bims-traimu 2024-09-22 papers

Issue of 2024–09–22
eight papers selected by
Yantong Wan, Southern Medical University

J Allergy Clin Immunol. 2024 Sep 13. pii: S0091-6749(24)00943-6. [Epub ahead of print]

Trained innate immunity: concept, nomenclature and future perspectives.

During the past decade, compelling evidence has accumulated demonstrating that innate immune cells can mount adaptive characteristics, leading to long-term changes in their function. This de-facto innate immune memory has been termed trained immunity. Trained immunity is mediated through extensive metabolic rewiring and epigenetic modifications, and has important effects in human diseases. While the upregulation of trained immunity by certain vaccines provides heterologous protection against infections, the inappropriate activation of trained immunity by endogenous stimuli contributes to the pathogenesis of inflammatory and neurodegenerative disorders. Development of vaccines that can induce both classical adaptive immunity and trained immunity may lead to a new generation of vaccines with increased efficacy. Activation of trained immunity can also lead to novel strategies for the treatment of cancer, while modulation of trained immunity can provide new approaches for the treatment of inflammatory diseases.

Keywords: Trained immunity; epigenetics; inflammation; innate immune memory

DOI: https://doi.org/10.1016/j.jaci.2024.09.005

Int J Biol Macromol. 2024 Sep 14. pii: S0141-8130(24)06471-7. [Epub ahead of print]280(Pt 1): 135663

Strategy against super-resistant bacteria: Curdlan-induced trained immunity combined with multi-epitope subunit vaccine.

Hai Li, Lingdi Niu, Jiaqing Wang, Qingru Chang, Shuhe Zhang, Jiaqi Wang, Jiankai Zeng, Mingchun Gao, Junwei Ge.

Methicillin-resistant Staphylococcus aureus (MRSA) is rapidly spreading worldwide, emerging as a leading cause of bacterial infections in healthcare and community settings. This poses serious risks to human health. The shortage of novel antibiotics and the absence of effective vaccines make MRSA particularly challenging to treat. Existing vaccine development strategies often fail to provide early protection against infections, highlighting the urgent need for solutions. Herein, we propose a novel strategy combining trained immunity with a multi-epitope subunit vaccine to combat MRSA infections. We comprehensively evaluated the trained immune phenotypes induced by β-glucan from barley and curdlan. Macrophages trained with curdlan exhibited a more balanced inflammatory response compared to β-glucan from barley, expressing higher levels of IL-1β, IFN-β, TGF-β, and CCL2 upon secondary stimulation. Furthermore, curdlan-induced trained immunity rapidly provided excellent protection against S. aureus infection in mice. RNA-sequencing analysis revealed that curdlan modulates the Wnt signaling pathway in macrophages, resolves inflammation, and promotes tissue repair. When combined with one or two doses of S. aureus multivalent epitope antigen against MRSA infection, curdlan-induced trained immunity enhanced early protection and promoted recovery. Our study demonstrates the feasibility of combining trained immunity with vaccine protection against MRSA, providing a strategy against multi-drug resistant bacteria.

Keywords: Curdlan; Methicillin-resistant Staphylococcus aureus; Trained immunity

DOI: https://doi.org/10.1016/j.ijbiomac.2024.135663

Curr Med Chem. 2024 Sep 12.

Features of Gene Regulation in Violation of the Inflammatory Response of Monocyte-like Cells Bearing Mitochondrial Mutations Associated with Atherosclerosis.

Alexander N Orekhov, Nikita G Nikiforov, Alexander D Zhuravlev, Svetlana S Verkhova, Andrey V Omelchenko, Daria D Borodko, Vasily N Sukhorukov, Vasily V Sinyov, Igor A Sobenin.

