trained immunity effect. Most studies show that the number of RTIs and their severity decrease in Bacterial Lysates-pretreated patients, without relevant side effects. The Bacterial Lysates treatment, in addition to reducing the number of RTIs, also prevents the deterioration of the underlying disease (i.e., COPD) induced by repeated infections. Despite these positive data, the most recent meta-analyses evidence the weakness of the studies performed, which are of low quality and have an inadequate number of patients, some of which were non-randomized while others were without a control group or were performed contemporarily in different clinical conditions or with different ages. The high heterogeneity of the studies does not allow us to state Bacterial Lysates' effectiveness in preventing RTIs with sufficient certainty. To completely define their indications, double-blind, placebo-controlled, multicenter, randomized clinical trials should be performed for each product and for each indication. The study population should be adequate for each indication. For this purpose, an adequate run-in phase will be necessary.

Keywords:  Bacterial Lysates; COPD; adaptive immune system; asthma; children; elderly; innate immune system; respiratory tract infection

DOI:  https://doi.org/10.3390/biom14101249
Nat Immunol. 2024 Nov;25(11): 1979

Innate memory against viruses.

Paula Jauregui.

DOI: https://doi.org/10.1038/s41590-024-02009-2
Nat Commun. 2024 Oct 29. 15(1): 9337

Alternations in inflammatory macrophage niche drive phenotypic and functional plasticity of Kupffer cells.

Han-Ying Huang, Yan-Zhou Chen, Chuang Zhao, Xin-Nan Zheng, Kai Yu, Jia-Xing Yue, Huai-Qiang Ju, Yan-Xia Shi, Lin Tian.

Inflammatory signals lead to recruitment of circulating monocytes and induce their differentiation into pro-inflammatory macrophages. Therefore, whether blocking inflammatory monocytes can mitigate disease progression is being actively evaluated. Here, we employ multiple lineage-tracing models and show that monocyte-derived macrophages (mo-mac) are the major population of immunosuppressive, liver metastasis-associated macrophages (LMAM), while the proportion of Kupffer cells (KC) as liver-resident macrophages is diminished in metastatic nodules. Paradoxically, genetic ablation of mo-macs results in only a marginal decrease in LMAMs. Using a proliferation-recording system and a KC-tracing model in a monocyte-deficient background, we find that LMAMs can be replenished either via increased local macrophage proliferation or by promoting KC infiltration. In the latter regard, KCs undergo transient proliferation and exhibit substantial phenotypic and functional alterations through epigenetic reprogramming following the vacating of macrophage niches by monocyte depletion. Our data thus suggest that a simultaneous blockade of monocyte recruitment and macrophage proliferation may effectively target immunosuppressive myelopoiesis and reprogram the microenvironment towards an immunostimulatory state.

DOI: https://doi.org/10.1038/s41467-024-53659-7
Mil Med Res. 2024 Oct 28. 11(1): 71

Mechanism of lactic acidemia-promoted pulmonary endothelial cells death in sepsis: role for CIRP-ZBP1-PANoptosis pathway.

Ting Gong, Qing-De Wang, Patricia A Loughran, Yue-Hua Li, Melanie J Scott, Timothy R Billiar, You-Tan Liu, Jie Fan.

   BACKGROUND: Sepsis is often accompanied by lactic acidemia and acute lung injury (ALI). Clinical studies have established that high serum lactate levels are associated with increased mortality rates in septic patients. We further observed a significant correlation between the levels of cold-inducible RNA-binding protein (CIRP) in plasma and bronchoalveolar lavage fluid (BALF), as well as lactate levels, and the severity of post-sepsis ALI. The underlying mechanism, however, remains elusive.
METHODS: C57BL/6 wild type (WT), Casp8-/-, Ripk3-/-, and Zbp1-/- mice were subjected to the cecal ligation and puncture (CLP) sepsis model. In this model, we measured intra-macrophage CIRP lactylation and the subsequent release of CIRP. We also tracked the internalization of extracellular CIRP (eCIRP) in pulmonary vascular endothelial cells (PVECs) and its interaction with Z-DNA binding protein 1 (ZBP1). Furthermore, we monitored changes in ZBP1 levels in PVECs and the consequent activation of cell death pathways.
RESULTS: In the current study, we demonstrate that lactate, accumulating during sepsis, promotes the lactylation of CIRP in macrophages, leading to the release of CIRP. Once eCIRP is internalized by PVEC through a Toll-like receptor 4 (TLR4)-mediated endocytosis pathway, it competitively binds to ZBP1 and effectively blocks the interaction between ZBP1 and tripartite motif containing 32 (TRIM32), an E3 ubiquitin ligase targeting ZBP1 for proteasomal degradation. This interference mechanism stabilizes ZBP1, thereby enhancing ZBP1-receptor-interacting protein kinase 3 (RIPK3)-dependent PVEC PANoptosis, a form of cell death involving the simultaneous activation of multiple cell death pathways, thereby exacerbating ALI.
CONCLUSIONS: These findings unveil a novel pathway by which lactic acidemia promotes macrophage-derived eCIRP release, which, in turn, mediates ZBP1-dependent PVEC PANoptosis in sepsis-induced ALI. This finding offers new insights into the molecular mechanisms driving sepsis-related pulmonary complications and provides potential new therapeutic strategies.

