bims-traimu 2023-11-19 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2023–11–19
nine papers selected by
Yantong Wan, Southern Medical University

Fatty acid desaturation and lipoxygenase pathways support trained immunity.
Trained immunity induced by high-salt diet impedes stroke recovery.
USP3 plays a critical role in the induction of innate immune tolerance.
Role of glycolysis in diabetic atherosclerosis.
Open questions in the NF-κB field.
Monocytes reprogrammed by 4-PBA potently contribute to the resolution of inflammation and atherosclerosis.
Immunobiotic Ligilactobacillus salivarius FFIG58 Confers Long-Term Protection against Streptococcus pneumoniae.
Microglia-Dependent Reversal of Depression-Like Behaviors in Chronically Stressed Mice by Administration of a Specific Immuno-stimulant β-Glucan.
Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation.

Nat Commun. 2023 Nov 15. 14(1): 7385

Fatty acid desaturation and lipoxygenase pathways support trained immunity.

Anaísa V Ferreira, Juan Carlos Alarcon-Barrera, Jorge Domínguez-Andrés, Özlem Bulut, Gizem Kilic, Priya A Debisarun, Rutger J Röring, Hatice N Özhan, Eva Terschlüsen, Athanasios Ziogas, Sarantos Kostidis, Yassene Mohammed, Vasiliki Matzaraki, George Renieris, Evangelos J Giamarellos-Bourboulis, Mihai G Netea, Martin Giera.

Infections and vaccines can induce enhanced long-term responses in innate immune cells, establishing an innate immunological memory termed trained immunity. Here, we show that monocytes with a trained immunity phenotype, due to exposure to the Bacillus Calmette-Guérin (BCG) vaccine, are characterized by an increased biosynthesis of different lipid mediators (LM) derived from long-chain polyunsaturated fatty acids (PUFA). Pharmacological and genetic approaches show that long-chain PUFA synthesis and lipoxygenase-derived LM are essential for the BCG-induced trained immunity responses of human monocytes. Furthermore, products of 12-lipoxygenase activity increase in monocytes of healthy individuals after BCG vaccination. Grasping the underscoring lipid metabolic pathways contributes to our understanding of trained immunity and may help to identify therapeutic tools and targets for the modulation of innate immune responses.

DOI: https://doi.org/10.1038/s41467-023-43315-x
EMBO Rep. 2023 Nov 15. e57164

Trained immunity induced by high-salt diet impedes stroke recovery.

Tze-Yen Lin, Danye Jiang, Wan-Ru Chen, Jhih Syuan Lin, Xin-Yu Zhang, Chih-Hung Chen, Chia-Lang Hsu, Liang-Chuan Lai, Ping-Hung Chen, Kai-Chien Yang, Lauren H Sansing, Che-Feng Chang.

  A high-salt diet (HSD) elicits sustained sterile inflammation and worsens tissue injury. However, how this occurs after stroke, a leading cause of morbidity and mortality, remains unknown. Here, we report that HSD impairs long-term brain recovery after intracerebral hemorrhage, a severe form of stroke, despite salt withdrawal prior to the injury. Mechanistically, HSD induces innate immune priming and training in hematopoietic stem and progenitor cells (HSPCs) by downregulation of NR4a family and mitochondrial oxidative phosphorylation. This training compromises alternative activation of monocyte-derived macrophages (MDMs) without altering the initial inflammatory responses of the stroke brain. Healthy mice transplanted with bone marrow from HSD-fed mice retain signatures of reduced MDM reparative functions, further confirming a persistent form of innate immune memory that originates in the bone marrow. Loss of NR4a1 in macrophages recapitulates HSD-induced negative impacts on stroke outcomes while gain of NR4a1 enables stroke recovery in HSD animals. Together, we provide the first evidence that links HSD-induced innate immune memory to the acquisition of persistent dysregulated inflammatory responses and unveils NR4a1 as a potential therapeutic target.

Keywords:  high-salt diet; intracerebral hemorrhage; macrophages; nr4a1; trained immunity

DOI:  https://doi.org/10.15252/embr.202357164
EMBO Rep. 2023 Nov 16. e57828

USP3 plays a critical role in the induction of innate immune tolerance.

