bims-traimu 2024-04-28 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2024‒04‒28
eighteen papers selected by
Yantong Wan, Southern Medical University

The causes and consequences of trained immunity in myeloid cells.
Establishment of an in vitro model of monocyte-like THP-1 cells for trained immunity induced by bacillus Calmette-Guérin.
Streptococcus pneumoniae endopeptidase O induces trained immunity against numerous pathogen infections, a key role for G-CSF.
Diabetes Primes Neutrophils for Neutrophil Extracellular Trap Formation through Trained Immunity.
Ischemia does not provoke the full immune training repertoire in human cardiac fibroblasts.
Vaccines Induce Homeostatic Immunity, Generating Several Secondary Benefits.
Short-chain fatty acids inhibit the activation of T lymphocytes and myeloid cells and induce innate immune tolerance.
Immunization with a low dose of zymosan A confers resistance to depression-like behavior and neuroinflammatory responses in chronically stressed mice.
IL-10 dependent adaptation allows macrophages to adjust inflammatory responses to TLR4 stimulation history.
A single dose of angiotensin-(1-7) resolves eosinophilic inflammation and protects the lungs from a secondary inflammatory challenge.
Investigating the role of itaconate in macrophage activation and oxidative stress injury in sepsis-associated acute kidney injury.
Characterization of the genetic determinants of context-specific DNA methylation in primary monocytes.
CETP inhibition enhances monocyte activation and bacterial clearance and reduces streptococcus pneumonia-associated mortality in mice.
Impact of inflammatory preconditioning on murine microglial proteome response induced by focal ischemic brain injury.
Trem2 promotes foamy macrophage lipid uptake and survival in atherosclerosis.
Preventive Effect of the Total Polyphenols from Nymphaea candida on Sepsis-Induced Acute Lung Injury in Mice via Gut Microbiota and NLRP3, TLR-4/NF-κB Pathway.
Temporal coordination of the transcription factor response to H2O2 stress.
Exploring the role of CITED transcriptional regulators in the control of macrophage polarization.

Front Immunol. 2024 ;15 1365127

The causes and consequences of trained immunity in myeloid cells.

Gunapati Bhargavi, Selvakumar Subbian.

  Conventionally, immunity in humans has been classified as innate and adaptive, with the concept that only the latter type has an immunological memory/recall response against specific antigens or pathogens. Recently, a new concept of trained immunity (a.k.a. innate memory response) has emerged. According to this concept, innate immune cells can exhibit enhanced responsiveness to subsequent challenges, after initial stimulation with antigen/pathogen. Thus, trained immunity enables the innate immune cells to respond robustly and non-specifically through exposure or re-exposure to antigens/infections or vaccines, providing enhanced resistance to unrelated pathogens or reduced infection severity. For example, individuals vaccinated with BCG to protect against tuberculosis were also protected from malaria and SARS-CoV-2 infections. Epigenetic modifications such as histone acetylation and metabolic reprogramming (e.g. shift towards glycolysis) and their inter-linked regulations are the key factors underpinning the immune activation of trained cells. The integrated metabolic and epigenetic rewiring generates sufficient metabolic intermediates, which is crucial to meet the energy demand required to produce proinflammatory and antimicrobial responses by the trained cells. These factors also determine the efficacy and durability of trained immunity. Importantly, the signaling pathways and regulatory molecules of trained immunity can be harnessed as potential targets for developing novel intervention strategies, such as better vaccines and immunotherapies against infectious (e.g., sepsis) and non-infectious (e.g., cancer) diseases. However, aberrant inflammation caused by inappropriate onset of trained immunity can lead to severe autoimmune pathological consequences, (e.g., systemic sclerosis and granulomatosis). In this review, we provide an overview of conventional innate and adaptive immunity and summarize various mechanistic factors associated with the onset and regulation of trained immunity, focusing on immunologic, metabolic, and epigenetic changes in myeloid cells. This review underscores the transformative potential of trained immunity in immunology, paving the way for developing novel therapeutic strategies for various infectious and non-infectious diseases that leverage innate immune memory.

Keywords:  animal models; cell signaling; epigenetics; inflammation; innate immunity; macrophage; metabolism; neutrophil

DOI:  https://doi.org/10.3389/fimmu.2024.1365127
BMC Microbiol. 2024 Apr 20. 24(1): 130

Establishment of an in vitro model of monocyte-like THP-1 cells for trained immunity induced by bacillus Calmette-Guérin.

Jin-Chuan Xu, Kang Wu, Rui-Qing Ma, Jian-Hui Li, Jie Tao, Zhidong Hu, Xiao-Yong Fan.