Аims: This research aimed to study the features of gene regulation of the inflammatory response in cells carrying mitochondrial mutations associated with atherosclerosis.
BACKGROUND: Inflammation plays an important, if not decisive, role in the occurrence of atherosclerotic lesions and then accompanies it throughout its further development. Thus, atherogenesis is a chronic inflammatory process. Chronification of inflammation is a consequence of disruption of the normal inflammatory response at the cell level of the vascular wall.
OBJECTIVES: In this study, we used cytoplasmic hybrids or cybrids carrying atherosclerosis-associated mitochondrial mutations to study gene regulation of inflammatory response. The main goal of the study was to identify the key genes responsible for the impaired inflammatory response revealed for some cybrids.
METHODS: Inflammatory stimulation of cybrids was induced with bacterial lipopolysaccharide, and assessed through secretion of pro-inflammatory cytokines CCL2, IL8, IL6, IL1b. A transcriptome analysis was performed to identify the key genes (master regulators) in the normal (tolerant) and intolerant response of cybrid cells.
RESULTS: Normal inflammatory response after re-stimulation elicited a much smaller secretion of pro-inflammatory cytokines. In an intolerant response, the level of secretion upon re-stimulation was the same or even higher than after the first stimulation. Normal and intolerant responses differed significantly both in terms of the number of signaling pathways involved and qualitatively, since the signaling pathways for normal and intolerant responses are completely different. Master regulators controlling normal and intolerant inflammatory response were identified. For a normal response to the first inflammatory stimulation, no common master up-regulators and 3 master down-regulators were identified. The reverse situation was observed with the intolerant inflammatory response: 6 master up-regulators, and no master down regulators were identified. After the second inflammatory stimulation, no master regulator common to all studied cytokines was found. Thus, key genes involved in the development of intolerant inflammatory response have been identified. In addition, other key genes were identified that were initially associated with an intolerant inflammatory response and thus determine disorders of the inflammatory reaction leading to chronification of inflammation.
CONCLUSION: We identified disturbances in gene associated with the development of intolerant immune response that may be relevant to atherosclerosis. Key genes responsible for the chronification of inflammation were discovered.

Keywords: Cybrid; cytokine; inflammatory stimulation; intolerant response; master regulator; mitochondrial mutations; signaling pathway; trained immunity.

DOI: https://doi.org/10.2174/0109298673303008240829075444

EMBO J. 2024 Sep 18.

Acetylation of TIR domains in the TLR4-Mal-MyD88 complex regulates immune responses in sepsis.

Activation of the Toll-like receptor 4 (TLR4) by bacterial endotoxins in macrophages plays a crucial role in the pathogenesis of sepsis. However, the mechanism underlying TLR4 activation in macrophages is still not fully understood. Here, we reveal that upon lipopolysaccharide (LPS) stimulation, lysine acetyltransferase CBP is recruited to the TLR4 signalosome complex leading to increased acetylation of the TIR domains of the TLR4 signalosome. Acetylation of the TLR4 signalosome TIR domains significantly enhances signaling activation via NF-κB rather than IRF3 pathways. Induction of NF-κB signaling is responsible for gene expression changes leading to M1 macrophage polarization. In sepsis patients, significantly elevated TLR4-TIR acetylation is observed in CD16+ monocytes combined with elevated expression of M1 macrophage markers. Pharmacological inhibition of HDAC1, which deacetylates the TIR domains, or CBP play opposite roles in sepsis. Our findings highlight the important role of TLR4-TIR domain acetylation in the regulation of the immune responses in sepsis, and we propose this reversible acetylation of TLR4 signalosomes as a potential therapeutic target for M1 macrophages during the progression of sepsis.

Keywords: HDAC1 Inhibitor; Macrophage; NF-κB Signaling Pathway; Sepsis; TLR4-TIR Acetylation

DOI: https://doi.org/10.1038/s44318-024-00237-8

Mitochondrion. 2024 Sep 12. pii: S1567-7249(24)00124-7. [Epub ahead of print] 101966

Krebs cycle derivatives, dimethyl fumarate and itaconate, control metabolic reprogramming in inflammatory human microglia cell line.

Moris Sangineto, Martina Ciarnelli, Archana Moola, Vidyasagar Naik Bukke, Tommaso Cassano, Rosanna Villani, Antonino D Romano, Giuseppe Di Gioia, Carlo Avolio, Gaetano Serviddio.

Metabolic reprogramming drives inflammatory activity in macrophages, including microglia, with Krebs cycle (KC) intermediates playing a crucial role as signaling molecules. Here, we show that the bioenergetic profile of LPS-activated human microglialclone 3 cell line (HMC3) is characterized by high levels of glycolysis and mitochondrial (mt) respiration, and the treatment with KC derivatives, namely dimethyl-fumarate (DMF) and itaconate (ITA), almost restores normal metabolism. However, despite comparable bioenergetic and anti-inflammatory effects, the mt hyper-activity was differentially modulated by DMF and ITA. DMF normalized complex I activity, while ITA dampened both complex I and II hyper-activity counteracting oxidative stress more efficiently.

Keywords: Dimethyl fumarate; Immunometabolism; Itaconate; Krebs cycle; Microglia; Mitochondria

DOI: https://doi.org/10.1016/j.mito.2024.101966

Commun Biol. 2024 Sep 17. 7(1): 1164

Activation of the NLRP1B inflammasome by caspase-8.

Justin J Meade, Sarah Stuart, Jana Neiman-Zenevich, Christian Krustev, Stephen E Girardin, Jeremy Mogridge.

