bims-traimu 2024-12-29 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2024–12–29
seven papers selected by
Yantong Wan, Southern Medical University

Trained Immunity Enhances Host Resistance to Infection in Aged Mice.
Bletilla striata polysaccharide-mediated trained immunity drives the hematopoietic progenitors' expansion and myelopoiesis.
Hematopoietic stem cell a reservoir of innate immune memory.
Itaconate facilitates viral infection via alkylating GDI2 and retaining Rab GTPase on the membrane.
Enhanced itaconic acid secretion from macrophages mediates the protection of mesenchymal stem cell-derived exosomes on lipopolysaccharide-induced acute lung injury mice.
Exploiting gasdermin-mediated pyroptosis for enhanced antimicrobial activity of phage endolysin against Pseudomonas aeruginosa.
Perception of a pathogenic signature initiates intergenerational protection.

J Leukoc Biol. 2024 Dec 26. pii: qiae259. [Epub ahead of print]

Trained Immunity Enhances Host Resistance to Infection in Aged Mice.

Dan Hao, Katherine R Caja, Margaret A McBride, Allison M Owen, Julia K Bohannon, Antonio Hernandez, Sabah Ali, Sujata Dalal, David L Williams, Edward R Sherwood.

  Aging significantly increases the incidence and severity of infections, with individuals aged 65 and above accounting for 65% of sepsis cases. Innate immune training, known as "trained immunity" or "innate immune memory", has emerged as a potential strategy to enhance infection resistance by modulating the aging immune system. We investigated the impact of β-glucan-induced trained immunity on aged mice (18-20 months old) compared to young adult mice (10-12 weeks old). Our findings showed that β-glucan equally augmented the host resistance to infection in both young and aged mice. This enhancement was characterized by augmented bacterial clearance, enhanced leukocyte recruitment and decreased cytokine production in response to Pseudomonas aeruginosa infection. Furthermore, young and aged trained macrophages displayed heightened metabolic capacity and improved antimicrobial functions, including enhanced phagocytosis and respiratory burst. RNA-seq analysis showed a distinctive gene expression pattern induced by trained immunity in macrophages characterized by activation of pathways regulating inflammation and the host response to infection and suppression of pathways regulating cell division, which was consistently observed in both young and aged groups. As compared to macrophages from young mice, aged macrophages showed increased activation of gene ontology pathways regulating angiogenesis, connective tissue deposition and wound healing. Our results indicate that immune training can be effectively induced in aging mice, providing valuable insights into potential strategies for enhancing infection resistance in the elderly.

Keywords:   β-glucan; immunometabolism; infection; trained immunity

DOI:  https://doi.org/10.1093/jleuko/qiae259
Int Immunopharmacol. 2024 Dec 24. pii: S1567-5769(24)02431-7. [Epub ahead of print]146 113909

Bletilla striata polysaccharide-mediated trained immunity drives the hematopoietic progenitors' expansion and myelopoiesis.

Jiangtao Zhang, Chao Zhong, Lanying Chen, Yingying Luo, Le Tang, Jing Yang, Jing Jia, Xinxu Xie, Peng Liu, Jun Yu, Yaru Cui.

  Trained immunity represents a functional state of the innate immune response, characterized by enduring epigenetic reprogramming of innate immune cells. This phenomenon facilitates a sustained and advantageous reaction of myeloid cells to subsequent challenges. Bletilla striata polysaccharide (BSP) is the primary active component of Bletilla striata, mainly consisting of mannose and glucose in its chemical structure. Previous studies have demonstrated BSP's immunomodulatory properties, highlighting its effectiveness in enhancing the immune response. In the present study, we demonstrated that BSP administration induced the trained innate immunity, as evidenced by the BSP-induced generation of mature myeloid cells, especially neutrophils in the peripheral circulation in amouse model of chemotherapy-induced myelosuppression. Furthermore, we showed that BSP-induced trained immunity acts at the level of hematopoietic stem and progenitor cells (HSPCs) and induces the expansion of HSPCs. Mechanistically, our study demonstrated that BSP induced the activation of Notch signaling in HSPCs, and Notch signaling is indispensable for the BSP-mediated generation of trained HSPCs. Collectively, our data demonstrated for the first time that BSP induced trained immunity by regulating theexpansion of the myeloid progenitors. Harnessing trained immunity could be a promising strategy for protection from chemotherapy-induced myelosuppression.

Keywords:  Bletilla striata polysaccharide; Chemotherapy; Hematopoietic stem and progenitor cells; Trained immunity

DOI:  https://doi.org/10.1016/j.intimp.2024.113909
Front Immunol. 2024 ;15 1491729

Hematopoietic stem cell a reservoir of innate immune memory.

Lucas Ruffinatto, Yann Groult, Johanna Iacono, Sandrine Sarrazin, Bérengère de Laval.