  BACKGROUND: Mycobacteria bloodstream infections are common in immunocompromised people and usually have disastrous consequences. As the primary phagocytes in the bloodstream, monocytes and neutrophils play critical roles in the fight against bloodstream mycobacteria infections. In contrast to macrophages, the responses of monocytes infected with the mycobacteria have been less investigated.RESULTS: In this study, we first established a protocol for infection of non-adherent monocyte-like THP-1 cells (i.e. without the differentiation induced by phorbol 12-myristate 13-acetate (PMA) by bacillus Calmette-Guérin (BCG). Via the protocol, we were then capable of exploring the global transcriptomic profiles of non-adherent THP-1 cells infected with BCG, and found that NF-κB, MAPK and PI3K-Akt signaling pathways were enhanced, as well as some inflammatory chemokine/cytokine genes (e.g. CCL4, CXCL10, TNF and IL-1β) were up-regulated. Surprisingly, the Akt-HIF-mTOR signaling pathway was also activated, which induces trained immunity. In this in vitro infection model, increased cytokine responses to lipopolysaccharides (LPS) restimulation, higher cell viability, and decreased Candida albicans loads were observed.
CONCLUSIONS: We have first characterized the transcriptomic profiles of BCG-infected non-adherent THP-1 cells, and first developed a trained immunity in vitro model of the cells.

Keywords:  Bacillus Calmette-Guérin (BCG); Monocyte; THP-1; Trained immunity

DOI:  https://doi.org/10.1186/s12866-024-03191-x
Clin Immunol. 2024 Apr 23. pii: S1521-6616(24)00117-7. [Epub ahead of print] 110226

Streptococcus pneumoniae endopeptidase O induces trained immunity against numerous pathogen infections, a key role for G-CSF.

Wenlong Xu, Yuan Yuan, Zhaoche Shu, Ting Guo, Bichen Liu, Jiangming Xiao, Lian Li, Yibin Yin, Xuemei Zhang.

  Antibiotic resistance and the surge of infectious diseases during the pandemic present significant threats to human health. Trained immunity emerges as a promising and innovative approach to address these infections. Synthetic or natural fungal, parasitic and viral components have been reported to induce trained immunity. However, it is not clear whether bacterial virulence proteins can induce protective trained immunity. Our research demonstrates Streptococcus pneumoniae virulence protein PepO, is a highly potent trained immunity inducer for combating broad-spectrum infection. Our findings showcase that rPepO training confers robust protection to mice against various pathogenic infections by enhancing macrophage functionality. rPepO effectively re-programs macrophages, re-configures their epigenetic modifications and bolsters their immunological responses, which is independent of T or B lymphocytes. In vivo and in vitro experiments confirm that trained macrophage-secreted complement C3 activates peritoneal B lymphocyte and enhances its bactericidal capacity. In addition, we provide the first evidence that granulocyte colony-stimulating factor (G-CSF) derived from trained macrophages plays a pivotal role in shaping central-trained immunity. In summation, our research demonstrates the capability of rPepO to induce both peripheral and central trained immunity in mice, underscoring its potential application in broad-spectrum anti-infection therapy. Our research provides a new molecule and some new target options for infectious disease prevention.

Keywords:  B lymphocyte; G-CSF; Macrophage; Streptococcus pneumoniae endopeptidase O (PepO); Trained immunity

DOI:  https://doi.org/10.1016/j.clim.2024.110226
Research (Wash D C). 2024 ;7 0365

Diabetes Primes Neutrophils for Neutrophil Extracellular Trap Formation through Trained Immunity.

Sanjeeb Shrestha, Yu-Bin Lee, Hoyul Lee, Yeon-Kyung Choi, Bo-Yoon Park, Mi-Jin Kim, Young-Jin Youn, Sun-Hwa Kim, Soo-Jung Jung, Dong-Keun Song, Hee Kyung Jin, Jae-Sung Bae, In-Kyu Lee, Jae-Han Jeon, Chang-Won Hong.

