bims-traimu 2024-06-02 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2024–06–02
nine papers selected by
Yantong Wan, Southern Medical University

Sarcoidosis immunopathogenesis - a new concept of maladaptive trained immunity.
Mesenchymal stromal cells dampen trained immunity in house dust mite-primed macrophages expressing human macrophage migration inhibitory factor polymorphism.
The cholera toxin B subunit induces trained immunity in dendritic cells and promotes CD8 T cell antitumor immunity.
Influenza vaccination as a prognostic factor of humoral IgA responses to SARS-CoV-2 infection.
Low-dose M.tb infection but not BCG or MTBVAC vaccination enhances heterologous antibody titres in non-human primates.
Low to moderate dose 137Cs (γ) radiation promotes M2 type macrophage skewing and reduces atherosclerotic plaque CD68+ cell content in ApoE(-/-) mice.
Lung infection with classical Klebsiella pneumoniae strains establishes robust macrophage-dependent protection against heterologous reinfection.
Multifaceted mitochondria in innate immunity.
[Strong as death or how efferocytotic macrophages promote the resolution of inflammation].

Trends Immunol. 2024 May 24. pii: S1471-4906(24)00101-7. [Epub ahead of print]

Sarcoidosis immunopathogenesis - a new concept of maladaptive trained immunity.

Marie Robert, Nader Yatim, Karim Sacré, Darragh Duffy.

  Sarcoidosis is a chronic immune disease of unknown origin for which we still lack an immunological framework unifying causal agents, host factors, and natural history of disease. Here, we discuss the initial triggers of disease, and how myeloid cells drive granuloma formation and contribute to immunopathogenesis. We highlight recent advances in our understanding of innate immune memory and propose the hypothesis that maladaptive innate immune training connects previous environmental exposure to granuloma maintenance and expansion. Lastly, we consider how this hypothesis may open novel therapeutic avenues, while corticosteroids remain the front-line treatment.

Keywords:  epigenetics; immunometabolism; myeloid cells; precision therapeutics; sarcoidosis; trained immunity

DOI:  https://doi.org/10.1016/j.it.2024.04.013
Cytotherapy. 2024 May 19. pii: S1465-3249(24)00717-5. [Epub ahead of print]

Mesenchymal stromal cells dampen trained immunity in house dust mite-primed macrophages expressing human macrophage migration inhibitory factor polymorphism.

Hazel Dunbar, Ian J Hawthorne, Courteney Tunstead, Eóin N McNamee, Daniel J Weiss, Michelle E Armstrong, Seamas C Donnelly, Karen English.

   BACKGROUND: Trained immunity results in long-term immunological memory, provoking a faster and greater immune response when innate immune cells encounter a secondary, often heterologous, stimulus. We have previously shown that house dust mite (HDM)-induced innate training is amplified in mice expressing the human macrophage migration inhibitory factor (MIF) CATT7 functional polymorphism.
AIM: This study investigated the ability of mesenchymal stromal cells (MSCs) to modulate MIF-driven trained immunity both in vitro and in vivo.
METHODS: Compared with wild-type mice, in vivo HDM-primed bone marrow-derived macrophages (BMDMs) from CATT7 mice expressed significantly higher levels of M1-associated genes following lipopolysaccharide stimulation ex vivo. Co-cultures of CATT7 BMDMs with MSCs suppressed this HDM-primed effect, with tumor necrosis factor alpha (TNF-α) being significantly decreased in a cyclooxygenase 2 (COX-2)-dependent manner. Interestingly, interleukin 6 (IL-6) was suppressed by MSCs independently of COX-2. In an in vitro training assay, MSCs significantly abrogated the enhanced production of pro-inflammatory cytokines by HDM-trained CATT7 BMDMs when co-cultured at the time of HDM stimulus on day 0, displaying their therapeutic efficacy in modulating an overzealous human MIF-dependent immune response. Utilizing an in vivo model of HDM-induced trained immunity, MSCs administered systemically on day 10 and day 11 suppressed this trained phenomenon by significantly reducing TNF-α and reducing IL-6 and C-C motif chemokine ligand 17 (CCL17) production.
CONCLUSIONS: This novel study elucidates how MSCs can attenuate an MIF-driven, HDM-trained response in CATT7 mice in a model of allergic airway inflammation.

Keywords:  bone marrow-derived macrophages; house dust mite; innate training; macrophage migration inhibitory factor; mesenchymal stromal cells; polarization

DOI:  https://doi.org/10.1016/j.jcyt.2024.05.010
Front Immunol. 2024 ;15 1362289

The cholera toxin B subunit induces trained immunity in dendritic cells and promotes CD8 T cell antitumor immunity.