Tianhao Duan, Yanchun Feng, Yang Du, Changsheng Xing, Junjun Chu, Jiayu Ou, Xin Liu, Motao Zhu, Chen Qian, Bingnan Yin, Helen Y Wang, Jun Cui, Rong-Fu Wang.

  Microbial products, such as lipopolysaccharide (LPS), can elicit efficient innate immune responses against invading pathogens. However, priming with LPS can induce a form of innate immune memory, termed innate immune "tolerance", which blunts subsequent NF-κB signaling. Although epigenetic and transcriptional reprogramming has been shown to play a role in innate immune memory, the involvement of post-translational regulation remains unclear. Here, we report that ubiquitin-specific protease 3 (USP3) participates in establishing "tolerance" innate immune memory through non-transcriptional feedback. Upon NF-κB signaling activation, USP3 is stabilized and exits the nucleus. The cytoplasmic USP3 specifically removes the K63-linked polyubiquitin chains on MyD88, thus negatively regulating TLR/IL1β-induced inflammatory signaling activation. Importantly, cytoplasmic translocation is a prerequisite step for USP3 to deubiquitinate MyD88. Additionally, LPS priming could induce cytoplasmic retention and faster and stronger cytoplasmic translocation of USP3, enabling it to quickly shut down NF-κB signaling upon the second LPS challenge. This work identifies a previously unrecognized post-translational feedback loop in the MyD88-USP3 axis, which is critical for inducing normal "tolerance" innate immune memory.

Keywords:  NF-κB signaling; inflammatory response; innate immune memory; toll-like receptors; ubiquitination

DOI:  https://doi.org/10.15252/embr.202357828
World J Diabetes. 2023 Oct 15. 14(10): 1478-1492

Role of glycolysis in diabetic atherosclerosis.

Qian-Jia Liu, Wei Yuan, Ping Yang, Chen Shao.

  Diabetes mellitus is a kind of typical metabolic disorder characterized by elevated blood sugar levels. Atherosclerosis (AS) is one of the most common complications of diabetes. Modern lifestyles and trends that promote overconsumption and unhealthy practices have contributed to an increase in the annual incidence of diabetic AS worldwide, which has created a heavy burden on society. Several studies have shown the significant effects of glycolysis-related changes on the occurrence and development of diabetic AS, which may serve as novel thera-peutic targets for diabetic AS in the future. Glycolysis is an important metabolic pathway that generates energy in various cells of the blood vessel wall. In particular, it plays a vital role in the physiological and pathological activities of the three important cells, Endothelial cells, macrophages and vascular smooth muscle cells. There are lots of similar mechanisms underlying diabetic and common AS, the former is more complex. In this article, we describe the role and mechanism underlying glycolysis in diabetic AS, as well as the therapeutic targets, such as trained immunity, microRNAs, gut microbiota, and associated drugs, with the aim to provide some new perspectives and potentially feasible programs for the treatment of diabetic AS in the foreseeable future.

Keywords:  Atherosclerotic plaque; Drugs; Gut microbiota; Hyperglycemia; Trained immunity; microRNAs

DOI:  https://doi.org/10.4239/wjd.v14.i10.1478
Biochim Biophys Acta Mol Cell Res. 2023 Apr 11. pii: S0167-4889(23)00040-X. [Epub ahead of print] 119469

Open questions in the NF-κB field.

Susanne Bacher, M Lienhard Schmitz.

  A variety of stress signals leads to activation of the inducible transcription factor NF-κB, one of the master regulators of the innate immune response. Despite a wealth of information available on the NF-κB core components and its control by different activation pathways and negative feedback loops, several levels of complexity hamper our understanding of the system. This has also contributed to the limited success of NF-κB inhibitors in the clinic and explains some of their unexpected effects. Here we consider the molecular and cellular events generating this complexity at all levels and point to a number of unresolved questions in the field. We also discuss the potential of future experimental and computational strategies to provide a deeper understanding of NF-κB and its coregulatory signaling networks.

Keywords:  Gene regulation; NF-κB; Signaling; Trained immunity

DOI:  https://doi.org/10.1016/j.bbamcr.2023.119469
bioRxiv. 2023 Oct 23. pii: 2023.10.19.563200. [Epub ahead of print]

Monocytes reprogrammed by 4-PBA potently contribute to the resolution of inflammation and atherosclerosis.

