bims-traimu 2023-10-01 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2023–10–01
eleven papers selected by
Yantong Wan, Southern Medical University

The mechanisms and factors that induce trained immunity in arthropods and mollusks.
The Formation of Non-Specific Immunological Memory Phenotype in Human Monocyte-Like THP-1 and U-937 Cell Lines.
Potential impact of trained innate immunity on the pathophysiology of metabolic dysfunction-associated fatty liver disease.
BCG mediated protection of the lung against experimental SARS-CoV-2 infection.
Using BCG vaccine to enhance non-specific protection of health care workers during the COVID-19 pandemic: a randomized controlled trial.
Pleiotropic Effects of Influenza Vaccination.
New Insights in Immunometabolism in Neonatal Monocytes and Macrophages in Health and Disease.
Utility of In Vitro Cellular Models of Low-Dose Lipopolysaccharide in Elucidating the Mechanisms of Anti-Inflammatory and Wound-Healing-Promoting Effects of Lipopolysaccharide Administration In Vivo.
Oxidized Low-Density Lipoprotein Accumulation Suppresses Glycolysis and Attenuates the Macrophage Inflammatory Response by Diverting Transcription from the HIF-1α to the Nrf2 Pathway.
A TLR4 Agonist Induces Osteosarcoma Regression by Inducing an Antitumor Immune Response and Reprogramming M2 Macrophages to M1 Macrophages.
SGLT2 inhibitors prevent LPS-induced M1 macrophage polarization and alleviate inflammatory bowel disease by downregulating NHE1 expression.

Front Immunol. 2023 ;14 1241934

The mechanisms and factors that induce trained immunity in arthropods and mollusks.

Mingming Zhao, Zhongyang Lin, Zhihong Zheng, Defu Yao, Shen Yang, Yongzhen Zhao, Xiuli Chen, Jude Juventus Aweya, Yueling Zhang.

  Besides dividing the organism's immune system into adaptive and innate immunity, it has long been thought that only adaptive immunity can establish immune memory. However, many studies have shown that innate immunity can also build immunological memory through epigenetic reprogramming and modifications to resist pathogens' reinfection, known as trained immunity. This paper reviews the role of mitochondrial metabolism and epigenetic modifications and describes the molecular foundation in the trained immunity of arthropods and mollusks. Mitochondrial metabolism and epigenetic modifications complement each other and play a key role in trained immunity.

Keywords:  arthropods; epigenetic modifications; metabolism; mollusks; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2023.1241934
Bull Exp Biol Med. 2023 Sep 28.

The Formation of Non-Specific Immunological Memory Phenotype in Human Monocyte-Like THP-1 and U-937 Cell Lines.

A P Lykov, S N Belogorodtsev, E K Nemkova, A Vetlugina, T M Terekhova, Y Sh Schwartz.

  We studied the formation of the phenotype of non-specific immunological memory (trained immunity) in human monocyte-like THP-1 and U-937 cell lines. The absence of the lag phase after primary contact with the pathogen (Mycobacterium bovis, BCG vaccine) does not contribute to the formation of the trained immunity phenotype in the cells. The presence of the lag phase promotes the development of the trained immunity phenotype, especially in THP-1 cells. The second stimulation (bacterial LPS) did not increase the production of lactate, nitric oxide, and glucose consumption by cells, which can be a consequence of the Warburg phenomenon in these monocyte-like human cell lines.

Keywords:  cytokines; glucose; lactate; monocyte-like lines; trained immunity

DOI:  https://doi.org/10.1007/s10517-023-05890-3
Clin Immunol. 2023 Sep 22. pii: S1521-6616(23)00539-9. [Epub ahead of print] 109776

Potential impact of trained innate immunity on the pathophysiology of metabolic dysfunction-associated fatty liver disease.

Jannis Kountouras, Evangelos Kazakos, Stergios A Polyzos, Apostolis Papaefthymiou, Christos Zavos, Maria Tzitiridou-Chatzopoulou, Dimitrios Chatzopoulos, Elisabeth Vardaka, Anthia Gatopoulou, Foteini Kyrailidi, Maria C Mouratidou, Michael Doulberis.