Keywords:  Extracellular cold-inducible RNA-binding protein (eCIRP); PANoptosis; Sepsis-induced acute lung injury (ALI); Ubiquitination; ZBP1

DOI:  https://doi.org/10.1186/s40779-024-00574-z
J Immunol. 2024 Oct 28. pii: ji2400332. [Epub ahead of print]

Local Controlled Delivery of IL-4 Decreases Inflammatory Bone Loss in a Murine Model of Periodontal Disease.

Mostafa Shehabeldin, Julie Kobyra, Yejin Cho, Jin Gao, Rong Chong, Tracy Tabib, Robert Lafyatis, Steven R Little, Charles Sfeir.

Chronic inflammatory diseases are a leading global health problem. In many of these diseases, the consistent presence of systemic low-grade inflammation induces tissue damage. This is true in conditions such as diabetes, arthritis, and autoimmune disorders, where an overactive and uncontrolled host immune response is a major driver of immunopathology. Central to this overactive and destructive host response are macrophages, the major phagocytic cells within the innate immune system. These cells exhibit a dual role in both host defense against invading pathogens and promotion of tissue repair during inflammation resolution. Those unique characteristics make macrophages an excellent target for therapeutic interventions in many chronic inflammatory conditions. Using periodontal disease as a model of chronic inflammation, we sought to assess the feasibility of using a controlled drug delivery strategy to target macrophages within the oral cavity. To that end, IL-4 was encapsulated within a biodegradable polymer carrier and locally delivered into the inflamed periodontal tissues. Our data indicate that local sustained delivery of IL-4 decreased inflammatory bone loss and promoted bone gain in the diseased mouse periodontium. Those effects correlated with a shift of local macrophage population toward a prorepair phenotype. Using single-cell RNA sequencing technology, we found that IL-4 delivery reversed several proinflammatory pathways associated with tissue destructive macrophages. Together, our data suggest that sustained delivery of IL-4 may be a viable therapeutic option for chronic diseases characterized by immune-mediated tissue damage.

DOI: https://doi.org/10.4049/jimmunol.2400332
Adv Healthc Mater. 2024 Oct 31. e2402966

TLR Agonist Nano Immune Therapy Clears Peritoneal and Systemic Ovarian Cancer.

Ben Marwedel, Henning De May, Lauren Anderson, Lorél Y Medina, Ellie Kennedy, Erica Flores, John O'Rourke, Marian Olewine, Irina Lagutina, Lillian Fitzpatrick, Fred Shultz, Donna F Kusewitt, Eric Bartee, Sarah Adams, Achraf Noureddine, Rita E Serda.

  Intraperitoneal (IP) administration of immunogenic mesoporous silica nanoparticles (iMSN) in a mouse model of metastatic ovarian cancer promotes the development of tumor-specific CD8+ T cells and protective immunity. IP delivery of iMSN functionalized with the Toll-like receptor (TLR) agonists polyethyleneimine (PEI), CpG oligonucleotide, and monophosphoryl lipid A (MPLA) stimulated rapid uptake by all peritoneal myeloid subsets. Myeloid cells quickly transported iMSN to milky spots and fat-associated lymphoid clusters (FALCs) present in tumor-burdened adipose tissues, leading to a reduction in suppressive T cells and an increase in activated memory T cells. Two doses of iMSN cleared or reduced ovarian and colorectal cancer and protected against future tumor engraftment. In contrast, subcutaneous (SC) and intravenous (IV) delivery of iMSN were without therapeutic effect in mice with peritoneal metastases, supporting the need for activation of regional immune cells. Remarkably, intraperitoneal delivery of iMSN cleared subcutaneously implanted ovarian cancer, supporting homing of antigen specific T cells to extraperitoneal tumor sites.