Neutrophils are primed for neutrophil extracellular trap (NET) formation during diabetes, and excessive NET formation from primed neutrophils compromises wound healing in patients with diabetes. Here, we demonstrate that trained immunity mediates diabetes-induced NET priming in neutrophils. Under diabetic conditions, neutrophils exhibit robust metabolic reprogramming comprising enhanced glycolysis via the pentose phosphate pathway and fatty acid oxidation, which result in the accumulation of acetyl-coenzyme A. Adenosine 5'-triphosphate-citrate lyase-mediated accumulation of acetyl-coenzyme A and histone acetyltransferases further induce the acetylation of lysine residues on histone 3 (AcH3K9, AcH3K14, and AcH3K27) and histone 4 (AcH4K8). The pharmacological inhibition of adenosine 5'-triphosphate-citrate lyase and histone acetyltransferases completely inhibited high-glucose-induced NET priming. The trained immunity of neutrophils was further confirmed in neutrophils isolated from patients with diabetes. Our findings suggest that trained immunity mediates functional changes in neutrophils in diabetic environments, and targeting neutrophil-trained immunity may be a potential therapeutic target for controlling inflammatory complications of diabetes.

DOI: https://doi.org/10.34133/research.0365
Naunyn Schmiedebergs Arch Pharmacol. 2024 Apr 23.

Ischemia does not provoke the full immune training repertoire in human cardiac fibroblasts.

Constantin Mann, Carolin van Alst, Simone Gorressen, Rachel Nega, Dobromir Dobrev, Maria Grandoch, Anke C Fender.

  Trained immunity of monocytes, endothelial, and smooth muscle cells augments the cytokine response to secondary stimuli. Immune training is characterized by stabilization of hypoxia-inducible factor (HIF)-1α, mTOR activation, and aerobic glycolysis. Cardiac fibroblast (CF)-myofibroblast transition upon myocardial ischemia/reperfusion (I/R) features epigenetic and metabolic adaptations reminiscent of trained immunity. We assessed the impact of I/R on characteristics of immune training in human CF and mouse myocardium. I/R was simulated in vitro with transient metabolic inhibition. CF primed with simulated I/R or control buffer were 5 days later re-stimulated with Pam3CSK for 24 h. Mice underwent transient left anterior descending artery occlusion or sham operation with reperfusion for up to 5 days. HIF-regulated metabolic targets and cytokines were assessed by qPCR, immunoblot, and ELISA and glucose consumption, lactate release, and lactate dehydrogenase (LDH) by chromogenic assay. Simulated I/R increased HIF-1α stabilization, mTOR phosphorylation, glucose consumption, lactate production, and transcription of PFKB3 and F2RL3, a HIF-regulated target gene, in human CF. PGK1 and LDH mRNAs were suppressed. Intracellular LDH transiently increased after simulated I/R, and extracellular LDH showed sustained elevation. I/R priming increased abundance of pro-caspase-1, auto-cleaved active caspase-1, and the expression and secretion of interleukin (IL)-1β, but did not augment Pam3CSK-stimulated cytokine transcription or secretion. Myocardial I/R in vivo increased abundance of HIF-1 and the precursor and cleaved forms of caspase-1, caspase-11, and caspase-8, but not of LDH-A or phospho-mTOR. I/R partially reproduces features of immune training in human CF, specifically HIF-1α stabilization, aerobic glycolysis, mTOR phosphorylation, and PFKB3 transcription. I/R does not augment PGK1 or LDH expression or the cytokine response to Pam3CSK. Regulation of PAR4 and inflammasome caspases likely occurs independently of an immune training repertoire.

Keywords:  Cardiac fibroblasts; Glycolysis; Inflammasome; Ischemia; Myocardial; Trained immunity

DOI:  https://doi.org/10.1007/s00210-024-03107-6
Vaccines (Basel). 2024 Apr 09. pii: 396. [Epub ahead of print]12(4):

Vaccines Induce Homeostatic Immunity, Generating Several Secondary Benefits.

Arun B Arunachalam.

  The optimal immune response eliminates invading pathogens, restoring immune equilibrium without inflicting undue harm to the host. However, when a cascade of immunological reactions is triggered, the immune response can sometimes go into overdrive, potentially leading to harmful long-term effects or even death. The immune system is triggered mostly by infections, allergens, or medical interventions such as vaccination. This review examines how these immune triggers differ and why certain infections may dysregulate immune homeostasis, leading to inflammatory or allergic pathology and exacerbation of pre-existing conditions. However, many vaccines generate an optimal immune response and protect against the consequences of pathogen-induced immunological aggressiveness, and from a small number of unrelated pathogens and autoimmune diseases. Here, we propose an "immuno-wave" model describing a vaccine-induced "Goldilocks immunity", which leaves fine imprints of both pro-inflammatory and anti-inflammatory milieus, derived from both the innate and the adaptive arms of the immune system, in the body. The resulting balanced, 'quiet alert' state of the immune system may provide a jump-start in the defense against pathogens and any associated pathological inflammatory or allergic responses, allowing vaccines to go above and beyond their call of duty. In closing, we recommend formally investigating and reaping many of the secondary benefits of vaccines with appropriate clinical studies.