  Hematopoietic stem cells (HSCs) are a rare, long-lived and multipotent population that give rise to majority of blood cells and some tissue-resident immune cells. There is growing evidence that inflammatory stimuli can trigger persistent reprogramming in HSCs that enhances or inhibits the cellular functions of these HSCs and their progeny in response to subsequent infections. This newly discovered property makes HSCs a reservoir for innate immune memory. The molecular mechanisms underlying innate immune memory in HSCs are similar to those observed in innate immune cells, although their full elucidation is still pending. In this review, we examine the current state of knowledge on how an inflammatory response leads to reprogramming of HSCs. Understanding the full spectrum of consequences of reshaping early hematopoiesis is critical for assessing the potential benefits and risks under physiological and pathological conditions.

Keywords:  emergency hematopoiesis; epigenetic; hematopoietic stem and progenitor cells (HSPCs); inflammation; innate immune memory; metabolism; myelopoiesis

DOI:  https://doi.org/10.3389/fimmu.2024.1491729
Signal Transduct Target Ther. 2024 Dec 27. 9(1): 371

Itaconate facilitates viral infection via alkylating GDI2 and retaining Rab GTPase on the membrane.

Shulei Yin, Yijie Tao, Tianliang Li, Chunzhen Li, Yani Cui, Yunyan Zhang, Shenhui Yin, Liyuan Zhao, Panpan Hu, Likun Cui, Yunyang Wu, Yixian He, Shu Yu, Jie Chen, Shaoteng Lu, Guifang Qiu, Mengqi Song, Qianshan Hou, Cheng Qian, Zui Zou, Sheng Xu, Yizhi Yu.

Metabolic reprogramming of host cells plays critical roles during viral infection. Itaconate, a metabolite produced from cis-aconitate in the tricarboxylic acid cycle (TCA) by immune responsive gene 1 (IRG1), is involved in regulating innate immune response and pathogen infection. However, its involvement in viral infection and underlying mechanisms remain incompletely understood. Here, we demonstrate that the IRG1-itaconate axis facilitates the infections of VSV and IAV in macrophages and epithelial cells via Rab GTPases redistribution. Mechanistically, itaconate promotes the retention of Rab GTPases on the membrane via directly alkylating Rab GDP dissociation inhibitor beta (GDI2), the latter of which extracts Rab GTPases from the membrane to the cytoplasm. Multiple alkylated residues by itaconate, including cysteines 203, 335, and 414 on GDI2, were found to be important during viral infection. Additionally, this effect of itaconate needs an adequate distribution of Rab GTPases on the membrane, which relies on Rab geranylgeranyl transferase (GGTase-II)-mediated geranylgeranylation of Rab GTPases. The single-cell RNA sequencing data revealed high expression of IRG1 primarily in neutrophils during viral infection. Co-cultured and in vivo animal experiments demonstrated that itaconate produced by neutrophils plays a dominant role in promoting viral infection. Overall, our study reveals that neutrophils-derived itaconate facilitates viral infection via redistribution of Rab GTPases, suggesting potential targets for antiviral therapy.

DOI: https://doi.org/10.1038/s41392-024-02077-8
Biol Direct. 2024 Dec 26. 19(1): 138

Enhanced itaconic acid secretion from macrophages mediates the protection of mesenchymal stem cell-derived exosomes on lipopolysaccharide-induced acute lung injury mice.

Yanmei Wen, Zong'an Liang.

   BACKGROUND: Alveolar macrophages (AMs) is critical to exacerbate acute lung injury (ALI) induced by lipopolysaccharide (LPS) via inhibiting inflammation, which could by shifted by mesenchymal stem cell-derived exosomes (MSC-exos). But the underlying rationale is not fully clarified. Our study aimed to analyze the significance of itaconic acid (ITA) in mediating the protective effects of MSC-exos on LPS-induced ALI.
METHODS: MSC-exos were used to treat pulmonary microvascular endothelial cells (PMVECs) co-cultured with AMs under LPS stimulation. si-IRG1 was transfected to AMs. PMVEC permeability, apoptosis rates, and inflammatory cytokine levels were assessed. In vivo, C57BL/6 wild-type (WT) and Irg1-/- mice were employed to explore the protection of MSC-exos against LPS-induced ALI. The lung injury was determined by histological and biochemical assays. ITA levels were measured using gas chromatography-mass spectrometry. Western blot and flow cytometry analyses were performed to assess M1/M2 polarization.
RESULTS: Co-culture with AMs significantly increased PMVEC permeability, apoptosis rates, IL-6, TNF-α levels and Claudin-5 and ZO-1 expression induced by LPS treatment, which were attenuated by MSC-exos accompanied by enhanced ITA level. After si-IRG1 transfection, MSC-exos' protective efficacy was reversed, with suppressed M2 polarization. In vivo, MSC-exos alleviated alveolar structure disruption, pulmonary edema, inflammation and increased ITA concentration in WT mice but had reduced effects in Irg1-/- mice, with neglected M2 polarization.
CONCLUSIONS: ITA secretion facilitated the MSC-exos' protective benefits on LPS-induced PMVEC damage and ALI in mice by promoting AM M2 polarization, highlighting a potential therapeutic strategy for ALI and related inflammatory lung diseases.