Shuo Geng, Ran Lu, Yao Zhang, Yajun Wu, Ling Xie, Blake Caldwell, Kisha Pradhan, Ziyue Yi, Jacqueline Hou, Feng Xu, Xian Chen, Liwu Li.

Background: Chronic inflammation initiated by inflammatory monocytes underlies the pathogenesis of atherosclerosis. However, approaches that can effectively resolve chronic low-grade inflammation targeting monocytes are not readily available. The small chemical compound 4-phenylbutyric acid (4-PBA) exhibits broad anti-inflammatory effects in reducing atherosclerosis. Selective delivery of 4-PBA reprogrammed monocytes may hold novel potential in providing targeted and precision therapeutics for the treatment of atherosclerosis.
Methods: Systems analyses integrating single-cell RNA-sequencing and complementary immunological approaches characterized key resolving characteristics as well as defining markers of reprogrammed monocytes trained by 4-PBA. Molecular mechanisms responsible for monocyte reprogramming was assessed by integrated biochemical and genetic approaches. The inter-cellular propagation of homeostasis resolution was evaluated by co-culture assays with donor monocytes trained by 4-PBA and recipient naïve monocytes. The in vivo effects of monocyte resolution and atherosclerosis prevention by 4-PBA were assessed with the high fat diet-fed ApoE -/- mouse model with i.p. 4-PBA administration. Furthermore, the selective efficacy of 4-PBA trained monocytes were examined by i.v. transfusion of ex vivo trained monocytes by 4-PBA into recipient high fat diet-fed ApoE -/- mice.
Results: In this study, we found that monocytes can be potently reprogrammed by 4-PBA into an immune-resolving state characterized by reduced adhesion and enhanced expression of anti-inflammatory mediator CD24. Mechanistically, 4-PBA reduced the expression of ICAM-1 via reducing peroxisome stress and attenuating SYK-mTOR signaling. Concurrently, 4-PBA enhanced the expression of resolving mediator CD24 through promoting PPARγ neddylation mediated by TOLLIP. 4-PBA trained monocytes can effectively propagate anti-inflammation activity to neighboring monocytes through CD24. Our data further demonstrated that 4-PBA trained monocytes effectively reduce atherosclerosis pathogenesis when administered in vivo .
Conclusion: Our study describes a robust and effective approach to generate resolving monocytes, characterizes novel mechanisms for targeted monocyte reprogramming, and offers a precision-therapeutics for atherosclerosis based on delivering reprogrammed resolving monocytes.

DOI: https://doi.org/10.1101/2023.10.19.563200
Int J Mol Sci. 2023 Oct 30. pii: 15773. [Epub ahead of print]24(21):

Immunobiotic Ligilactobacillus salivarius FFIG58 Confers Long-Term Protection against Streptococcus pneumoniae.

Mariano Elean, Fernanda Raya Tonetti, Kohtaro Fukuyama, Luciano Arellano-Arriagada, Fu Namai, Yoshihito Suda, Nadia Gobbato, Keita Nishiyama, Julio Villena, Haruki Kitazawa.

  Previously, we isolated potentially probiotic Ligilactobacillus salivarius strains from the intestines of wakame-fed pigs. The strains were characterized based on their ability to modulate the innate immune responses triggered by the activation of Toll-like receptor (TLR)-3 or TLR4 signaling pathways in intestinal mucosa. In this work, we aimed to evaluate whether nasally administered L. salivarius strains are capable of modulating the innate immune response in the respiratory tract and conferring long-term protection against the respiratory pathogen Streptococcus pneumoniae. Infant mice (3-weeks-old) were nasally primed with L. salivarius strains and then stimulated with the TLR3 agonist poly(I:C). Five or thirty days after the last poly(I:C) administration mice were infected with pneumococci. Among the strains evaluated, L. salivarius FFIG58 had a remarkable ability to enhance the protection against the secondary pneumococcal infection by modulating the respiratory immune response. L. salivarius FFIG58 improved the ability of alveolar macrophages to produce interleukin (IL)-6, interferon (IFN)-γ, IFN-β, tumor necrosis factor (TNF)-α, IL-27, chemokine C-C motif ligand 2 (CCL2), chemokine C-X-C motif ligand 2 (CXCL2), and CXCL10 in response to pneumococcal challenge. Furthermore, results showed that the nasal priming of infant mice with the FFIG58 strain protected the animals against secondary infection until 30 days after stimulation with poly(I:C), raising the possibility of using nasally administered immunobiotics to stimulate trained immunity in the respiratory tract.