Keywords:  adaptive immunity; cytokine storm; homeostasis; immuno-wave model; infections; innate immunity; para-specific effect; trained immunity; vaccine

DOI:  https://doi.org/10.3390/vaccines12040396
Benef Microbes. 2023 Sep 01. 14(4): 401-419

Short-chain fatty acids inhibit the activation of T lymphocytes and myeloid cells and induce innate immune tolerance.

M Porbahaie, A Hummel, H Saouadogo, R M L Coelho, H F J Savelkoul, M Teodorowicz, R J J van Neerven.

The intestinal microbiota contributes to gut immune homeostasis, where short-chain fatty acids (SCFAs) function as the major mediators. We aimed to elucidate the immunomodulatory effects of acetate, propionate, and butyrate. With that in mind, we sought to characterise the expression of SCFA receptors and transporters as well as SCFAs' impact on the activation of different immune cells. Whereas all three SCFAs decreased tumour necrosis factor (TNF)-α production in activated T cells, only butyrate and propionate inhibited interferon (IFN)-γ, interleukin (IL)-17, IL-13, and IL-10 production. Butyrate and propionate inhibited the expression of the chemokine receptors CCR9 and CCR10 in activated T- and B-cells, respectively. Similarly, butyrate and propionate were effective inhibitors of IL-1β, IL-6, TNF-α, and IL-10 production in myeloid cells upon lipopolysaccharide and R848 stimulation. Acetate was less efficient at inhibiting cytokine production except for IFN-α. Moreover, SCFAs inhibited the production of IL-6 and TNF-α in monocytes, myeloid dendritic cells (mDC), and plasmacytoid dendritic cells (pDC), whereas acetate effects were relatively more prominent in pDCs. In monocytes and mDCs, acetate was a less efficient inhibitor, but it was equally effective in inhibiting pDCs activation. We also studied the ability of SCFAs to induce trained immunity or tolerance. Butyrate and propionate - but not acetate - prevented Toll-like receptor-mediated activation in SCFA-trained cells, as demonstrated by a reduced production of IL-6 and TNF-α. Our findings indicate that butyrate and propionate are equally efficient in inhibiting the adaptive and innate immune response and did not induce trained immunity. The findings may be explained by differential SCFA receptor and transporter expression profiles of the immune cells.

DOI: https://doi.org/10.1163/18762891-20220113
Behav Pharmacol. 2024 Apr 24.

Immunization with a low dose of zymosan A confers resistance to depression-like behavior and neuroinflammatory responses in chronically stressed mice.

Huijun Liu, Tao Zhu, Linlin Zhang, Fu Li, Meng Zheng, Bingran Chen, Haojie Zhu, Jie Ren, Xu Lu, Chao Huang.

Stimulation of the innate immune system prior to stress exposure is a possible strategy to prevent depression under stressful conditions. Based on the innate immune system stimulating activities of zymosan A, we hypothesize that zymosan A may prevent the development of chronic stress-induced depression-like behavior. Our results showed that a single injection of zymosan A 1 day before stress exposure at a dose of 2 or 4 mg/kg, but not at a dose of 1 mg/kg, prevented the development of depression-like behaviors in mice treated with chronic social defeat stress (CSDS). The prophylactic effect of a single zymosan A injection (2 mg/kg) on CSDS-induced depression-like behaviors disappeared when the time interval between zymosan A and stress exposure was extended from 1 day or 5 days to 10 days, which was rescued by a second zymosan A injection 10 days after the first zymosan A injection and 4 days (4×, once daily) of zymosan A injections 10 days before stress exposure. Further analysis showed that a single zymosan A injection (2 mg/kg) 1 day before stress exposure could prevent the CSDS-induced increase in pro-inflammatory cytokines in the hippocampus and prefrontal cortex. Inhibition of the innate immune system by pretreatment with minocycline (40 mg/kg) abolished the preventive effect of zymosan A on CSDS-induced depression-like behaviors and CSDS-induced increase in pro-inflammatory cytokines in the brain. These results suggest that activation of the innate immune system triggered by zymosan A prevents the depression-like behaviors and neuroinflammatory responses in the brain induced by chronic stress.

DOI: https://doi.org/10.1097/FBP.0000000000000774
bioRxiv. 2024 Mar 31. pii: 2024.03.28.587272. [Epub ahead of print]

IL-10 dependent adaptation allows macrophages to adjust inflammatory responses to TLR4 stimulation history.

