bims-traimu 2024-10-13 papers

Issue of 2024–10–13
six papers selected by
Yantong Wan, Southern Medical University

Cell Rep. 2024 Oct 10. pii: S2211-1247(24)01201-4. [Epub ahead of print]43(10): 114850

Persistent bone marrow hemozoin accumulation confers a survival advantage against bacterial infection via cell-intrinsic Myd88 signaling.

Yanhui Zhu, Qingxiang Gao, Jia Zhang, Yu Cheng, Shuzhen Yang, Ren Xu, Jing Yuan, Boris Novakovic, Mihai G Netea, Shih-Chin Cheng.

Malaria remains a global health challenge, affecting millions annually. Hemozoin (Hz) deposition in the bone marrow disrupts hematopoiesis and modulates immune responses, but the mechanisms are not fully understood. Here, we show that persistent hemozoin deposition induces a sustained bias toward myelopoiesis, increasing peripheral myeloid cell numbers. Hz drives this process through a cell-intrinsic, MyD88-dependent pathway, enhancing chromatin accessibility of transcription factors such as Runx1 and Etv6 in granulocyte-macrophage progenitors. These findings are confirmed by intraosseous Hz injections and bone marrow chimeras. Single-cell RNA sequencing reveals increased reactive oxygen species production in monocytes from malaria-recovered mice, correlating with enhanced bactericidal capacity. This highlights an alternative aspect of post-malarial immunity and extends our understanding of trained immunity, suggesting that pathogen by-products like Hz can induce innate immune memory. These results offer insights into therapeutic strategies that harness trained immunity to combat infectious diseases.

Keywords: CP: Immunology; hemozoin; innate immune memory; malaria; myelopoiesis; trained immunity

DOI: https://doi.org/10.1016/j.celrep.2024.114850

Cell Rep. 2024 Oct 08. pii: S2211-1247(24)01200-2. [Epub ahead of print]43(10): 114849

LPS-induced lung tissue-resident trained innate immunity provides differential protection against pneumococci and SARS-CoV-2.

Alisha Kang, Gluke Ye, Sam Afkhami, Fatemah Aleithan, Kanwaldeep Singh, Anna Dvorkin-Gheva, Tobias Berg, Matthew S Miller, Mangalakumari Jeyanathan, Zhou Xing.

Recent evidence indicates that tissue-resident innate immune memory and trained innate immunity (TII) can be induced centrally in myeloid cells within the bone marrow and locally in tissue-resident macrophages in respiratory mucosal tissues. However, it remains unclear whether acute exposure to airborne microbial components like lipopolysaccharide (LPS) induces lasting innate immune memory in airway macrophages and TII capable of protection against heterologous pathogens. Using a murine model, we demonstrate that acute LPS exposure leads to dynamic changes in the immune phenotype of airway macrophages that persist long after the acute inflammatory response has subsided. The original airway-resident alveolar macrophage pool remains stable in size despite these changes and the earlier transient acute inflammatory responses, including monocytic recruitment in the lung. We further demonstrate that the induction of innate immune memory in airway macrophages is accompanied by TII capable of robust protection against acute pneumococcal infection, whereas it provides minimal protection against acute SARS-CoV-2 infection.

Keywords: CP: Immunology

DOI: https://doi.org/10.1016/j.celrep.2024.114849

bioRxiv. 2024 Sep 26. pii: 2024.09.24.614798. [Epub ahead of print]

Lipopolysaccharide Induces Trained Innate Immune Tolerance in the Heart Through Interferon Signaling in a Model of Stress-Induced Cardiomyopathy.

Kenji Rowel Q Lim, Junedh Amrute, Attila Kovacs, Abhinav Diwan, David L Williams, Douglas L Mann.

Background: Although the ability of the heart to adapt to environmental stress has been studied extensively, the molecular and cellular mechanisms responsible for cardioprotection are not yet fully understood.
Methods: We administered Toll-like receptor (TLR) agonists or a diluent to wild-type mice and assessed their potential to induce cardiac protection against injury from a high intraperitoneal dose of isoproterenol (ISO) administered 7 days later. Cardioprotective effects were analyzed through serum cardiac troponin I levels, immune cell profiling via flow cytometry, echocardiography, and multiomic single-nuclei RNA and ATAC sequencing.
Results: Pretreatment with the TLR4 agonist lipopolysaccharide (LPS), but not TLR1/2 or TLR3 agonists, conferred cardioprotection against ISO, as demonstrated by reduced cardiac troponin I leakage, decreased inflammation, preservation of cardiac structure and function, and improved survival. Remarkably, LPS-induced tolerance was reversed by β-glucan treatment. Multiomic analysis showed that LPS-tolerized hearts had greater chromatin accessibility and upregulated gene expression compared to hearts treated with LPS and β-glucan (reverse-tolerized). The LPS tolerance was associated with upregulation of interferon response pathways across various cell types, including cardiac myocytes and stromal cells. Blocking both type 1 and type 2 interferon signaling eliminated LPS-induced tolerance against ISO, while pretreatment with recombinant type 1 and 2 interferons conferred cardiac protection. Multiomic sequencing further revealed enhanced cytoprotective signaling in interferon-treated hearts. Analysis of cell-cell communication networks indicated increased autocrine signaling by cardiac myocytes, as well as greater paracrine signaling between stromal cells and myeloid cells, in LPS-tolerized versus reverse-tolerized hearts.
Conclusions: LPS pretreatment confers cardiac protection against ISO-induced injury through TLR4 mediated type 1 and 2 interferon signaling, consistent with trained innate immune tolerance. The observation that LPS-induced protection in cardiac myocytes involves both cell-autonomous and non-cell-autonomous mechanisms underscores the complexity of innate immune tolerance in the heart, warranting further investigation into this cardioprotective phenotype.
Clinical Perspective: What is new?: The Toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS) confers cardiac protection against isoproterenol-mediated injury in a manner consistent with trained innate immune tolerance, which is reversed by β-glucan treatment.Activation of type 1 and 2 interferon signaling, which is downstream of Toll-like receptor 4, is necessary and sufficient for LPS-induced cardiac protection.LPS-tolerized hearts show heightened autocrine signaling by cardiac myocytes and, to a greater degree, increased cell-cell communication between cardiac myocytes and stromal and myeloid cells compared to reverse-tolerized hearts.What are the clinical implications?: TLR4 and interferon signaling play key roles in the establishment of cardiac protection and LPS-induced trained innate immune tolerance.The protective effects of LPS are mediated by cell-autonomous and non-cell-autonomous mechanisms, suggesting that a deeper understanding of the molecular and cellular signatures of innate immune tolerance is required for the development of targeted approaches to modulate trained innate immunity, and consequently cytoprotection, in the heart.