Araceli Tepale-Segura, Julián A Gajón, Samira Muñoz-Cruz, Octavio Castro-Escamilla, Laura C Bonifaz.

   Introduction: Innate immune training is a metabolic, functional, and epigenetic long-term reprogramming of innate cells triggered by different stimuli. This imprinting also reaches hematopoietic precursors in the bone marrow to sustain a memory-like phenotype. Dendritic cells (DCs) can exhibit memory-like responses, enhanced upon subsequent exposure to a pathogen; however, whether this imprinting is lineage and stimulus-restricted is still being determined. Nevertheless, the functional consequences of DCs training on the adaptive and protective immune response against non-infectious diseases remain unresolved.
Methods: We evaluated the effect of the nontoxic cholera B subunit (CTB), LPS and LTA in the induction of trained immunity in murine DCs revealed by TNFa and LDH expression, through confocal microscopy. Additionally, we obtained bone marrow DCs (BMDCs) from mice treated with CTB, LPS, and LTA and evaluated training features in DCs and their antigen-presenting cell capability using multiparametric cytometry. Finally, we design an experimental melanoma mouse model to demonstrate protection induced by CTB-trained DCs in vivo.
Results: CTB-trained DCs exhibit increased expression of TNFa, and metabolic reprogramming indicated by LDH expression. Moreover, CTB training has an imprint on DC precursors, increasing the number and antigen-presenting function in BMDCs. We found that training by CTB stimulates the recruitment of DC precursors and DCs infiltration at the skin and lymph nodes. Interestingly, training-induced by CTB promotes a highly co-stimulatory phenotype in tumor-infiltrating DCs (CD86+) and a heightened functionality of exhausted CD8 T cells (Ki67+, GZMB+), which were associated with a protective response against melanoma challenge in vivo.
Conclusion: Our work indicates that CTB can induce innate immune training on DCs, which turns into an efficient adaptive immune response in the melanoma model and might be a potential immunotherapeutic approach for tumor growth control.

Keywords:  CD8 T cells; CTB adjuvant; dendritic cells; melanoma; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2024.1362289
Cent Eur J Immunol. 2024 ;49(1): 11-18

Influenza vaccination as a prognostic factor of humoral IgA responses to SARS-CoV-2 infection.

Barbara Poniedziałek, Dominika Sikora, Ewelina Hallmann, Lidia Brydak, Piotr Rzymski.

  There is evidence that influenza vaccination may provide additional benefits by inducing training of innate immunity and increasing humoral responses to heterologous challenges. Immunoglobulin A (IgA) antibodies dominate the early phase of the adaptive response to SARS-CoV-2 infection, but whether their production may be associated with previous influenza vaccination has not been a subject of any study. This study compared serum SARS-CoV-2-specific IgA responses, measured with Microblot-Array assay, in individuals who experienced COVID-19 (N = 1318) and differed in the status of the seasonal influenza vaccine, age, sex, and disease severity. Influenza-vaccinated individuals had a higher seroprevalence of IgA antibodies against nucleocapsid (anti-NP; by 10.1%), receptor-binding domain of spike protein (anti-RBD; by 11.8%) and the S2 subunit of spike protein (anti-S2; by 6.8%). Multivariate analysis, including age, sex, and COVID-19 severity, confirmed that receiving the influenza vaccine was associated with higher odds of being seropositive for anti-NP (OR, 95% CI = 1.57, 1.2-2.0), anti-RBD (OR, 95% CI = 1.6, 1.3-2.0), and anti-S2 (OR, 95% CI = 1.9, 1.4-2.7), as well as being seropositive for at least one anti-SARS-CoV-2 IgA antibody (OR, 95% CI = 1.7, 1.3-2.1) and all three of them (OR, 95% CI = 2.6, 1.7-4.0). Age ≥ 50 years was an additional factor predicting better IgA responses. However, the concentration of particular antibodies in seropositive subjects did not differ in relation to the influenza vaccination status. The study evidenced that influenza vaccination was associated with improved serum IgA levels produced in response to SARS-CoV-2 infection. Further studies are necessary to assess whether trained immunity is involved in the observed phenomenon.

Keywords:  SARS-CoV-2; adaptive immunity; heterologous protection; immunology; pandemic; trained immunity

DOI:  https://doi.org/10.5114/ceji.2024.135462
Front Immunol. 2024 ;15 1387454

Low-dose M.tb infection but not BCG or MTBVAC vaccination enhances heterologous antibody titres in non-human primates.

