bims-traimu 2023-10-08 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2023–10–08
ten papers selected by
Yantong Wan, Southern Medical University

Trained immunity in diabetes and hyperlipidemia: Emerging opportunities to target cardiovascular complications and design new therapies.
The Role of NLRP3 Inflammasomes in Trained Immunity.
The effect of leptin on trained innate immunity and on systemic inflammation in subjects with obesity.
Mesenchymal Stromal Cells Facilitate Neutrophil Trained Immunity by Reprogramming Hematopoietic Stem Cells.
Bacteria- and Fungus-derived PAMPs Induce Innate Immune Memory via Similar Functional, Metabolic and Transcriptional Adaptations.
Bacillus Calmette-Guérin vaccination as defense against SARS-CoV-2 (BADAS): a randomized controlled trial to protect healthcare workers in the USA by enhanced trained immune responses.
A protein-free vaccine stimulates innate immunity and protects against nosocomial pathogens.
Repeated social defeat stress leads to immunometabolic shifts in innate immune cells of the spleen.
miR-182/183-Rasa1 axis induced macrophage polarization and redox regulation promotes repair after ischemic cardiac injury.
Intravenous administration of BCG in mice promotes natural killer and T cell-mediated antitumor immunity in the lung.

FASEB J. 2023 11;37(11): e23231

Trained immunity in diabetes and hyperlipidemia: Emerging opportunities to target cardiovascular complications and design new therapies.

Katherine A Robinson, Naveed Akbar, Kajus Baidžajevas, Robin P Choudhury.

  Some metabolic diseases, such as diabetes and hyperlipidemia, are associated with a state of inflammation, which adversely affects cardiovascular health. Emerging evidence suggests that long-term hyperactivation of innate immune cells and their bone marrow progenitors, termed trained immunity, functions to accelerate atherosclerosis and its complications in cardiometabolic diseases. This review will focus on how trained immunity is established, particularly through metabolic and epigenetic reprogramming, to cause persistent and deleterious changes in immune cell function, even after the original stimulus has been corrected or removed. Understanding the mechanisms driving maladaptive trained immunity and its fundamental contribution to cardiovascular disease might enable the development of novel disease-modifying therapeutics for the reduction in cardiovascular risk in diabetes, hyperlipidemia, and related cardiometabolic states.

Keywords:  cardiovascular; diabetes; epigenetics; macrophages; metabolism; trained immunity

DOI:  https://doi.org/10.1096/fj.202301078R
Front Biosci (Landmark Ed). 2023 Sep 22. 28(9): 210

The Role of NLRP3 Inflammasomes in Trained Immunity.

Gilyoung Lee, Huijeong Ahn, Eunsong Lee, Geun-Shik Lee.

  Inflammasomes are cytosolic multi-protein complexes that play an important role in the innate immune system, inducing cytokine maturation and pyroptosis. Trained immunity is the induction of memory in innate immune cells by epigenetic reprogramming due to repeated inflammatory stimuli that alter the inflammatory response and increase resistance to infection or disease. Although it is speculated that nucleotide-binding oligomerization domain (NOD), leucine-rich repeat (LRR), and the NLR family pyrin domain containing 3 (NLRP3) inflammasomes respond to various inflammatory stimuli and are associated with trained immunity, the exact relationship is still unclear. This paper aims to introduce data from recent research on the role of inflammasomes in trained immunity through cellular immunometabolic and epigenetic reprogramming. It also suggests a new therapeutic strategy for inflammatory diseases through the complementary regulation of inflammasomes and trained immunity.

Keywords:  NLRP3; inflammasome; inflammatory diseases; trained immunity

DOI:  https://doi.org/10.31083/j.fbl2809210
J Leukoc Biol. 2023 Sep 30. pii: qiad118. [Epub ahead of print]

The effect of leptin on trained innate immunity and on systemic inflammation in subjects with obesity.

Daniela Flores Gomez, Siroon Bekkering, Rob Ter Horst, Benjamin Cossins, Inge C L van den Munckhof, Joost H W Rutten, Leo A B Joosten, Mihai G Netea, Niels P Riksen.

