bims-traimu 2023-07-02 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2023‒07‒02
nine papers selected by
Yantong Wan
Southern Medical University

Innate (learned) memory.
Infection with hypervirulent Mycobacterium tuberculosis triggers emergency myelopoiesis but not trained immunity.
Early hyperlipidemia triggers metabolomic reprogramming with increased SAH, increased acetyl-CoA-cholesterol synthesis, and decreased glycolysis.
BCG vaccination policy, natural boosting and pediatric brain and CNS tumor incidences.
Chronic IFNα treatment induces leukopoiesis, increased plasma succinate and immune cell metabolic rewiring.
Intranasal Monophosphoryl Lipid a Administration Ameliorates depression-like Behavior in Chronically Stressed Mice Through Stimulation of Microglia.
Bacterial Binding, Phagocytosis, and Killing Capacity: Measurements Using Colony Forming Units.
New Insights into NF-κB Signaling in Innate Immunity: Focus on Immunometabolic Crosstalks.
Enhancing Spns2/S1P in macrophages alleviates hyperinflammation and prevents immunosuppression in sepsis.

J Allergy Clin Immunol. 2023 Jun 27. pii: S0091-6749(23)00810-2. [Epub ahead of print]

Innate (learned) memory.

Burcu Al, Tsz K Suen, Katarzyna Placek, Mihai G Netea.

  With the growing body of evidence, it is now clear that not only adaptive immune cells but also innate immune cells can mount a more rapid and potent non-specific immune response to subsequent exposures. This process is known as trained immunity or innate (learned) immune memory. In this review, we discuss the different immune and non-immune cell types of the central and peripheral immune systems which can develop trained immunity. We highlight the intracellular signaling, metabolic and epigenetic mechanisms underlying the formation of innate immune memory. Finally, we explore the health implications together with the potential therapeutic interventions harnessing trained immunity.

Keywords:  Cellular signaling; Epigenetics; Immune memory; Metabolism; Trained immunity

DOI:  https://doi.org/10.1016/j.jaci.2023.06.014
Front Immunol. 2023 ;14 1211404

Infection with hypervirulent Mycobacterium tuberculosis triggers emergency myelopoiesis but not trained immunity.

Ana Raquel Maceiras, Diogo Silvério, Rute Gonçalves, Marcos S Cardoso, Margarida Saraiva.

  Introduction: During infection, bone marrow (BM) hematopoiesis is reprogrammed toward myeloid cell production, a mechanism named emergency myelopoiesis. In addition to replenishing myeloid cells, emergency myelopoiesis has been linked to trained immunity, a process that allows enhanced innate immune responses to secondary challenges. Although hematopoietic alterations during tuberculosis (TB) have been described and Mycobacterium tuberculosis may colonize the BM, studies using the mouse model of infection and the laboratory reference strain M. tuberculosis H37Rv have demonstrated limited emergency myelopoiesis and trained immunity.Methods: To further address this issue, we aerosol- infected C57BL/6 mice with high doses of the hypervirulent M. tuberculosis isolate HN878 and monitored alterations to the BM. This experimental model better resembles the human blood immune signature of TB.
Results and discussion: We found increased frequencies of lineage-Sca-1+cKit+ (LSK) cells and the granulocyte/macrophage progenitor (GMP) population. At the mature cell level, we observed an increase of monocytes and neutrophils in the blood and lung, likely reflecting the increased BM myeloid output. Monocytes or monocyte-derived macrophages recovered from the BM of M. tuberculosis HN878-infected mice did not show signs of trained immunity, suggesting an uncoupling of emergency myelopoiesis and trained immunity in the BM. Surprisingly, M. tuberculosis HN878-induced emergency myelopoiesis was not fully dependent on IFNγ, as mice lacking this cytokine and infected under the same conditions as wild-type mice still presented BM alterations. These data expand our understanding of the immune response to M. tuberculosis and raise awareness of pathogen strain-imposed differences to host responses.