Marco Polo Peralta Alvarez, Holly Jones, Hugo Redondo Azema, Chloe Davis, Andrew D White, Charlotte Sarfas, Mike Dennis, Shuailin Li, Daniel Wright, Eugenia Puentes, Simon Kimuda, Sandra Belij-Rammerstorfer, Nacho Aguilo, Carlos Martin, Sally Sharpe, Helen McShane, Rachel Tanner.

   Introduction: Mycobacteria are known to exert a range of heterologous effects on the immune system. The mycobacteria-based Freund's Complete Adjuvant is a potent non-specific stimulator of the immune response used in immunization protocols promoting antibody production, and Mycobacterium bovis Bacille Calmette Guérin (BCG) vaccination has been linked with decreased morbidity and mortality beyond the specific protection it provides against tuberculosis (TB) in some populations and age groups. The role of heterologous antibodies in this phenomenon, if any, remains unclear and under-studied.
Methods: We set out to evaluate antibody responses to a range of unrelated pathogens following infection with Mycobacterium tuberculosis (M.tb) and vaccination with BCG or a candidate TB vaccine, MTBVAC, in non-human primates.
Results: We demonstrate a significant increase in the titer of antibodies against SARS-CoV-2, cytomegalovirus, Epstein-Barr virus, tetanus toxoid, and respiratory syncytial virus antigens following low-dose aerosol infection with M.tb. The magnitude of some of these responses correlated with TB disease severity. However, vaccination with BCG administered by the intradermal, intravenous or aerosol routes, or intradermal delivery of MTBVAC, did not increase antibody responses against unrelated pathogens.
Discussion: Our findings suggest that it is unlikely that heterologous antibodies contribute to the non-specific effects of these vaccines. The apparent dysregulation of B cell responses associated with TB disease warrants further investigation, with potential implications for risk of B cell cancers and novel therapeutic strategies.

Keywords:  BCG; MTBVAC; Mycobacterium tuberculosis; antibodies; heterologous immune responses; tuberculosis

DOI:  https://doi.org/10.3389/fimmu.2024.1387454
Sci Rep. 2024 05 30. 14(1): 12450

Low to moderate dose 137Cs (γ) radiation promotes M2 type macrophage skewing and reduces atherosclerotic plaque CD68+ cell content in ApoE(-/-) mice.

N Rey, T Ebrahimian, C Gloaguen, D Kereselidze, E Christelle, C Brizais, F Bachelot, G Riazi, V Monceau, C Demarquay, I Garali Zineddine, D Klokov, S Lehoux, Teni G Ebrahimian.

The effects of low doses of ionizing radiation on atherosclerosis remain uncertain, particularly as regards the generation of pro- or anti-inflammatory responses, and the time scale at which such effects can occur following irradiation. To explore these phenomena, we exposed atheroprone ApoE(-/-) mice to a single dose of 0, 0.05, 0.5 or 1 Gy of 137Cs (γ) administered at a 10.35 mGy min-1 dose rate and evaluated short-term (1-10 days) and long-term consequences (100 days). Bone marrow-derived macrophages were derived from mice 1 day after exposure. Irradiation was associated with a significant skewing of M0 and M2 polarized macrophages towards the M2 phenotype, as demonstrated by an increased mRNA expression of Retnla, Arg1, and Chil3 in cells from mice exposed to 0.5 or 1 Gy compared with non-irradiated animals. Minimal effects were noted in M1 cells or M1 marker mRNA. Concurrently, we observed a reduced secretion of IL-1β but enhanced IL-10 release from M0 and M2 macrophages. Effects of irradiation on circulating monocytes were most marked at day 10 post-exposure, when the 1 Gy dose was associated with enhanced numbers of both Ly6CHigh and Ly6Low cells. By day 100, levels of circulating monocytes in irradiated and non-irradiated mice were equivalent, but anti-inflammatory Ly6CLow monocytes were significantly increased in the spleen of mice exposed to 0.05 or 1 Gy. Long term exposures did not affect atherosclerotic plaque size or lipid content, as determined by Oil red O staining, whatever the dose applied. Similarly, irradiation did not affect atherosclerotic plaque collagen or smooth muscle cell content. However, we found that lesion CD68+ cell content tended to decrease with rising doses of radioactivity exposure, culminating in a significant reduction of plaque macrophage content at 1 Gy. Taken together, our results show that short- and long-term exposures to low to moderate doses of ionizing radiation drive an anti-inflammatory response, skewing bone marrow-derived macrophages towards an IL-10-secreting M2 phenotype and decreasing plaque macrophage content. These results suggest a low-grade athero-protective effect of low and moderate doses of ionizing radiation.