  Leptin is associated with cardiometabolic complications of obesity, such as metabolic syndrome and atherosclerosis. In obese men, the presence of metabolic syndrome is associated with higher circulating leptin and interleukin-6 concentrations, and increased monocyte cytokine production capacity. Here we investigated the effects of leptin on monocyte function and systemic inflammatory markers in obese individuals. We specifically explored whether leptin can induce long-term changes in innate immune function by inducing innate immune memory (also called trained immunity). We exposed human primary monocytes for 24 hours to relevant leptin concentrations in vitro and measured cytokine production. In addition, after removing leptin, we incubated monocytes for 5 days in culture medium, and we restimulated them on day 6 to assess cytokine production capacity, phagocytosis and foam cell formation. Direct stimulation with leptin did not induce cytokine production, but exposure to 50 ng/ml leptin augmented LPS- and R848-induced tumor necrosis factor (TNF-α) production after 1 week. In a separate in vivo study in a cohort of 302 obese subjects (BMI>27, 55-81 years), we measured circulating leptin, inflammatory markers, and cytokine production upon ex-vivo stimulation of isolated peripheral blood mononuclear cells. Circulating leptin concentrations positively correlated with circulating IL-1β and IL-6, which was more pronounced in men than in women. Four single nucleotide polymorphisms in the leptin gene influenced circulating IL-6 concentrations in men, suggesting a direct effect of leptin on IL-6. In conclusion, in vitro, leptin does not directly stimulate monocytes to produce cytokines, yet induces long-term monocyte hyperresponsiveness, i.e. trained immunity. In obese subjects, leptin is associated with circulating IL-6 in a sex-dependent manner. The underlying mechanisms of the sex-specific effect of leptin on innate immune cells remain to be further investigated.

Keywords:  Adipokines; atherosclerosis; cytokines; metabolic syndrome

DOI:  https://doi.org/10.1093/jleuko/qiad118
J Innate Immun. 2023 Oct 05.

Mesenchymal Stromal Cells Facilitate Neutrophil Trained Immunity by Reprogramming Hematopoietic Stem Cells.

Julie Ng, Anna E Marneth, Alec Griffith, Daniel Younger, Sailaja Ghanta, Alan Jiao, Gareth Willis, Junwen Han, Jewel Imani, Bailin Niu, Joshua W Keegan, Brandon Hancock, Fei Guo, Yang Shi, Mark A Perrella, James A Lederer.

Novel therapeutics are urgently needed to prevent opportunistic infections in immunocompromised individuals undergoing cancer treatments or other immune suppressive therapies. Trained immunity is a promising strategy to reduce this burden of disease. We previously demonstrated that mesenchymal stromal cells (MSCs) preconditioned with a class A CpG oligodeoxynucleotide (CpG-ODN), a Toll-like receptor 9 (TLR9) agonist, can augment emergency granulopoiesis in a murine model of neutropenic sepsis. Here, we used a chimeric mouse model to demonstrate that MSCs secrete paracrine factors that act on lineage negative c-kit+ hematopoietic stem cells (HSCs), leaving them 'poised' to enhance emergency granulopoiesis months after transplantation. Chimeric mice developed from HSCs exposed to conditioned media from MSCs and CpG-ODN preconditioned MSCs showed significantly higher bacterial clearance and increased neutrophil granulopoiesis following lung infection than control mice. By CUT&RUN chromatin sequencing and cytometry by time of flight (CyTOF) approaches, we identified that MSC conditioned media leaves H3K4me3 histone marks in HSCs at genes involved in myelopoiesis and in signaling persistence by the mTOR pathway. Both soluble factors and extracellular vesicles (EV) from MSCs mediated these effects on HSCs and proteomic analysis by mass spectrometry revealed soluble calreticulin as a potential mediator. In summary, this study demonstrates that trained immunity can be mediated by paracrine factors from MSCs to induce neutrophil trained immunity by reprogramming HSCs for long-lasting functional changes in neutrophil mediated anti-microbial immunity.

DOI: https://doi.org/10.1159/000533732
J Leukoc Biol. 2023 Oct 04. pii: qiad120. [Epub ahead of print]

Bacteria- and Fungus-derived PAMPs Induce Innate Immune Memory via Similar Functional, Metabolic and Transcriptional Adaptations.