Keywords:  intraperitoneal administration; mesoporous silica nanoparticle; ovarian cancer; peritoneal metastasis; toll‐like receptor agonist

DOI:  https://doi.org/10.1002/adhm.202402966
Sci Immunol. 2024 Nov;9(101): eadq9704

Kupffer cell reverse migration into the liver sinusoids mitigates neonatal sepsis and meningitis.

Bruna Araujo David, Jawairia Atif, Fernanda Vargas E Silva Castanheira, Tamanna Yasmin, Adrien Guillot, Yeni Ait Ahmed, Moritz Peiseler, Josefien W Hommes, Lilian Salm, Marie-Anne Brundler, Bas G J Surewaard, Wael Elhenawy, Sonya MacParland, Florent Ginhoux, Kathy McCoy, Paul Kubes.

In adults, liver-resident macrophages, or Kupffer cells (KCs), reside in the sinusoids and sterilize circulating blood by capturing rapidly flowing microbes. We developed quantitative intravital imaging of 1-day-old mice combined with transcriptomics, genetic manipulation, and in vivo infection assays to interrogate increased susceptibility of newborns to bloodstream infections. Whereas 1-day-old KCs were better at catching Escherichia coli in vitro, we uncovered a critical 1-week window postpartum when KCs have limited access to blood and must translocate from liver parenchyma into the sinusoids. KC migration was independent of the microbiome but depended on macrophage migration inhibitory factor, its receptor CD74, and the adhesion molecule CD44. On the basis of our findings, we propose a model of progenitor macrophage seeding of the liver sinusoids via a reverse transmigration process from liver parenchyma. These results also illustrate the importance of developing newborn mouse models to understand newborn immunity and disease.

DOI: https://doi.org/10.1126/sciimmunol.adq9704
EMBO Mol Med. 2024 Oct 28.

Sepsis-induced changes in pyruvate metabolism: insights and potential therapeutic approaches.

Louise Nuyttens, Jolien Vandewalle, Claude Libert.

  Sepsis is a heterogeneous syndrome resulting from a dysregulated host response to infection. It is considered as a global major health priority. Sepsis is characterized by significant metabolic perturbations, leading to increased circulating metabolites such as lactate. In mammals, pyruvate is the primary substrate for lactate production. It plays a critical role in metabolism by linking glycolysis, where it is produced, with the mitochondrial oxidative phosphorylation pathway, where it is oxidized. Here, we provide an overview of all cytosolic and mitochondrial enzymes involved in pyruvate metabolism and how their activities are disrupted in sepsis. Based on the available data, we also discuss potential therapeutic strategies targeting these pyruvate-related enzymes leading to enhanced survival.

Keywords:  Lactate; Metabolism; Mitochondria; Pyruvate; Sepsis

DOI:  https://doi.org/10.1038/s44321-024-00155-6
Adv Sci (Weinh). 2024 Oct 28. e2410880

E2F2 Reprograms Macrophage Function By Modulating Material and Energy Metabolism in the Progression of Metabolic Dysfunction-Associated Steatohepatitis.

Zheng Liu, Hao Wang, Yuan Liang, Mu Liu, Qiyuan Huang, Mingming Wang, Jinren Zhou, Qingfa Bu, Haoming Zhou, Ling Lu.

  Macrophages are essential for the development of steatosis, hepatic inflammation, and fibrosis in metabolic dysfunction-associated steatohepatitis(MASH). However, the roles of macrophage E2F2 in the progression of MASH have not been elucidated. This study reveals that the expression of macrophage E2F2 is dramatically downregulated in MASH livers from mice and humans, and that this expression is adversely correlated with the severity of the disease. Myeloid-specific E2F2 depletion aggravates intrahepatic inflammation, hepatic stellate cell activation, and hepatocyte lipid accumulation during MASH progression. Mechanistically, E2F2 can inhibit the SLC7A5 transcription directly. E2F2 deficiency upregulates the expression of SLC7A5 to mediate amino acids flux, resulting in enhanced glycolysis, impaired mitochondrial function, and increased macrophages proinflammatory response in a Leu-mTORC1-dependent manner. Moreover, bioinformatics analysis and CUT &Tag assay identify the direct binding of Nrf2 to E2F2 promoter to promote its transcription and nuclear translocation. Genetic or pharmacological activation of Nrf2 effectively activates E2F2 to attenuate the MASH progression. Finally, patients treated with CDK4/6 inhibitors demonstrate reduced E2F2 activity but increased SLC7A5 activity in PBMCs. These findings indicated macrophage E2F2 suppresses MASH progression by reprogramming amino acid metabolism via SLC7A5- Leu-mTORC1 signaling pathway. Activating E2F2 holds promise as a therapeutic strategy for MASH.