  Metabolic dysfunction-associated fatty liver disease (MAFLD) occurs in a low-grade inflammatory milieu dependent on highly complex networks that span well-beyond the hepatic tissue injury. Dysfunctional systemic metabolism that characterizes the disease, is further induced in response to environmental cues that modify energy and metabolic cellular demands, thereby altering the availability of specific substrates that profoundly regulate, through epigenetic mechanisms, the phenotypic heterogeneity of immune cells and influence hematopoietic stem cell differentiation fate. This immuno-metabolic signaling drives the initiation of downstream effector pathways and results in the decompensation of hepatic homeostasis that precedes pro-fibrotic events. Recent evidence suggests that innate immune cells reside in different tissues in a memory effector state, a phenomenon termed trained immunity, that may be activated by subsequent exogenous (e.g., microbial, dietary) or endogenous (e.g., metabolic, apoptotic) stimuli. This process leads to long-term modifications in the epigenetic landscape that ultimately precondition the cells towards enhanced transcription of inflammatory mediators that accelerates MAFLD development and/or progression. In this mini review we aimed to present current evidence on the potential impact of trained immunity on the pathophysiology of MAFLD, shedding light on the complex immunobiology of the disease and providing novel potential therapeutic strategies to restrain the burden of the disease.

Keywords:  Autoimmune disorders; Epigenetic reprogramming; Metabolic dysfunction-associated fatty liver disease; Metabolic rewiring; Trained immunity

DOI:  https://doi.org/10.1016/j.clim.2023.109776
Front Immunol. 2023 ;14 1232764

BCG mediated protection of the lung against experimental SARS-CoV-2 infection.

Kerry L Hilligan, Sivaranjani Namasivayam, Alan Sher.

  The observation of reduced COVID-19 incidence and severity in populations receiving neonatal intradermal BCG vaccination vaccine raised the question of whether BCG can induce non-specific protection against the SARS-CoV-2 (SCV2) virus. Subsequent epidemiologic studies and clinical trials have largely failed to support this hypothesis. Furthermore, in small animal model studies all investigators have failed to observe resistance to viral challenge in response to BCG immunization by the conventional and clinically acceptable intradermal or subcutaneous routes. Nevertheless, BCG administered by the intravenous (IV) route has been shown to strongly protect both hamsters and mice against SCV2 infection and disease. In this Perspective, we review the current data on the effects of BCG vaccination on resistance to COVID-19 as well as summarize recent work in rodent models on the mechanisms by which IV administered BCG promotes resistance to the virus and discuss the translational implications of these findings.

Keywords:  Bacille Calmette-Guérin (BCG); COVID-19; interferon gamma (IFNγ); lung; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2023.1232764
J Infect Dis. 2023 Sep 29. pii: jiad422. [Epub ahead of print]

Using BCG vaccine to enhance non-specific protection of health care workers during the COVID-19 pandemic: a randomized controlled trial.

Anne Marie Rosendahl Madsen, Frederik Schaltz-Buchholzer, Sebastian Nielsen, Thomas Benfield, Morten Bjerregaard-Andersen, Lars Skov Dalgaard, Christine Dam, Sisse Bolm Ditlev, Gulia Faizi, Mihnaz Azizi, Zainab Nadhim Hameed, Isik Somuncu Johansen, Poul-Erik Kofoed, Tyra Grove Krause, Gitte Schultz Kristensen, Ellen Christine Leth Loekkegaard, Christian Backer Mogensen, Libin Mohamed, Emilie Sundhaugen Oedegaard, Anne Ostenfeld, Marcus Kjaer Soerensen, Christian Wejse, Mihai G Netea, Peter Aaby, Christine Stabell Benn.

   BACKGROUND: The BCG (Bacillus Calmette-Guérin) vaccine can induce non-specific protection against unrelated infections. We aimed to test the effect of BCG on absenteeism and health of Danish health care workers (HCWs) during the COVID-19 pandemic.
METHODS: A single-blinded randomized controlled trial including 1,221 HCWs from nine Danish hospitals. Participants were randomized 1:1 to standard dose BCG or placebo. Primary outcome was days of unplanned absenteeism. Main secondary outcomes were incidence of COVID-19, all-cause hospitalization, and infectious disease episodes.
RESULTS: There was no significant effect of BCG on unplanned absenteeism. Mean number of days absent per 1000 workdays was 20 in the BCG group and 17 in the placebo group (RR 1.23, 95% credibility interval: 0.98 to 1.53). BCG had no effect on incidence of COVID-19 or all-cause hospitalization overall. In secondary analyses BCG re-vaccination was associated with higher COVID-19 incidence (HR 2.47, 95% confidence interval (CI): 1.07 to 5.71), but also reduced risk of hospitalization (HR 0.28, CI: 0.09 to 0.86). The incidence of infectious disease episodes was similar between randomization groups (HR 1.09, CI: 0.96 to 1.24).
CONCLUSIONS: In this relatively healthy cohort of HCWs, there was no overall effect of BCG on any of the study outcomes.