Keywords:  bone marrow; interferon-gamma; myelopoiesis; trained immunity; tuberculosis

DOI:  https://doi.org/10.3389/fimmu.2023.1211404
Redox Biol. 2023 Jun 16. pii: S2213-2317(23)00172-6. [Epub ahead of print]64 102771

Early hyperlipidemia triggers metabolomic reprogramming with increased SAH, increased acetyl-CoA-cholesterol synthesis, and decreased glycolysis.

Keman Xu, Fatma Saaoud, Ying Shao, Yifan Lu, Sheng Wu, Huaqing Zhao, Kaifu Chen, Roberto Vazquez-Padron, Xiaohua Jiang, Hong Wang, Xiaofeng Yang.

  To identify metabolomic reprogramming in early hyperlipidemia, unbiased metabolome was screened in four tissues from ApoE-/- mice fed with high fat diet (HFD) for 3 weeks. 30, 122, 67, and 97 metabolites in the aorta, heart, liver, and plasma, respectively, were upregulated. 9 upregulated metabolites were uremic toxins, and 13 metabolites, including palmitate, promoted a trained immunity with increased syntheses of acetyl-CoA and cholesterol, increased S-adenosylhomocysteine (SAH) and hypomethylation and decreased glycolysis. The cross-omics analysis found upregulation of 11 metabolite synthetases in ApoE‾/‾ aorta, which promote ROS, cholesterol biosynthesis, and inflammation. Statistical correlation of 12 upregulated metabolites with 37 gene upregulations in ApoE‾/‾ aorta indicated 9 upregulated new metabolites to be proatherogenic. Antioxidant transcription factor NRF2-/- transcriptome analysis indicated that NRF2 suppresses trained immunity-metabolomic reprogramming. Our results have provided novel insights on metabolomic reprogramming in multiple tissues in early hyperlipidemia oriented toward three co-existed new types of trained immunity.

Keywords:  Early atherosclerosis; Metabolomes; Proinflammatory and anti-inflammatory metabolites; Trained immunity; Transcriptome

DOI:  https://doi.org/10.1016/j.redox.2023.102771
Front Immunol. 2023 ;14 1174006

BCG vaccination policy, natural boosting and pediatric brain and CNS tumor incidences.

Samer Singh, Amita Diwakar, Rakesh K Singh.

  Bacille Calmette-Guérin (BCG) vaccination supposedly imparts and augments "trained immunity" that cross-protects against multiple unrelated pathogens and enhances general immune surveillance. Gradual reductions in tuberculosis burden over the last 3-5 decades have resulted in the withdrawal of BCG vaccination mandates from developed industrialized countries while reducing to a single neonatal shot in the rest. Concurrently, a steady increase in early childhood Brain and CNS (BCNS) tumors has occurred. Though immunological causes of pediatric BCNS cancer are suspected, the identification of a causal protective variable with intervention potential has remained elusive. An examination of the countries with contrasting vaccination policies indicates significantly lower BCNS cancer incidence in 0-4-year-olds (per hundredthousand) of countries following neonatal BCG inoculations (n=146) vs. non-BCG countries (n=33) [Mean: 1.26 vs. 2.64; Median: 0.985 vs. 2.8; IQR: 0.31-2.0 vs. 2.4-3.2; P=<0.0001 (two-tailed)]. Remarkably, natural Mycobacterium spp. reexposure likelihood is negatively correlated with BCNS cancer incidence in 0-4-year-olds of all affected countries [r(154): -0.6085, P=<0.0001]. Seemingly, neonatal BCG vaccination and natural "boosting" are associated with a 15-20-fold lower BCNS cancer incidence. In this opinion article, we attempt to synthesize existing evidence implying the immunological basis of early childhood BCNS cancer incidence and briefly indicate possible causes that could have precluded objective analysis of the existing data in the past. We draw the attention of the stakeholders to consider the comprehensive evaluation of immune training as a potential protective variable through well-designed controlled clinical trials or registry-based studies as feasible for its potential applications in reducing childhood BCNS cancer incidence.

Keywords:  BCG vaccine; Mycobacterium spp.; brain and CNS cancer; cancer discovery; cancer prevention; childhood vaccinations; pediatric cancer; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2023.1174006
Cell Immunol. 2023 Jun 20. pii: S0008-8749(23)00080-1. [Epub ahead of print]390 104741

Chronic IFNα treatment induces leukopoiesis, increased plasma succinate and immune cell metabolic rewiring.