Keywords:  amino acid transportation; glycolysis; macrophage; metabolic dysfunction‐associated steatohepatitis; slc7a5

DOI:  https://doi.org/10.1002/advs.202410880
Microbes Infect. 2024 Oct 24. pii: S1286-4579(24)00175-8. [Epub ahead of print] 105433

Intranasal immunization with poly I:C and CpG ODN adjuvants enhances the protective efficacy against Helicobacter pylori infection in mice.

Min Sun, Yu Liu, Xiumei Ni, Runqing Tan, Yi Wang, Yajun Jiang, Dingxin Ke, Han Du, Gang Guo, Kaiyun Liu.

  Helicobacter pylori (H. pylori) infection is a serious public health issue, and development of vaccines is a desirable preventive strategy for H. pylori. Toll-like receptor (TLR) ligands have shown potential as vaccine adjuvants that induce immune responses, but polyinosinic-polycytidylic acid (poly I:C), a nucleic acid-based TLR9 ligand, is less well studied in H. pylori vaccine research. Here, we evaluated the effects of poly I:C and CpG oligodeoxynucleotide (CpG ODN), a nucleic acid TLR3 ligand, as adjuvants in combination with the H. pylori recombinant proteins LpoB and UreA to protect against H. pylori infection. For analysis of specific immune responses, the levels of specific antibodies and splenic cytokines were measured in the immunized mice. Compared with CpG ODN, poly I:C could induce mucosal sIgA antibody responses and reduce H. pylori colonization. Additionally, the combination of poly I:C and CpG ODN caused greater immunoprotection and significantly reduced gastritis, exerting synergistic effects. Analysis of splenic cytokines revealed that poly I:C mainly triggered a mixed Th1/Th2/Th17 immune response, whereas the combination of CpG ODN and poly I:C induced a Th1/Th17 immune response. Our findings indicated that increased levels of mucosal sIgA antibodies and a robust splenic Th1/Th17 immune response were associated with reduced H. pylori colonization in vaccinated mice. This study identified a potential TLR ligand adjuvant for developing more effective H. pylori vaccines.

Keywords:  CpG ODN; Helicobacter pylori; Th1/Th17 immune response; Toll-like receptor ligand; immune adjuvant; poly I:C

DOI:  https://doi.org/10.1016/j.micinf.2024.105433
Adv Sci (Weinh). 2024 Oct 28. e2409499

Dexmedetomidine Ameliorates Myocardial Ischemia-Reperfusion Injury by Inhibiting MDH2 Lactylation via Regulating Metabolic Reprogramming.

Han She, Yi Hu, Guozhi Zhao, Yunxia Du, Yinyu Wu, Wei Chen, Yong Li, Yi Wang, Lei Tan, Yuanqun Zhou, Jie Zheng, Qinghui Li, Hong Yan, Qingxiang Mao, Deyu Zuo, Liangming Liu, Tao Li.

  Myocardial ischemia-reperfusion injury (MIRI) significantly worsens the outcomes of patients with cardiovascular diseases. Dexmedetomidine (Dex) is recognized for its cardioprotective properties, but the related mechanisms, especially regarding metabolic reprogramming, have not been fully clarified. A total of 60 patients with heart valve disease are randomly assigned to Dex or control group. Blood samples are collected to analyze cardiac injury biomarkers and metabolomics. In vivo and vitro rat models of MIRI are utilized to assess the effects of Dex on cardiac function, lactate production, and mitochondrial function. It is found that postoperative CK-MB and cTNT levels are significantly lower in the Dex group. Metabolomics reveals that Dex regulates metabolic reprogramming and reduces lactate level. In Dex-treated rats, the myocardial infarction area is reduced, and myocardial contractility is improved. Dex inhibits glycolysis, reduces lactate, and improves mitochondrial function following MIRI. Lactylation proteomics identifies that Dex reduces the lactylation of Malate Dehydrogenase 2（MDH2), thus alleviating myocardial injury. Further studies reveal that MDH2 lactylation induces ferroptosis, leading to MIRI by impairing mitochondrial function. Mechanistic analyses reveal that Dex upregulates Nuclear Receptor Subfamily 3 Group C Member 1（NR3C1) phosphorylation, downregulates Pyruvate Dehydrogenase Kinase 4 (PDK4), and reduces lactate production and MDH2 lactylation. These findings provide new therapeutic targets and mechanisms for the treatment for MIRI.

Keywords:  dexmedetomidine; ferroptosis; lactylation; metabolic reprogramming; myocardial ischemia‐reperfusion injury

DOI:  https://doi.org/10.1002/advs.202409499