Cleavage of the innate immune receptor NLRP1B by various microbial proteases causes the proteasomal degradation of its N-terminal fragment and the subsequent release of a C-terminal fragment that forms an inflammasome. We reported previously that metabolic stress caused by intracellular bacteria triggers NLRP1B activation, but the mechanism by which this occurs was not elucidated. Here we demonstrate that TLR4 signaling in metabolically stressed macrophages promotes the formation of a TRIF/RIPK1/caspase-8 complex. Caspase-8 activity, induced downstream of this TLR4 pathway or through a distinct TNF receptor pathway, causes cleavage and activation of NLRP1B, which facilitates the maturation of both pro-caspase-1 and pro-caspase-8. Thus, our findings indicate that caspase-8 and NLRP1B generate a positive feedback loop that amplifies cell death processes and promotes a pro-inflammatory response through caspase-1. The ability of NLRP1B to detect caspase-8 activity suggests that this pattern recognition receptor may play a role in the defense against a variety of pathogens that induce apoptosis.

DOI: https://doi.org/10.1038/s42003-024-06882-3

Neurosci Lett. 2024 Sep 12. pii: S0304-3940(24)00367-7. [Epub ahead of print]842 137989

Long-term effects of a single high-dose intraperitoneal injection of lipopolysaccharide on depression-like behavior in adolescent mice.

Osamu Nakagawasai, Kohei Takahashi, Takuto Suzuki, Ryota Yamagata, Wataru Nemoto, Koichi Tan-No.

The commonly used lipopolysaccharide (LPS)-induced depression models often evaluate depression-like behaviors in the acute phase after a single intraperitoneal injection of LPS, and are not suitable for examining long-term depression-like behaviors. To overcome this limitation, we developed a mice LPS model for elucidating the long-term pathophysiology of depression. Using the tail-suspension test, we show that a single intraperitoneal injection of a high dose (1.66 mg/kg) of LPS prolonged depression-like behavior to 14 days after LPS administration unlike 4 days after administration for the most commonly used LPS dose (0.83 mg/kg). Upon high-LPS dose administration, TNF-α levels in the cerebrospinal fluid were increased only on the first day after administration. Moreover, LPS-induced depression-like behavior on day 10 after LPS administration was prevented by imipramine or minocycline. Immunohistochemical analysis revealed reduced neurogenesis in the hippocampal dentate gyrus of LPS-treated mice on day 10 of LPS administration. The LPS model, in which a single intraperitoneal administration of LPS at a dose double of the standard dose used currently, exhibits depression-like behavior via reduced neurogenesis mediated by neuroinflammation, and should be useful for elucidating the long-term pathophysiology of depression and for studying antidepressant drugs.

Keywords: Depression; Hippocampus; Imipramine; Lipopolysaccharide; Minocycline; Neurogenesis; TNF-α

DOI: https://doi.org/10.1016/j.neulet.2024.137989

Cell Rep. 2024 Sep 13. pii: S2211-1247(24)01092-1. [Epub ahead of print]43(9): 114741

Integrated metabolic-transcriptomic network identifies immunometabolic modulations in human macrophages.

Hung-Jen Chen, Daniel C Sévin, Guillermo R Griffith, Johanna Vappiani, Lee M Booty, Cindy P A A van Roomen, Johan Kuiper, Jeroen den Dunnen, Wouter J de Jonge, Rab K Prinjha, Palwinder K Mander, Paola Grandi, Beata S Wyspianska, Menno P J de Winther.

Macrophages exhibit diverse phenotypes and respond flexibly to environmental cues through metabolic remodeling. In this study, we present a comprehensive multi-omics dataset integrating intra- and extracellular metabolomes with transcriptomic data to investigate the metabolic impact on human macrophage function. Our analysis establishes a metabolite-gene correlation network that characterizes macrophage activation. We find that the concurrent inhibition of tryptophan catabolism by IDO1 and IL4I1 inhibitors suppresses the macrophage pro-inflammatory response, whereas single inhibition leads to pro-inflammatory activation. We find that a subset of anti-inflammatory macrophages activated by Fc receptor signaling promotes glycolysis, challenging the conventional concept of reduced glycolysis preference in anti-inflammatory macrophages. We demonstrate that cholesterol accumulation suppresses macrophage IFN-γ responses. Our integrated network enables the discovery of immunometabolic features, provides insights into macrophage functional metabolic reprogramming, and offers valuable resources for researchers exploring macrophage immunometabolic characteristics and potential therapeutic targets for immune-related disorders.

Keywords: CP: Immunology; CP: Metabolism; Fc receptor; IDO1; IL4I1; cholesterol; glycolysis; immunometabolism; interferon; macrophage; metabolomics; tryptophan metabolism

DOI: https://doi.org/10.1016/j.celrep.2024.114741