Margaret A McBride, Cody L Stothers, Benjamin A Fensterheim, Katherine R Caja, Allison M Owen, Antonio Hernandez, Julia K Bohannon, Naeem K Patil, Sabah Ali, Sujata Dalal, Mohsin Rahim, Irina A Trenary, Jamey D Young, David L Williams, Edward R Sherwood.

  Exposure to pathogen-associated molecular patterns (PAMPs) induces an augmented, broad-spectrum antimicrobial response to subsequent infection, a phenomenon termed innate immune memory. This study examined the effects of treatment with β-glucan, a fungus-derived Dectin-1 ligand, or monophosphoryl lipid A (MPLA), a bacteria-derived TLR4 ligand, on innate immune memory with a focus on identifying common cellular and molecular pathways activated by these diverse PAMPs. Treatment with either PAMP prepared the innate immune system to respond more robustly to Pseudomonas aeruginosa infection in vivo by facilitating mobilization of innate leukocytes into blood, recruitment of leukocytes to the site of infection, augmentation of microbial clearance and attenuation of cytokine production. Examination of macrophages ex vivo showed amplification of metabolism, phagocytosis, and respiratory burst after treatment with either agent, although MPLA more robustly augmented these activities and more effectively facilitated killing of bacteria. Both agents activated gene expression pathways in macrophages that control inflammation, antimicrobial functions and protein synthesis and suppressed pathways regulating cell division. β-glucan treatment minimally altered macrophage differential gene expression in response to LPS challenge whereas MPLA attenuated the magnitude of the LPS-induced transcriptional response, especially cytokine gene expression. These results show that β-glucan and MPLA similarly augment the innate response to infection in vivo. Yet, MPLA more potently induces alterations in macrophage metabolism, antimicrobial functions, gene transcription and the response to LPS.

Keywords:  Innate Immune Memory; Macrophages; Monophosphoryl Lipid A; β-glucan

DOI:  https://doi.org/10.1093/jleuko/qiad120
Trials. 2023 Oct 04. 24(1): 636

Bacillus Calmette-Guérin vaccination as defense against SARS-CoV-2 (BADAS): a randomized controlled trial to protect healthcare workers in the USA by enhanced trained immune responses.

Andrew R DiNardo, Moshe Arditi, Ashish M Kamat, Kent J Koster, Santiago Carrero, Tomoki Nishiguchi, Maxim Lebedev, Aaron B Benjamin, Pablo Avalos, Marisa Lozano, Madeleine G Moule, Brittany McCune, Baysia Herron, Malik Ladki, Daanish Sheikh, Matthew Spears, Ivan A Herrejon, Courtney Dodge, Sathish Kumar, Robert W Hutchison, Theresa U Ofili, Lynne A Opperman, Jessica A Bernard, Seth P Lerner, George Udeani, Gabriel Neal, Mihai G Netea, Jeffrey D Cirillo.

   BACKGROUND: A large epidemic, such as that observed with SARS-CoV-2, seriously challenges available hospital capacity, and this would be augmented by infection of healthcare workers (HCW). Bacillus Calmette-Guérin (BCG) is a vaccine against tuberculosis, with protective non-specific effects against other respiratory tract infections in vitro and in vivo. Preliminary analyses suggest that regions of the world with existing BCG vaccination programs have lower incidence and mortality from COVID-19. We hypothesize that BCG vaccination can reduce SARS-CoV-2 infection and disease severity.
METHODS: This will be a placebo-controlled adaptive multi-center randomized controlled trial. A total of 1800 individuals considered to be at high risk, including those with comorbidities (hypertension, diabetes, obesity, reactive airway disease, smokers), racial and ethnic minorities, elderly, teachers, police, restaurant wait-staff, delivery personnel, health care workers who are defined as personnel working in a healthcare setting, at a hospital, medical center or clinic (veterinary, dental, ophthalmology), and first responders (paramedics, firefighters, or law enforcement), will be randomly assigned to two treatment groups. The treatment groups will receive intradermal administration of BCG vaccine or placebo (saline) with groups at a 1:1 ratio. Individuals will be tracked for evidence of SARS-CoV-2 infection and severity as well as obtaining whole blood to track immunological markers, and a sub-study will include cognitive function and brain imaging. The majority of individuals will be followed for 6 months, with an option to extend for another 6 months, and the cognitive sub-study duration is 2 years. We will plot Kaplan-Meier curves that will be plotted comparing groups and hazard ratios and p-values reported using Cox proportional hazard models.
DISCUSSION: It is expected this trial will allow evaluation of the effects of BCG vaccination at a population level in high-risk healthcare individuals through a mitigated clinical course of SARS-CoV-2 infection and inform policy making during the ongoing epidemic.
TRIAL REGISTRATION: ClinicalTrials.gov NCT04348370. Registered on April 16, 2020.