Keywords:  BCG vaccination; COVID-19; SARS-CoV-2; epidemic; health care worker; non-specific effects of vaccines; randomised controlled trial

DOI:  https://doi.org/10.1093/infdis/jiad422
Vaccines (Basel). 2023 Aug 25. pii: 1419. [Epub ahead of print]11(9):

Pleiotropic Effects of Influenza Vaccination.

Astrid Johannesson Hjelholt, Cecilia Bergh, Deepak L Bhatt, Ole Fröbert, Mads Fuglsang Kjolby.

  Influenza vaccines are designed to mimic natural influenza virus exposure and stimulate a long-lasting immune response to future infections. The evolving nature of the influenza virus makes vaccination an important and efficacious strategy to reduce healthcare-related complications of influenza. Several lines of evidence indicate that influenza vaccination may induce nonspecific effects, also referred to as heterologous or pleiotropic effects, that go beyond protection against infection. Different explanations are proposed, including the upregulation and downregulation of cytokines and epigenetic reprogramming in monocytes and natural killer cells, imprinting an immunological memory in the innate immune system, a phenomenon termed "trained immunity". Also, cross-reactivity between related stimuli and bystander activation, which entails activation of B and T lymphocytes without specific recognition of antigens, may play a role. In this review, we will discuss the possible nonspecific effects of influenza vaccination in cardiovascular disease, type 1 diabetes, cancer, and Alzheimer's disease, future research questions, and potential implications. A discussion of the potential effects on infections by other pathogens is beyond the scope of this review.

Keywords:  Alzheimer’s disease; cancer; cardiovascular disease; epigenetic modification; heterologous effects; influenza vaccine; nonspecific effects; pleiotropic effects; trained immunity; type 1 diabetes mellitus

DOI:  https://doi.org/10.3390/vaccines11091419
Int J Mol Sci. 2023 Sep 16. pii: 14173. [Epub ahead of print]24(18):

New Insights in Immunometabolism in Neonatal Monocytes and Macrophages in Health and Disease.

Renske de Jong, Klaus Tenbrock, Kim Ohl.

  It is well established that the neonatal immune system is different from the adult immune system. A major task of the neonatal immune system is to bridge the achievement of tolerance towards harmless antigens and commensal bacteria while providing protection against pathogens. This is highly important because neonates are immunologically challenged directly after birth by a rigorous change from a semi-allogeneic sterile environment into a world rich with microbes. A so called disease tolerogenic state is typical for neonates and is anticipated to prevent immunopathological damage potentially at the cost of uncontrolled pathogen proliferation. As a consequence, neonates are more susceptible than adults to life-threatening infections. At the basis of a well-functioning immune response, both for adults and neonates, innate immune cells such as monocytes and monocyte-derived macrophages play an essential role. A well-responsive monocyte will alter its cellular metabolism to subsequently induce certain immune effector function, a process which is called immunometabolism. Immunometabolism has received extensive attention in the last decade; however, it has not been broadly studied in neonates. This review focuses on carbohydrate metabolism in monocytes and macrophages in neonates. We will exhibit pathways involving glycolysis, the tricarboxylic acid (TCA) cycle and oxidative phosphorylation and their role in shaping neonates' immune systems to a favorable tolerogenic state. More insight into these pathways will elucidate potential treatments targets in life-threatening conditions including neonatal sepsis or expose potential targets which can be used to induce tolerance in conditions where tolerance is harmfully impaired such as in autoimmune diseases.

Keywords:  bacterial; commensals; neonatal infection; neonatal tolerance

DOI:  https://doi.org/10.3390/ijms241814173
Int J Mol Sci. 2023 Sep 21. pii: 14387. [Epub ahead of print]24(18):

Utility of In Vitro Cellular Models of Low-Dose Lipopolysaccharide in Elucidating the Mechanisms of Anti-Inflammatory and Wound-Healing-Promoting Effects of Lipopolysaccharide Administration In Vivo.

Teruko Honda, Hiroyuki Inagawa.