H Bongartz, C Bradfield, J Gross, I D C Fraser, A Nita-Lazar, M Meier-Schellersheim.

During an infection, innate immune cells must adjust nature and strength of their responses to changing pathogen abundances. To determine how stimulation of the pathogen sensing TLR4 shapes subsequent macrophage responses, we systematically varied priming and restimulation concentrations of its ligand KLA. We find that different priming strengths have very distinct effects at multiple stages of the signaling response, including receptor internalization, MAPK activation, cytokine and chemokine production, and nuclear translocation and chromatin association of NFκB and IκB members. In particular, restimulation-induced TNF-α production required KLA doses equal to or greater than those used for prior exposure, indicating that macrophages can detect and adaptively respond to changing TLR4 stimuli. Interestingly, while such adaptation was dependent on the anti-inflammatory cytokine IL-10, exogenous concentrations of IL-10 corresponding to those secreted after strong priming did not exert suppressive effects on TNF-α without such prior priming, confirming the critical role of TLR4 stimulation history.

DOI: https://doi.org/10.1101/2024.03.28.587272
Inflamm Res. 2024 Apr 24.

A single dose of angiotensin-(1-7) resolves eosinophilic inflammation and protects the lungs from a secondary inflammatory challenge.

Giselle Santos Magalhaes, Juliana Fabiana Gregorio, Vinicius Amorim Beltrami, Franciel Batista Felix, Livia Oliveira-Campos, Caio Santos Bonilha, Renato Fraga Righetti, Iolanda de Fátima Lopes Calvo Tibério, Frederico B De Sousa, Barbara Maximino Rezende, Andréa Teixeira-Carvalho, Robson As Santos, Maria José Campagnole-Santos, Maria da Gloria Rodrigues-Machado, Mauro Martins Teixeira, Vanessa Pinho.

  OBJECTIVE: Angiotensin-(1-7) [Ang-(1-7)] is a pro-resolving mediator. It is not known whether the pro-resolving effects of Ang-(1-7) are sustained and protect the lung from a subsequent inflammatory challenge. This study sought to investigate the impact of treatment in face of a second allergic or lipopolysaccharide (LPS) challenge.METHODS: Mice, sensitized and challenged with ovalbumin (OVA), received a single Ang-(1-7) dose at the peak of eosinophilic inflammation, 24 h after the final OVA challenge. Subsequently, mice were euthanized at 48, 72, 96, and 120 h following the OVA challenge, and cellular infiltrate, inflammatory mediators, lung histopathology, and macrophage-mediated efferocytic activity were evaluated. The secondary inflammatory stimulus (OVA or LPS) was administered 120 h after the last OVA challenge, and subsequent inflammatory analyses were performed.
RESULTS: Treatment with Ang-(1-7) resulted in elevated levels of IL-10, CD4+Foxp3+, Mres in the lungs and enhanced macrophage-mediated efferocytic capacity. Moreover, in allergic mice treated with Ang-(1-7) and then subjected to a secondary OVA challenge, inflammation was also reduced. Similarly, in mice exposed to LPS, Ang-(1-7) effectively prevented the lung inflammation.
CONCLUSION: A single dose of Ang-(1-7) resolves lung inflammation and protect the lung from a subsequent inflammatory challenge highlighting its potential therapeutic for individuals with asthma.

Keywords:  Ang-(1–7); Chronic inflammation; Eosinophil; Inflammation; Resolution of inflammation

DOI:  https://doi.org/10.1007/s00011-024-01880-x
Mol Biol Rep. 2024 Apr 20. 51(1): 533

Investigating the role of itaconate in macrophage activation and oxidative stress injury in sepsis-associated acute kidney injury.