DOI: https://doi.org/10.1101/2024.09.24.614798

Cell Immunol. 2024 Oct 02. pii: S0008-8749(24)00084-4. [Epub ahead of print]405-406 104881

Netosis and trained immunity in tick-borne diseases: a possible pathogenetic role.

Giusto Davide Badami, Bartolo Tamburini, Leila Mohammadnezhad, Rita Vaz-Rodrigues, Lidia La Barbera, José de la Fuente, Guido Sireci.

Various types of pathogens transmitted by ticks elicit distinct immune responses just like the emerging α-Gal syndrome that is associated with allergic reactions to tick bites. The mechanisms of Neutrophil Extracellular Traps release (called NETosis) and trained immunity in response to tick-borne microbes have not been extensively investigated. In our paper, we explored the intricate interplay of NETosis and trained immunity within the realm of infectious diseases triggered by tick bites and their possible pathogenetic role in autoimmunity. We conducted an extensive literature search to identify studies for this review, considering articles and reviews published in English within the last years. Additionally, we scrutinized the references of all included papers and relevant review articles to ensure comprehensive coverage. We shed light on a plausible correlation between these innate immune responses and their potential implication in certain pathological conditions, with a specific focus on some autoimmune diseases. These findings offer new perspectives for a more profound comprehension of the immunopathogenesis of certain autoimmune-like signs where clinicians should include Tick-Borne Diseases (TBDs) in their differential diagnoses, in those geographical areas of tick infestation.

Keywords: Autoimmunity; NETosis; Tick-borne; Trained Immunity

DOI: https://doi.org/10.1016/j.cellimm.2024.104881

J Neuroinflammation. 2024 Oct 07. 21(1): 252

Extracellular vesicles in sepsis plasma mediate neuronal inflammation in the brain through miRNAs and innate immune signaling.

Chanhee Park, Zhuofan Lei, Yun Li, Boyang Ren, Junyun He, Huang Huang, Fengqian Chen, Hui Li, Kavitha Brunner, Jing Zhu, Steven M Jay, Brittney Williams, Wei Chao, Junfang Wu, Lin Zou.

BACKGROUND: Neuroinflammation reportedly plays a critical role in the pathogenesis of sepsis-associated encephalopathy (SAE). We previously reported that circulating plasma extracellular vesicles (EVs) from septic mice are proinflammatory. In the current study, we tested the role of sepsis plasma EVs in neuroinflammation.
METHODS: To track EVs in cells and tissues, HEK293T cell-derived EVs were labeled with the fluorescent dye PKH26. Cecal ligation and puncture (CLP) was conducted to model polymicrobial sepsis in mice. Plasma EVs were isolated by ultracentrifugation and their role in promoting neuronal inflammation was tested following intracerebroventricular (ICV) injection. miRNA inhibitors (anti-miR-146a, -122, -34a, and -145a) were applied to determine the effects of EV cargo miRNAs in the brain. A cytokine array was performed to profile microglia-released protein mediators. TLR7- or MyD88-knockout (KO) mice were utilized to determine the underlying mechanism of EVs-mediated neuroinflammation.
RESULTS: We observed the uptake of fluorescent PKH26-EVs inside the cell bodies of both microglia and neurons. Sepsis plasma EVs led to a dose-dependent cytokine release in cultured microglia, which was partially attenuated by miRNA inhibitors against the target miRNAs and in TLR7-KO cells. When administered via the ICV, sepsis plasma EVs resulted in a marked increase in the accumulation of innate immune cells, including monocyte and neutrophil and cytokine gene expression, in the brain. Although sepsis plasma EVs had no direct effect on cytokine production or neuronal injury in vitro, the conditioned media (CM) of microglia treated with sepsis plasma EVs induced neuronal cell death as evidenced by increased caspase-3 cleavage and Annexin-V staining. Cytokine arrays and bioinformatics analysis of the microglial CM revealed multiple cytokines/chemokines and other factors functionally linked to leukocyte chemotaxis and migration, TLR signaling, and neuronal death. Moreover, sepsis plasma EV-induced brain inflammation in vivo was significantly dependent on MyD88.
CONCLUSIONS: Circulating plasma EVs in septic mice cause a microglial proinflammatory response in vitro and a brain innate immune response in vivo, some of which are in part mediated by TLR7 in vitro and MyD88 signaling in vivo. These findings highlight the importance of circulating EVs in brain inflammation during sepsis.

Keywords: Extracellular miRNA; Extracellular vesicles (EVs); Microglia; Myeloid differentiation primary response 88 (MyD88); Neuroinflammation; Neuronal apoptosis; Sepsis; Sepsis-associated encephalopathy (SAE); Toll-like receptor 7 (TLR7)

DOI: https://doi.org/10.1186/s12974-024-03250-0