Keywords:  Acute lung injury; Alveolar macrophages; Inflammation; Itaconic acid; Mesenchymal stem cell-derived exosomes

DOI:  https://doi.org/10.1186/s13062-024-00586-8
mSystems. 2024 Dec 26. e0110624

Exploiting gasdermin-mediated pyroptosis for enhanced antimicrobial activity of phage endolysin against Pseudomonas aeruginosa.

Dorota Kuc-Ciepluch, Karol Ciepluch, Daria Augustyniak, Grzegorz Guła, Barbara Maciejewska, Artur Kowalik, Ewelina Jop, Zuzanna Drulis-Kawa, Michał Arabski.

  Pyroptosis is an inflammatory immune response of eukaryotic cells to bacterial lipopolysaccharide (LPS) and other pathological stimuli, leading to the activation of the gasdermin D (GSDMD) and secretion of pore-forming domain GSDMDNterm, facilitating the release of cytokines. Additionally, GSDMDNterm exhibits antibacterial properties through interactions with bacterial outer membranes (OM). We explored alternative antimicrobial strategy to determine whether inducing natural pyroptosis via GSDMD activation by P. aeruginosa LPS could enhance the effectiveness of recombinant phage endopeptidase KP27 (peptidoglycan-degrading enzyme) against P. aeruginosa, enabling penetration through OM and bacterial killing synergistically. Our findings demonstrated that recombinant GSDMD alone exhibited antibacterial effects against wild-type P. aeruginosa with smooth LPS, while recombinant GSDMDNterm efficiently permeabilized both smooth LPS-bearing and O-chain-deficient P. aeruginosa potentially synergizing with endolysin KP27. Transcriptomic analyses revealed the activation of the immune system pathways in response to LPS, mainly in monocytic cells, in contrast to epithelial A549 or HeLa cell lines. LPS-induced pyroptosis in monocytes led to GSDMD cleavage and the release of interleukins, regardless of the nature/origin of the LPS used. However, the pyroptosis stimulation by LPS in the antibacterial assay was not effective enough for bacterial OM permeabilization and enhancement of endolysin activity. We assume that leveraging pyroptosis induction in monocytic cells to augment the bactericidal activity of endolysins may be limited.
IMPORTANCE: Recombinant GSDMDNterm protein was able to efficiently permeabilize P. aeruginosa outer membranes and increase endolysin activity against bacteria, producing either long LPS O-chains or lack them entirely. The obtained results suggest the limited possibility of using the natural process of pyroptosis occurring in monocytic cells to enhance the bactericidal effect of recombinant phage endolysins against Gram-negative bacteria infection.

Keywords:  Pseudomonas aeruginosa LPS; endolysin; gasdermin D; outer membrane permeabilization; pyroptosis

DOI:  https://doi.org/10.1128/msystems.01106-24
Cell. 2024 Dec 24. pii: S0092-8674(24)01342-4. [Epub ahead of print]

Perception of a pathogenic signature initiates intergenerational protection.

Corinne L Pender, Julian G Dishart, Holly K Gildea, Kelsie M Nauta, Emily M Page, Talha F Siddiqi, Shannon S Cheung, Larry Joe, Nicholas O Burton, Andrew Dillin.

  Transmission of immune responses from one generation to the next represents a powerful adaptive mechanism to protect an organism's descendants. Parental infection by the natural C. elegans pathogen Pseudomonas vranovensis induces a protective response in progeny, but the bacterial cues and intergenerational signal driving this response were previously unknown. Here, we find that animals activate a protective stress response program upon exposure to P. vranovensis-derived cyanide and that a metabolic byproduct of cyanide detoxification, β-cyanoalanine, acts as an intergenerational signal to protect progeny from infection. Remarkably, this mechanism does not require direct parental infection; rather, exposure to pathogen-derived volatiles is sufficient to enhance the survival of the next generation, indicating that parental surveillance of environmental cues can activate a protective intergenerational response. Therefore, the mere perception of a pathogen-derived toxin, in this case cyanide, can protect an animal's progeny from future pathogenic challenges.

Keywords:  C. elegans; CYSL-2; MDT-15; Pseudomonas; SKN-1; cyanide; intergenerational inheritance; pathogen sensing; volatile response; β-cyanoalanine

DOI:  https://doi.org/10.1016/j.cell.2024.11.026