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

  BACKGROUND: Sepsis may be linked to oxidative stress and can be controlled by itaconate, an activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Nevertheless, the itaconate impact on sepsis-associated acute kidney injury (SA-AKI) has yet to be definitively established.METHODS: We employed SA-AKI mouse model through a cecal ligation and puncture (CLP) procedure for the in vivo investigation of the potential nephroprotective effect of itaconate in this study. A plasmid was transfected into RAW264.7 cells to examine the Nrf2 pathway function after itaconate administration. Finally, the immune-responsive gene 1-knockout (IRG1-/-) mice were used to study the itaconate impacts on oxidative stress-induced SA-AKI.
RESULTS: We have shown that 4-octyl itaconate (OI) significantly reduced CD11b-positive macrophage aggregation and activated the Nrf2 pathway in the bone marrow-derived macrophages (BMDM). The impacts of Nrf2 inhibitor ML385 on the anti-inflammatory and antioxidant properties of itaconate were found to be partial. OI inhibited lipopolysaccharide-induced oxidative stress injury in RAW264.7 macrophages and activated Nrf2 in the nucleus to hinder the expression of nuclear factor kappa B p65, thereby suppressing oxidative stress injury in the macrophages. Additionally, the introduction of the transfected plasmid resulted in a partial inhibition of the anti-inflammatory impact of itaconate. The kidney injury caused by sepsis exhibited greater severity in the IRG1-/- mice than in the wild type mice. Exogenous OI partially attenuated the kidney injury induced by sepsis in the IRG1-/- mice and suppressed the oxidative stress injury in macrophages.
CONCLUSIONS: This investigation offers new proof to support the itaconate function in the development and progression of SA-AKI and shows a new possible therapeutic agent for the SA-AKI treatment.

Keywords:  Acute kidney injury; Itaconate; Nrf2; Oxidative stress; Sepsis

DOI:  https://doi.org/10.1007/s11033-024-09462-0
Cell Genom. 2024 Apr 22. pii: S2666-979X(24)00097-1. [Epub ahead of print] 100541

Characterization of the genetic determinants of context-specific DNA methylation in primary monocytes.

James J Gilchrist, Hai Fang, Sara Danielli, Marketa Tomkova, Isar Nassiri, Esther Ng, Orion Tong, Chelsea Taylor, Dylan Muldoon, Lea R Z Cohen, Hussein Al-Mossawi, Evelyn Lau, Matt Neville, Benjamin Schuster-Boeckler, Julian C Knight, Benjamin P Fairfax.

  To better understand inter-individual variation in sensitivity of DNA methylation (DNAm) to immune activity, we characterized effects of inflammatory stimuli on primary monocyte DNAm (n = 190). We find that monocyte DNAm is site-dependently sensitive to lipopolysaccharide (LPS), with LPS-induced demethylation occurring following hydroxymethylation. We identify 7,359 high-confidence immune-modulated CpGs (imCpGs) that differ in genomic localization and transcription factor usage according to whether they represent a gain or loss in DNAm. Demethylated imCpGs are profoundly enriched for enhancers and colocalize to genes enriched for disease associations, especially cancer. DNAm is age associated, and we find that 24-h LPS exposure triggers approximately 6 months of gain in epigenetic age, directly linking epigenetic aging with innate immune activity. By integrating LPS-induced changes in DNAm with genetic variation, we identify 234 imCpGs under local genetic control. Exploring shared causal loci between LPS-induced DNAm responses and human disease traits highlights examples of disease-associated loci that modulate imCpG formation.

Keywords:  DNA methylation; LPS; cancer; epigenetic aging; genetics; innate immune activation; mQTL; monocytes

DOI:  https://doi.org/10.1016/j.xgen.2024.100541
JCI Insight. 2024 04 22. pii: e173205. [Epub ahead of print]9(8):

CETP inhibition enhances monocyte activation and bacterial clearance and reduces streptococcus pneumonia-associated mortality in mice.

Haoyu Deng, Wan Yi Liang, Le Qi Chen, Tin Ho Yuen, Basak Sahin, Dragoș M Vasilescu, Mark Trinder, Keith Walley, Patrick C.N. Rensen, John H Boyd, Liam R Brunham.

  Sepsis is a leading cause of mortality worldwide, and pneumonia is the most common cause of sepsis in humans. Low levels of high-density lipoprotein cholesterol (HDL-C) levels are associated with an increased risk of death from sepsis, and increasing levels of HDL-C by inhibition of cholesteryl ester transfer protein (CETP) decreases mortality from intraabdominal polymicrobial sepsis in APOE*3-Leiden.CETP mice. Here, we show that treatment with the CETP inhibitor (CETPi) anacetrapib reduced mortality from Streptococcus pneumoniae-induced sepsis in APOE*3-Leiden.CETP and APOA1.CETP mice. Mechanistically, CETP inhibition reduced the host proinflammatory response via attenuation of proinflammatory cytokine transcription and release. This effect was dependent on the presence of HDL, leading to attenuation of immune-mediated organ damage. In addition, CETP inhibition promoted monocyte activation in the blood prior to the onset of sepsis, resulting in accelerated macrophage recruitment to the lung and liver. In vitro experiments demonstrated that CETP inhibition significantly promoted the activation of proinflammatory signaling in peripheral blood mononuclear cells and THP1 cells in the absence of HDL; this may represent a mechanism responsible for improved bacterial clearance during sepsis. These findings provide evidence that CETP inhibition represents a potential approach to reduce mortality from pneumosepsis.