DOI: https://doi.org/10.1038/s41598-024-63084-x
Microbes Infect. 2024 May 28. pii: S1286-4579(24)00105-9. [Epub ahead of print] 105369

Lung infection with classical Klebsiella pneumoniae strains establishes robust macrophage-dependent protection against heterologous reinfection.

Joseph J Mackel, Casey L Goltz, Emily Guo, David A Rosen.

  At present there is no approved vaccine for prevention of infection by the opportunistic bacterium Klebsiella pneumoniae (Kp); success in treating these infections is increasingly challenged by the spread of antibiotic resistance. Preclinical investigation of adaptive immunity elicited by lung infection with live classical Kp may reveal host mechanisms of protection against this pathogen. Here, we utilize multiple virulent classical Kp strains to demonstrate that following lung infection, surviving wild-type mice develop protective immunity against both homologous and heterologous (heterotypic) reinfection. For Kp strains with low capacity to disseminate from the lung, this immunity is B-cell-independent. We further demonstrate that this immune protection is also effective against subsequent challenge with hypervirulent Kp if the strains share the same capsule type. Systemic inoculation fails to elicit the same protective effect as lung inoculation, revealing a lung-specific immune effector function is responsible for this protection. We therefore utilized clodronate-loaded liposomes to substantially deplete both alveolar macrophages and lung interstitial macrophages, finding that simultaneous depletion of both subsets entirely ablates protection. These findings indicate that following initial lung infection with Kp, lung macrophages mediate protection against ensuing Kp challenge.

Keywords:  Klebsiella pneumoniae; clodronate depletion; heterologous infection; lung immunity; lung macrophage; pneumonia

DOI:  https://doi.org/10.1016/j.micinf.2024.105369
NPJ Metab Health Dis. 2024 ;2(1): 6

Multifaceted mitochondria in innate immunity.

Eloïse Marques, Robbin Kramer, Dylan G Ryan.

  The ability of mitochondria to transform the energy we obtain from food into cell phosphorylation potential has long been appreciated. However, recent decades have seen an evolution in our understanding of mitochondria, highlighting their significance as key signal-transducing organelles with essential roles in immunity that extend beyond their bioenergetic function. Importantly, mitochondria retain bacterial motifs as a remnant of their endosymbiotic origin that are recognised by innate immune cells to trigger inflammation and participate in anti-microbial defence. This review aims to explore how mitochondrial physiology, spanning from oxidative phosphorylation (OxPhos) to signalling of mitochondrial nucleic acids, metabolites, and lipids, influences the effector functions of phagocytes. These myriad effector functions include macrophage polarisation, efferocytosis, anti-bactericidal activity, antigen presentation, immune signalling, and cytokine regulation. Strict regulation of these processes is critical for organismal homeostasis that when disrupted may cause injury or contribute to disease. Thus, the expanding body of literature, which continues to highlight the central role of mitochondria in the innate immune system, may provide insights for the development of the next generation of therapies for inflammatory diseases.

Keywords:  Energy metabolism; Mitochondria

DOI:  https://doi.org/10.1038/s44324-024-00008-3
Med Sci (Paris). 2024 May;40(5): 428-436

[Strong as death or how efferocytotic macrophages promote the resolution of inflammation].

Mathieu Vetter, Philippe Saas.

The resolution of inflammation is an active process leading to the restoration of tissue homeostasis. A critical step in the initiation of this process is the elimination of apoptotic immune cells by macrophages. This well-organized process, called efferocytosis, involves four different steps, namely the attraction of macrophages to the site where the cells die, the recognition of apoptotic cells, their internalization and their digestion leading to the activation of different metabolic pathways. All these steps are responsible for the reprogramming of macrophages towards a pro-resolving profile. Efferocytic macrophages produce several factors involved in the resolution of inflammation. These factors include lipids (i.e., specialized pro-resolving mediators such as lipoxins), and proteins (e.g., IL-10 or TGF-β). Here, we describe the different steps of efferocytosis and the mechanisms responsible for both macrophage reprogramming and the release of pro-resolving factors. These factors may represent a new therapeutic approach, called resolution therapy.

DOI: https://doi.org/10.1051/medsci/2024050