Anjali S Yennemadi, Gráinne Jameson, Mary Glass, Carolina De Pasquale, Joseph Keane, Massimiliano Bianchi, Gina Leisching.

  Although clinically effective, the actions of IFNα, either produced endogenously or by therapeutic delivery, remain poorly understood. Emblematic of this research gap is the disparate array of notable side effects that occur in susceptible individuals, such as neuropsychiatric consequences, autoimmune phenomena, and infectious complications. We hypothesised that these complications are driven at least in part by dysregulated cellular metabolism. Male Wistar rats were treated with either 170,000 IU/kg human recombinant IFNα-2a or BSA/saline (0.9% NaCl) three times per week for three weeks. Bone marrow (BM) immune cells were isolated from the excised femurs for glycolytic rate and mitochondrial function assessment using Agilent Seahorse Technology. Frequencies of immune cell populations were assessed by flow cytometry to determine whether leukopoietic changes had occurred in both blood and BM. Plasma levels of lactate and succinate were also determined. BMDMs were metabolically assessed as above, as well as their metabolic response to an antigenic stimulus (iH37Rv). We observed that BM immune cells from IFN-treated rats exhibit a hypermetabolic state (increased basal OCR/GlycoPER) with decreased mitochondrial metabolic respiration and increased non-mitochondrial OCR. Flow cytometry results indicated an increase in immature granulocytes (RP1- SSChi CD45lo) only in the blood, together with increased succinate levels in the plasma. BMDMs from IFN-treated rats retained the hypermetabolic phenotype after differentiation and failed to induce a step-up in glycolysis and mitochondrial respiration after bacterial stimulation. This work provides the first evidence of the effects of IFNα treatment in inducing hypermetabolic immune features that are associated with markers of inflammation, leukopoiesis, and defective responses to bacterial stimulation.

Keywords:  Glycolysis; Interferon alpha; Interferon therapy; Macrophages; Metabolism; Mitochondria; Oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.cellimm.2023.104741
Neurochem Res. 2023 Jun 26.

Intranasal Monophosphoryl Lipid a Administration Ameliorates depression-like Behavior in Chronically Stressed Mice Through Stimulation of Microglia.

Meng Zheng, Tao Zhu, Bingran Chen, Hui Zhao, Xu Lu, Qun Lu, Mingxie Ni, Li Cheng, Han Han, Ting Ye, Ying Ye, Huijun Liu, Chao Huang.

  We and others have reported that systematic stimulation of the central innate immune system by a low dose of lipopolysaccharide (LPS) can improve depression-like behavior in chronically stressed animals. However, it is unclear whether similar stimulation by intranasal administration could improve depression-like behavior in animals. We investigated this question using monophosphoryl lipid A (MPL), a derivative of LPS that lacks the adverse effects of LPS but is still immuno-stimulatory. We found that a single intranasal administration of MPL at a dose of 10 or 20 µg/mouse, but not at a dose of 5 µg/mouse, ameliorated chronic unpredictable stress (CUS)-induced depression-like behavior in mice, as evidenced by the decrease in immobility time in tail suspension test and forced swimming test and the increase in sucrose intake in sucrose preference test. In the time-dependent analysis, the antidepressant-like effect of a single intranasal MPL administration (20 µg/mouse) was observed 5 and 8 h but not 3 h after drug administration and persisted for at least 7 days. Fourteen days after the first intranasal MPL administration, a second intranasal MPL administration (20 µg/mouse) still showed an antidepressant-like effect. The innate immune response mediated by microglia might mediate the antidepressant-like effect of intranasal MPL administration, because both inhibition of microglial activation by pretreatment with minocycline and depletion of microglia by pretreatment with PLX3397 prevented the antidepressant-like effect of intranasal MPL administration. These results suggest that intranasal administration of MPL can produce significant antidepressant-like effects in animals under chronic stress conditions via stimulation of microglia.