Keywords:  Bacterial infections; Cardiology; Infectious disease; Lipoproteins

DOI:  https://doi.org/10.1172/jci.insight.173205
Front Immunol. 2024 ;15 1227355

Impact of inflammatory preconditioning on murine microglial proteome response induced by focal ischemic brain injury.

Dario Lucas Helbing, Fabienne Haas, Emilio Cirri, Norman Rahnis, Therese Thuy Dung Dau, Erika Kelmer Sacramento, Nova Oraha, Leopold Böhm, Trim Lajqi, Pascal Fehringer, Helen Morrison, Reinhard Bauer.

  Preconditioning with lipopolysaccharide (LPS) induces neuroprotection against subsequent cerebral ischemic injury, mainly involving innate immune pathways. Microglia are resident immune cells of the central nervous system (CNS) that respond early to danger signals through memory-like differential reprogramming. However, the cell-specific molecular mechanisms underlying preconditioning are not fully understood. To elucidate the distinct molecular mechanisms of preconditioning on microglia, we compared these cell-specific proteomic profiles in response to LPS preconditioning and without preconditioning and subsequent transient focal brain ischemia and reperfusion, - using an established mouse model of transient focal brain ischemia and reperfusion. A proteomic workflow, based on isolated microglia obtained from mouse brains by cell sorting and coupled to mass spectrometry for identification and quantification, was applied. Our data confirm that LPS preconditioning induces marked neuroprotection, as indicated by a significant reduction in brain infarct volume. The established brain cell separation method was suitable for obtaining an enriched microglial cell fraction for valid proteomic analysis. The results show a significant impact of LPS preconditioning on microglial proteome patterns by type I interferons, presumably driven by the interferon cluster regulator proteins signal transducer and activator of transcription1/2 (STAT1/2).

Keywords:  inflammatory preconditioning; ischemic stroke; mice; microglia; neuroinflammation; phagocytosis; type I interferons

DOI:  https://doi.org/10.3389/fimmu.2024.1227355
Nat Cardiovasc Res. 2023 Nov;2(11): 1015-1031

Trem2 promotes foamy macrophage lipid uptake and survival in atherosclerosis.

Michael T Patterson, Maria M Firulyova, Yingzheng Xu, Hannah Hillman, Courtney Bishop, Alisha Zhu, Grant H Hickok, Patricia R Schrank, Christine E Ronayne, Zakariya Caillot, Gavin Fredrickson, Ainsley E Kennedy, Nisha Acharya, Jaap G Neels, Giulia Chinetti, Xavier Revelo, Ingunn M Stromnes, Stoyan Ivanov, Tyler D Bold, Konstantin Zaitsev, Jesse W Williams.

Atherosclerosis is driven by the expansion of cholesterol-loaded 'foamy' macrophages in the arterial intima. Factors regulating foamy macrophage differentiation and survival in plaque remain poorly understood. Here we show, using trajectory analysis of integrated single-cell RNA sequencing data and a genome-wide CRISPR screen, that triggering receptor expressed on myeloid cells 2 (Trem2) is associated with foamy macrophage specification. Loss of Trem2 led to a reduced ability of foamy macrophages to take up oxidized low-density lipoprotein (oxLDL). Myeloid-specific deletion of Trem2 showed an attenuation of plaque progression, even when targeted in established atherosclerotic lesions, and was independent of changes in circulating cytokines, monocyte recruitment or cholesterol levels. Mechanistically, we link Trem2-deficient macrophages with a failure to upregulate cholesterol efflux molecules, resulting in impaired proliferation and survival. Overall, we identify Trem2 as a regulator of foamy macrophage differentiation and atherosclerotic plaque growth and as a putative therapeutic target for atherosclerosis.

DOI: https://doi.org/10.1038/s44161-023-00354-3
Int J Mol Sci. 2024 Apr 12. pii: 4276. [Epub ahead of print]25(8):

Preventive Effect of the Total Polyphenols from Nymphaea candida on Sepsis-Induced Acute Lung Injury in Mice via Gut Microbiota and NLRP3, TLR-4/NF-κB Pathway.

Chenyang Li, Xinxin Qi, Lei Xu, Yuan Sun, Yan Chen, Yuhan Yao, Jun Zhao.