Keywords:  Ligilactobacillus salivarius FFIG58; Streptococcus pneumoniae; antiviral immunity; immunobiotics; poly(I:C); respiratory superinfection

DOI:  https://doi.org/10.3390/ijms242115773
Neurochem Res. 2023 Nov 14.

Microglia-Dependent Reversal of Depression-Like Behaviors in Chronically Stressed Mice by Administration of a Specific Immuno-stimulant β-Glucan.

Cheng Zhao, Zhuo Chen, Xu Lu, Wenfeng Hu, Rongrong Yang, Qun Lu, Bingran Chen, Chao Huang.

  In recent years, the decline of microglia in the hippocampus has been shown to play a role in the development of depression, and its reversal shows marked antidepressant-like effects. β-glucan is a polysaccharide from Saccharomyces cerevisiae and has numerous beneficial effects on the nervous system, including improving axon regeneration and cognition. Considering its immuno-stimulatory activities in cultured microglia and brain tissues, we hypothesize that β-glucan may be a potential candidate to correct the functional deficiency of microglia and thereby alleviate depression-like behaviors in chronically stressed animals. An expected, our results showed that a single injection of β-glucan 5 h before behavioral tests at a dose of 10 or 20 mg/kg, but not at a dose of 5 mg/kg, reversed the depression-like behavior induced by chronic stress in mice in the tail suspension test, forced swimming test, and sucrose preference test. The effect of β-glucan (20 mg/kg) also showed time-dependent properties that were statistically significant 5 and 8, but not 3, hours after drug injection and persisted for at least 7 days. Fourteen days after β-glucan injection, no antidepressant-like effect was observed anymore. However, this effect was overcome by a second β-glucan injection (20 mg/kg) 14 days after the first β-glucan injection. Stimulation of microglia appeared to mediate the antidepressant-like effect of β-glucan, because both inhibition of microglia and their depletion prevented the antidepressant-like effect of β-glucan. Based on these effects of β-glucan, β-glucan administration could be developed as a new strategy for the treatment of depression.

Keywords:  Antidepressant; Hippocampus; Microglia; β-glucan

DOI:  https://doi.org/10.1007/s11064-023-04056-x
Nat Commun. 2023 Nov 17. 14(1): 7471

Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation.

Marlies Cortés, Agnese Brischetto, M C Martinez-Campanario, Chiara Ninfali, Verónica Domínguez, Sara Fernández, Raquel Celis, Anna Esteve-Codina, Juan J Lozano, Julia Sidorova, Gloria Garrabou, Anna-Maria Siegert, Carlos Enrich, Belén Pintado, Manuel Morales-Ruiz, Pedro Castro, Juan D Cañete, Antonio Postigo.

Acute inflammation can either resolve through immunosuppression or persist, leading to chronic inflammation. These transitions are driven by distinct molecular and metabolic reprogramming of immune cells. The anti-diabetic drug Metformin inhibits acute and chronic inflammation through mechanisms still not fully understood. Here, we report that the anti-inflammatory and reactive-oxygen-species-inhibiting effects of Metformin depend on the expression of the plasticity factor ZEB1 in macrophages. Using mice lacking Zeb1 in their myeloid cells and human patient samples, we show that ZEB1 plays a dual role, being essential in both initiating and resolving inflammation by inducing macrophages to transition into an immunosuppressed state. ZEB1 mediates these diverging effects in inflammation and immunosuppression by modulating mitochondrial content through activation of autophagy and inhibition of mitochondrial protein translation. During the transition from inflammation to immunosuppression, Metformin mimics the metabolic reprogramming of myeloid cells induced by ZEB1. Mechanistically, in immunosuppression, ZEB1 inhibits amino acid uptake, leading to downregulation of mTORC1 signalling and a decrease in mitochondrial translation in macrophages. These results identify ZEB1 as a driver of myeloid cell metabolic plasticity, suggesting that targeting its expression and function could serve as a strategy to modulate dysregulated inflammation and immunosuppression.

DOI: https://doi.org/10.1038/s41467-023-42277-4