Keywords:  BCG vaccination; COVID-19; Healthcare workers; Immune training; Pandemic; Randomized controlled trial

DOI:  https://doi.org/10.1186/s13063-023-07662-w
Sci Transl Med. 2023 Oct 04. 15(716): eadf9556

A protein-free vaccine stimulates innate immunity and protects against nosocomial pathogens.

Jun Yan, Travis B Nielsen, Peggy Lu, Yuli Talyansky, Matt Slarve, Hernan Reza, Boris Novakovic, Mihai G Netea, Ashley E Keller, Troy Warren, Antonio DiGiandomenico, Bret R Sellman, Brian M Luna, Brad Spellberg.

Traditional vaccines are difficult to deploy against the diverse antimicrobial-resistant, nosocomial pathogens that cause health care-associated infections. We developed a protein-free vaccine composed of aluminum hydroxide, monophosphoryl lipid A, and fungal mannan that improved survival and reduced bacterial burden of mice with invasive blood or lung infections caused by methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecalis, extended-spectrum beta-lactamase-expressing Escherichia coli, and carbapenem-resistant strains of Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The vaccine also conferred protection against the fungi Rhizopus delemar and Candida albicans. Efficacy was apparent by 24 hours and lasted for up to 28 days after a single vaccine dose, with a second dose restoring efficacy. The vaccine acted through stimulation of the innate, rather than the adaptive, immune system, as demonstrated by efficacy in the absence of lymphocytes that were abrogated by macrophage depletion. A role for macrophages was further supported by the finding that vaccination induced macrophage epigenetic alterations that modulated phagocytosis and the inflammatory response to infection. Together, these data show that this protein-free vaccine is a promising strategy to prevent deadly antimicrobial-resistant health care-associated infections.

DOI: https://doi.org/10.1126/scitranslmed.adf9556
Brain Behav Immun Health. 2023 Dec;34 100690

Repeated social defeat stress leads to immunometabolic shifts in innate immune cells of the spleen.

Mandakh Bekhbat, John Drake, Emily C Reed, Tatlock H Lauten, Tamara Natour, Vladimir I Vladimirov, Adam J Case.

Psychosocial stress has been shown to prime peripheral innate immune cells, which take on hyper-inflammatory phenotypes and are implicated in depressive-like behavior in mouse models. However, the impact of stress on cellular metabolic states that are thought to fuel inflammatory phenotypes in immune cells are unknown. Using single cell RNA-sequencing, we investigated mRNA enrichment of immunometabolic pathways in innate immune cells of the spleen in mice subjected to repeated social defeat stress (RSDS) or no stress (NS). RSDS mice displayed a significant increase in the number of splenic macrophages and granulocytes (p < 0.05) compared to NS littermates. RSDS-upregulated genes in macrophages, monocytes, and granulocytes significantly enriched immunometabolic pathways thought to play a role in myeloid-driven inflammation (glycolysis, HIF-1 signaling, MTORC1 signaling) as well as pathways related to oxidative phosphorylation (OXPHOS) and oxidative stress (p < 0.05 and FDR<0.1). These results suggest that the metabolic enhancement reflected by upregulation of glycolytic and OXPHOS pathways may be important for cellular proliferation of splenic macrophages and granulocytes following repeated stress exposure. A better understanding of these intracellular metabolic mechanisms may ultimately help develop novel strategies to reverse the impact of stress and associated peripheral immune changes on the brain and behavior.