Keywords:  Depression; Hippocampus; Innate immune response; Intranasal MPL administration

DOI:  https://doi.org/10.1007/s11064-023-03974-0
Methods Mol Biol. 2023 ;2692 1-13

Bacterial Binding, Phagocytosis, and Killing Capacity: Measurements Using Colony Forming Units.

Kyle E Novakowski, Dessi Loukov, Dawn M E Bowdish.

  Herein, we provide a colony forming unit (CFU)-based counting method for quantitating the bacterial binding, phagocytosis, and killing capacity of phagocytes. Although these functions can be measured by immunofluorescence- and dye-based assays, quantitating CFUs are comparatively inexpensive and easy to perform. The protocol described below is easily modified for use with different phagocytes (e.g., macrophages, neutrophils, cell lines), types of bacteria, or opsonic conditions.

Keywords:  Bacterial killing; Gentamicin protection; Macrophage; Particle binding; Phagocyte; Phagocytosis

DOI:  https://doi.org/10.1007/978-1-0716-3338-0_1
Biology (Basel). 2023 May 27. pii: 776. [Epub ahead of print]12(6):

New Insights into NF-κB Signaling in Innate Immunity: Focus on Immunometabolic Crosstalks.

Dominga Iacobazzi, Paolo Convertini, Simona Todisco, Anna Santarsiero, Vito Iacobazzi, Vittoria Infantino.

  The nuclear factor kappa B (NF-κB) is a family of transcription factors that, beyond their numberless functions in various cell processes, play a pivotal role in regulating immune cell activation. Two main pathways-canonical and non-canonical-are responsible for NF-κB activation and heterodimer translocation into the nucleus. A complex crosstalk between NF-κB signaling and metabolism is emerging in innate immunity. Metabolic enzymes and metabolites regulate NF-κB activity in many cases through post-translational modifications such as acetylation and phosphorylation. On the other hand, NF-κB affects immunometabolic pathways, including the citrate pathway, thereby building an intricate network. In this review, the emerging findings about NF-κB function in innate immunity and the interplay between NF-κB and immunometabolism have been discussed. These outcomes allow for a deeper comprehension of the molecular mechanisms underlying NF-κB function in innate immune cells. Moreover, the new insights are important in order to perceive NF-κB signaling as a potential therapeutic target for inflammatory/immune chronic diseases.

Keywords:  NF-κB; gene expression; immunometabolism; innate immunity; macrophages

DOI:  https://doi.org/10.3390/biology12060776
EMBO Rep. 2023 Jun 26. e56635

Enhancing Spns2/S1P in macrophages alleviates hyperinflammation and prevents immunosuppression in sepsis.

Chao Fang, Pan Ren, Ganlan Bian, Jian Wang, Jiaxin Bai, Jiaxing Huang, Yixiao Ding, Xueyong Li, Mingkai Li, Zheng Hou.

  Sepsis is a leading cause of in-hospital mortality resulting from a dysregulated response to infection. Novel immunomodulatory therapies targeting macrophage metabolism have emerged as an important focus for current sepsis research. However, understanding the mechanisms underlying macrophage metabolic reprogramming and how they impact immune response requires further investigation. Here, we identify macrophage-expressed Spinster homolog 2 (Spns2), a major transporter of sphingosine-1-phosphate (S1P), as a crucial metabolic mediator that regulates inflammation through the lactate-reactive oxygen species (ROS) axis. Spns2 deficiency in macrophages significantly enhances glycolysis, thereby increasing intracellular lactate production. As a key effector, intracellular lactate promotes pro-inflammatory response by increasing ROS generation. The overactivity of the lactate-ROS axis drives lethal hyperinflammation during the early phase of sepsis. Furthermore, diminished Spns2/S1P signaling impairs the ability of macrophages to sustain an antibacterial response, leading to significant innate immunosuppression in the late stage of infection. Notably, reinforcing Spns2/S1P signaling contributes to balancing the immune response during sepsis, preventing both early hyperinflammation and later immunosuppression, making it a promising therapeutic target for sepsis.

Keywords:  Spinster homolog 2; immunomodulation; macrophages; sepsis; sphingosine-1-phosphate

DOI:  https://doi.org/10.15252/embr.202256635