  This study aimed to investigate the preventive effects of the total polyphenols from Nymphaea candida (NCTP) on LPS-induced septic acute lung injury (ALI) in mice and its mechanisms. NCTP could significantly ameliorate LPS-induced lung tissue pathological injury in mice as well as lung wet/dry ratio and MPO activities (p < 0.05). NCTP could significantly decrease the blood leukocyte, neutrophil, monocyte, basophil, and eosinophil amounts and LPS contents in ALI mice compared with the model group (p < 0.05), improving lymphocyte amounts (p < 0.05). Moreover, compared with the model group, NCTP could decrease lung tissue TNF-α, IL-6, and IL-1β levels (p < 0.05) and downregulate the protein expression of TLR4, MyD88, TRAF6, IKKβ, IκB-α, p-IκB-α, NF-κB p65, p-NF-κB p65, NLRP3, ASC, and Caspase1 in lung tissues (p < 0.05). Furthermore, NCTP could inhibit ileum histopathological injuries, restoring the ileum tight junctions by increasing the expression of ZO-1 and occludin. Simultaneously, NCTP could reverse the gut microbiota disorder, restore the diversity of gut microbiota, increase the relative abundance of Clostridiales and Lachnospiraceae, and enhance the content of SCFAs (acetic acid, propionic acid, and butyric acid) in feces. These results suggested that NCTP has preventive effects on septic ALI, and its mechanism is related to the regulation of gut microbiota, SCFA metabolism, and the TLR-4/NF-κB and NLRP3 pathways.

Keywords:  NLRP3; Nymphaea candida; TLR-4/NF-κB pathway; acute lung injury; gut microbiota; inflammatory response; polyphenols; short-chain fatty acids

DOI:  https://doi.org/10.3390/ijms25084276
Nat Commun. 2024 Apr 23. 15(1): 3440

Temporal coordination of the transcription factor response to H2O2 stress.

Elizabeth Jose, Woody March-Steinman, Bryce A Wilson, Lisa Shanks, Chance Parkinson, Isabel Alvarado-Cruz, Joann B Sweasy, Andrew L Paek.

Oxidative stress from excess H2O2 activates transcription factors that restore redox balance and repair oxidative damage. Although many transcription factors are activated by H2O2, it is unclear whether they are activated at the same H2O2 concentration, or time. Dose-dependent activation is likely as oxidative stress is not a singular state and exhibits dose-dependent outcomes including cell-cycle arrest and cell death. Here, we show that transcription factor activation is both dose-dependent and coordinated over time. Low levels of H2O2 activate p53, NRF2 and JUN. Yet under high H2O2, these transcription factors are repressed, and FOXO1, NF-κB, and NFAT1 are activated. Time-lapse imaging revealed that the order in which these two groups of transcription factors are activated depends on whether H2O2 is administered acutely by bolus addition, or continuously through the glucose oxidase enzyme. Finally, we provide evidence that 2-Cys peroxiredoxins control which group of transcription factors are activated.

DOI: https://doi.org/10.1038/s41467-024-47837-w
Front Immunol. 2024 ;15 1365718

Exploring the role of CITED transcriptional regulators in the control of macrophage polarization.

Derek A Wiggins, Jack N Maxwell, David E Nelson.

  Macrophages are tissue resident innate phagocytic cells that take on contrasting phenotypes, or polarization states, in response to the changing combination of microbial and cytokine signals at sites of infection. During the opening stages of an infection, macrophages adopt the proinflammatory, highly antimicrobial M1 state, later shifting to an anti-inflammatory, pro-tissue repair M2 state as the infection resolves. The changes in gene expression underlying these transitions are primarily governed by nuclear factor kappaB (NF-κB), Janus kinase (JAK)/signal transducer and activation of transcription (STAT), and hypoxia-inducible factor 1 (HIF1) transcription factors, the activity of which must be carefully controlled to ensure an effective yet spatially and temporally restricted inflammatory response. While much of this control is provided by pathway-specific feedback loops, recent work has shown that the transcriptional co-regulators of the CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxy-terminal domain (CITED) family serve as common controllers for these pathways. In this review, we describe how CITED proteins regulate polarization-associated gene expression changes by controlling the ability of transcription factors to form chromatin complexes with the histone acetyltransferase, CBP/p300. We will also cover how differences in the interactions between CITED1 and 2 with CBP/p300 drive their contrasting effects on pro-inflammatory gene expression.

Keywords:  CBP/p300; CITED1; CITED2; NF-κB; STAT1; inflammation; innate immunity; macrophage

DOI:  https://doi.org/10.3389/fimmu.2024.1365718