  Lipopolysaccharide (LPS) is a bacterial component that activates intracellular signaling pathways upon binding to the Toll-like receptor (TLR)-4/MD-2 complex. It is well known that LPS injected into animals and high-dose (100 ng/mL to 1 μg/mL) LPS treatment to innate immune cells induce an inflammatory response. In contrast, LPS is naturally present in the gastrointestinal tract, respiratory tract, and skin of humans and animals, and it has been shown that TLR-4-deficient animals cannot maintain their immune balance and gut homeostasis. LPS from commensal bacteria can help maintain homeostasis against mucosal stimulation in healthy individuals. Oral LPS administration has been shown to be effective in preventing allergic and lifestyle-related diseases. However, this effect was not observed after treatment with LPS at high doses. In mice, oral LPS administration resulted in the detection of LPS at a low concentration in the peritoneal fluid. Therefore, LPS administered at low and high doses have different effects. Moreover, the results of in vitro experiments using low-dose LPS may reflect the effects of oral LPS administration. This review summarizes the utility of in vitro models using cells stimulated with LPS at low concentrations (50 pg/mL to 50 ng/mL) in elucidating the mechanisms of oral LPS administration. Low-dose LPS administration has been demonstrated to suppress the upregulation of proinflammatory cytokines and promote wound healing, suggesting that LPS is a potential agent that can be used for the treatment and prevention of lifestyle-related diseases.

Keywords:  inflammation; lifestyle-related diseases; lipopolysaccharide; macrophage; monocyte

DOI:  https://doi.org/10.3390/ijms241814387
J Immunol. 2023 Sep 27. pii: ji2300293. [Epub ahead of print]

Oxidized Low-Density Lipoprotein Accumulation Suppresses Glycolysis and Attenuates the Macrophage Inflammatory Response by Diverting Transcription from the HIF-1α to the Nrf2 Pathway.

Kenneth K Y Ting, Pei Yu, Riley Dow, Eric Floro, Hisham Ibrahim, Corey A Scipione, Sharon J Hyduk, Chanele K Polenz, Olga Zaslaver, Peer W F Karmaus, Michael B Fessler, Hannes L Röst, Michael Ohh, Sue Tsai, Daniel A Winer, Minna Woo, Jonathan Rocheleau, Jenny Jongstra-Bilen, Myron I Cybulsky.

Lipid accumulation in macrophages (Mφs) is a hallmark of atherosclerosis, yet how lipid accumulation affects inflammatory responses through rewiring of Mφ metabolism is poorly understood. We modeled lipid accumulation in cultured wild-type mouse thioglycolate-elicited peritoneal Mφs and bone marrow-derived Mφs with conditional (Lyz2-Cre) or complete genetic deficiency of Vhl, Hif1a, Nos2, and Nfe2l2. Transfection studies employed RAW264.7 cells. Mφs were cultured for 24 h with oxidized low-density lipoprotein (oxLDL) or cholesterol and then were stimulated with LPS. Transcriptomics revealed that oxLDL accumulation in Mφs downregulated inflammatory, hypoxia, and cholesterol metabolism pathways, whereas the antioxidant pathway, fatty acid oxidation, and ABC family proteins were upregulated. Metabolomics and extracellular metabolic flux assays showed that oxLDL accumulation suppressed LPS-induced glycolysis. Intracellular lipid accumulation in Mφs impaired LPS-induced inflammation by reducing both hypoxia-inducible factor 1-α (HIF-1α) stability and transactivation capacity; thus, the phenotype was not rescued in Vhl-/- Mφs. Intracellular lipid accumulation in Mφs also enhanced LPS-induced NF erythroid 2-related factor 2 (Nrf2)-mediated antioxidative defense that destabilizes HIF-1α, and Nrf2-deficient Mφs resisted the inhibitory effects of lipid accumulation on glycolysis and inflammatory gene expression. Furthermore, oxLDL shifted NADPH consumption from HIF-1α- to Nrf2-regulated apoenzymes. Thus, we postulate that repurposing NADPH consumption from HIF-1α to Nrf2 transcriptional pathways is critical in modulating inflammatory responses in Mφs with accumulated intracellular lipid. The relevance of our in vitro models was established by comparative transcriptomic analyses, which revealed that Mφs cultured with oxLDL and stimulated with LPS shared similar inflammatory and metabolic profiles with foamy Mφs derived from the atherosclerotic mouse and human aorta.