DOI: https://doi.org/10.1016/j.bbih.2023.100690
Redox Biol. 2023 Sep 29. pii: S2213-2317(23)00310-5. [Epub ahead of print]67 102909

miR-182/183-Rasa1 axis induced macrophage polarization and redox regulation promotes repair after ischemic cardiac injury.

Yijun Yang, Jaslyn Johnson, Constantine D Troupes, Eric A Feldsott, Lindsay Kraus, Emily Megill, Zilin Bian, Ngefor Asangwe, Tabito Kino, Deborah M Eaton, Tao Wang, Marcus Wagner, Lena Ma, Christopher Bryan, Markus Wallner, Hajime Kubo, Remus M Berretta, Mohsin Khan, Hong Wang, Raj Kishore, Steven R Houser, Sadia Mohsin.

  Few therapies have produced significant improvement in cardiac structure and function after ischemic cardiac injury (ICI). Our possible explanation is activation of local inflammatory responses negatively impact the cardiac repair process following ischemic injury. Factors that can alter immune response, including significantly altered cytokine levels in plasma and polarization of macrophages and T cells towards a pro-reparative phenotype in the myocardium post-MI is a valid strategy for reducing infarct size and damage after myocardial injury. Our previous studies showed that cortical bone stem cells (CBSCs) possess reparative effects after ICI. In our current study, we have identified that the beneficial effects of CBSCs appear to be mediated by miRNA in their extracellular vesicles (CBSC-EV). Our studies showed that CBSC-EV treated animals demonstrated reduced scar size, attenuated structural remodeling, and improved cardiac function versus saline treated animals. These effects were linked to the alteration of immune response, with significantly altered cytokine levels in plasma, and polarization of macrophages and T cells towards a pro-reparative phenotype in the myocardium post-MI. Our detailed in vitro studies demonstrated that CBSC-EV are enriched in miR-182/183 that mediates the pro-reparative polarization and metabolic reprogramming in macrophages, including enhanced OXPHOS rate and reduced ROS, via Ras p21 protein activator 1 (RASA1) axis under Lipopolysaccharides (LPS) stimulation. In summary, CBSC-EV deliver unique molecular cargoes, such as enriched miR-182/183, that modulate the immune response after ICI by regulating macrophage polarization and metabolic reprogramming to enhance repair.

Keywords:  Cardiac repair; Cortical bone stem cells; Extracellular vesicles; Immune modulation

DOI:  https://doi.org/10.1016/j.redox.2023.102909
Nat Commun. 2023 10 04. 14(1): 6090

Intravenous administration of BCG in mice promotes natural killer and T cell-mediated antitumor immunity in the lung.

Eduardo Moreo, Aitor Jarit-Cabanillas, Iñaki Robles-Vera, Santiago Uranga, Claudia Guerrero, Ana Belén Gómez, Pablo Mata-Martínez, Luna Minute, Miguel Araujo-Voces, María José Felgueres, Gloria Esteso, Iratxe Uranga-Murillo, Maykel Arias, Julián Pardo, Carlos Martín, Mar Valés-Gómez, Carlos Del Fresno, David Sancho, Nacho Aguiló.

Intravesical administration of Bacillus Calmette-Guérin (BCG) was one of the first FDA-approved immunotherapies and remains a standard treatment for bladder cancer. Previous studies have demonstrated that intravenous (IV) administration of BCG is well-tolerated and effective in preventing tuberculosis infection in animals. Here, we examine IV BCG in several preclinical lung tumor models. Our findings demonstrate that BCG inoculation reduced tumor growth and prolonged mouse survival in models of lung melanoma metastasis and orthotopic lung adenocarcinoma. Moreover, IV BCG treatment was well-tolerated with no apparent signs of acute toxicity. Mechanistically, IV BCG induced tumor-specific CD8+ T cell responses, which were dependent on type 1 conventional dendritic cells, as well as NK cell-mediated immunity. Lastly, we also show that IV BCG has an additive effect on anti-PD-L1 checkpoint inhibitor treatment in mouse lung tumors that are otherwise resistant to anti-PD-L1 as monotherapy. Overall, our study demonstrates the potential of systemic IV BCG administration in the treatment of lung tumors, highlighting its ability to enhance immune responses and augment immune checkpoint blockade efficacy.

DOI: https://doi.org/10.1038/s41467-023-41768-8