DOI: https://doi.org/10.4049/jimmunol.2300293
Cancers (Basel). 2023 Sep 19. pii: 4635. [Epub ahead of print]15(18):

A TLR4 Agonist Induces Osteosarcoma Regression by Inducing an Antitumor Immune Response and Reprogramming M2 Macrophages to M1 Macrophages.

Iseulys Richert, Paul Berchard, Lhorra Abbes, Alexey Novikov, Kamel Chettab, Alexandra Vandermoeten, Charles Dumontet, Marie Karanian, Jerome Kerzerho, Martine Caroff, Jean-Yves Blay, Aurélie Dutour.

  Osteosarcoma (OsA) has limited treatment options and stagnant 5-year survival rates. Its immune microenvironment is characterized by a predominance of tumor-associated macrophages (TAMs), whose role in OsA progression remain unclear. Nevertheless, immunotherapies aiming to modulate macrophages activation and polarization could be of interest for OsA treatment. In this study, the antitumor effect of a liposome-encapsulated chemically detoxified lipopolysaccharide (Lipo-MP-LPS) was evaluated as a therapeutic approach for OsA. Lipo-MP-LPS is a toll-like receptor 4 (TLR4) agonist sufficiently safe and soluble to be IV administered at effective doses. Lipo-MP-LPS exhibited a significant antitumor response, with tumor regression in 50% of treated animals and delayed tumor progression in the remaining 50%. The agent inhibited tumor growth by 75%, surpassing the efficacy of other immunotherapies tested in OsA. Lipo-MP-LPS modulated OsA's immune microenvironment by favoring the transition of M2 macrophages to M1 phenotype, creating a proinflammatory milieu and facilitating T-cell recruitment and antitumor immune response. Overall, the study demonstrates the potent antitumor effect of Lipo-MP-LPS as monotherapy in an OsA immunocompetent model. Reprogramming macrophages and altering the immune microenvironment likely contribute to the observed tumor control. These findings support the concept of immunomodulatory approaches for the treatment of highly resistant tumors like OsA.

Keywords:  growth inhibition; immunotherapy TLR4 agonist; macrophages reprograming; osteosarcoma

DOI:  https://doi.org/10.3390/cancers15184635
Inflamm Res. 2023 Sep 28.

SGLT2 inhibitors prevent LPS-induced M1 macrophage polarization and alleviate inflammatory bowel disease by downregulating NHE1 expression.

Ye Jin Kim, Jonghwa Jin, Dong-Ho Kim, Daehoon Kim, You Mie Lee, Jun-Kyu Byun, Yeon-Kyung Choi, Keun-Gyu Park.

   BACKGROUND: Classically activated M1 macrophages, characterized by aberrant glycolysis and secretion of inflammatory cytokines, play pivotal roles in inflammatory diseases, including inflammatory bowel disease (IBD). Recently, sodium-glucose co-transporter 2 (SGLT2) inhibitors were shown to suppress Na+/H+ exchanger 1 (NHE1) and Na+/Ca2+ exchanger 1 (NCX1) activity, regulating downstream intracellular Ca2+ concentrations in cardiomyocytes. However, whether SGLT2 inhibitors regulate M1 macrophage polarization by downregulating NHE1 and NCX1 remains unknown.
METHODS: We analyzed cellular responses to SGLT2 inhibitors using mouse bone marrow-derived macrophages and peritoneal macrophages treated with lipopolysaccharide (LPS). To induce IBD, we used a dextran sulfate sodium salt-induced colitis mouse model.
RESULTS: We observed that NHE1 and NCX1 were overexpressed in LPS-treated macrophages, leading to M1 macrophage polarization. Mechanistically, NHE1 and NCX1-mediated Ca2+ accumulation in the macrophage resulted in enhanced glycolysis by promoting PI3K/AKT/mTORC1 signaling. SGLT2 inhibitors suppressed both the expression levels and activities of NHE1 and NCX1, and consequently downregulated PI3K/AKT/mTORC1 signaling and glycolysis in LPS-treated macrophages. We observed inhibition of LPS-stimulated M1 polarization and cytokine production by SGLT2 inhibitors in vitro, ex vivo, and in an IBD mouse model.
CONCLUSIONS: NHE1 promotes M1 macrophage polarization and SGLT2 inhibitors are a novel strategy to treat M1 macrophage-mediated inflammatory diseases, including IBD.

Keywords:  Glycolysis; Inflammatory bowel disease; Macrophage; NHE1; SGLT2 inhibitors

DOI:  https://doi.org/10.1007/s00011-023-01796-y