bims-traimu 2024-07-07 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2024–07–07
ten papers selected by
Yantong Wan, Southern Medical University

The effect of β-Glucan induced intestinal trained immunity against Trichinella spiralis infection.
Post-COVID-19 pandemic increased incidence of invasive bacterial infections: potential links with altered herd trained immunity.
Chronic NOD2 stimulation by MDP confers protection against parthanatos through M2b macrophage polarization in RAW264.7 cells.
Epithelial cells maintain memory of prior infection with Streptococcus pneumoniae through di-methylation of histone H3.
Glutamate oxaloacetate transaminase 1 is dispensable in macrophage differentiation and anti-pathogen response.
Hypoxia and inflammation induce synergistic transcriptome turnover in macrophages.
Exosome-shuttled miR-150-5p from LPS-preconditioned mesenchymal stem cells down-regulate PI3K/Akt/mTOR pathway via Irs1 to enhance M2 macrophage polarization and confer protection against sepsis.
Advances in Bacterial Lysate Immunotherapy for Infectious Diseases and Cancer.
Interleukin-1β stimulated macrophage derived exosomes improve myocardial injury in sepsis via regulation of mitochondrial homeostasis: Experimental research.
Acod1-mediated inhibition of aerobic glycolysis suppresses osteoclast differentiation and attenuates bone erosion in arthritis.

Vet Parasitol. 2024 Jun 20. pii: S0304-4017(24)00126-2. [Epub ahead of print] 110238

The effect of β-Glucan induced intestinal trained immunity against Trichinella spiralis infection.

Hanhai Mao, Yi Liu, Qingbo Lv, Chengyao Li, Yaming Yang, Fangwei Wu, Ning Xu, Xuemin Jin.

  Parasitic helminth Trichinella spiralis (Ts) induce mixed Th1/Th2 response with predominant type 2 immune responses, with protective immunity mediated by interleukin (IL)-4, IL-5, and IL-13. β-Glucan (BG) has been shown to have the ability to induce trained immunity, confers non-specific protection from secondary infections. However, whether BG-induced trained immunity played a role in protective type 2 immunity against Ts infection is unclear. In this study, BG was administered five days before Ts infection to induce trained immunity. Our findings demonstrate that BG pretreatment effectively reduced the number of T. spiralis adults and muscle larvae, whereas inhibition of trained immunity abolished the effect of BG. Additionally, we observed a significant increase in goblet cells and mucus production as evidenced by Alcian blue periodic acid-Schiff staining. Furthermore, quantitative real-time PCR analysis revealed a significant upregulation of IL-4, IL-5, and IL-13 expression in response to BG. Conversely, the inhibitor of trained immunity reversed these effects, suggesting that BG-induced trained immunity confers strong protection against Ts infection. In conclusion, these findings suggest that BG-induced trained immunity may play a role in protection against infections caused by other helminths.

Keywords:  Trained immunity; Trichinella spiralis; Type 2 immunity; β-Glucan

DOI:  https://doi.org/10.1016/j.vetpar.2024.110238
Pol Arch Intern Med. 2024 Jul 05. pii: 16794. [Epub ahead of print]

Post-COVID-19 pandemic increased incidence of invasive bacterial infections: potential links with altered herd trained immunity.

Janusz Marcinkiewicz.

There has been a global increase in the incidence of various infectious diseases observed since the end of the COVID-19 pandemic. It could be hypothesized that this increase results from two independent phenomena. One is related to impaired immunity of long Covid patients. The second, the major, is associated with the long-term isolation of many people during the global pandemic lockdown resulting in an extreme reduction of contact with natural environmental human microbiota. This, in turn, led to a silencing state of the body's defense systems, including a decline of the pre-pandemic trained immunity (innate memory) that persists only for weeks to months after exposure. This decrease in trained immunity may be especially important for morbidity of infectious diseases without currently available vaccines, such as invasive Group A Streptococcus pyogenes (GAS) infections, primarily streptococcal toxic shock syndrome (STSS). This review discusses the data that support the important role of trained macrophages in host defense and demonstrates the potential clinical implications of β-glucan, the major inducer of trained macrophages, for prophylactic and therapeutic use in a case of impaired personal innate immunity. Altogether, it might be speculated that trained innate immunity within an entire population can lead to the development of Herd Trained Immunity, the novel coined the medical term. HTI can supplement classical antigen-specific herd immunity (memory B and T cells) and plays a key role in preventing various infectious diseases, including invasive GAS infections. Unfortunately, the global HTI has been overthrown during the COVID-19 pandemic but it should be restored shortly.

DOI: https://doi.org/10.20452/pamw.16794
Immunobiology. 2024 Jun 29. pii: S0171-2985(24)00051-2. [Epub ahead of print]229(5): 152833

Chronic NOD2 stimulation by MDP confers protection against parthanatos through M2b macrophage polarization in RAW264.7 cells.

Florencia C Mansilla, María C Miraglia, Silvina S Maidana, Randazzo Cecilia, Alejandra V Capozzo.

  Innate immune cells show enhanced responsiveness to secondary challenges after an initial non-related stimulation (Trained Innate Immunity, TII). Acute NOD2 activation by Muramyl-Dipeptide (MDP) promotes TII inducing the secretion of pro-inflammatory mediators, while a sustained MDP-stimulation down-regulates the inflammatory response, restoring tolerance. Here we characterized in-vitro the response of murine macrophages to lipopolysaccharide (LPS) challenge under NOD2-chronic stimulation. RAW264.7 cells were trained with MDP (1 μg/ml, 48 h) and challenged with LPS (5 μg/ml, 24 h). Trained cells formed multinucleated giant cells with increased phagocytosis rates compared to untrained/challenged cells. They showed a reduced mitochondrial activity and a switch to aerobic glycolysis. TNF-α, ROS and NO were upregulated in both trained and untrained cultures (MDP+, MDP- cells, p > 0.05); while IL-10, IL-6 IL-12 and MHCII were upregulated only in trained cells after LPS challenge (MDP + LPS+, p < 0.05). A slight upregulation in the expression of B7.2 was also observed in this group, although differences were not statistically significant. MDP-training induced resistance to LPS challenge (p < 0.01). The relative expression of PARP-1 was downregulated after the LPS challenge, which may contribute to the regulatory milieu and to the innate memory mechanisms exhibited by MDP-trained cells. Our results demonstrate that a sustained MDP-training polarizes murine macrophages towards a M2b profile, inhibiting parthanatos. These results may impact on the development of strategies to immunomodulate processes in which inflammation should be controlled.

Keywords:  LPS resistance; M2b macrophages; Muramyl-dipeptide; NOD2; PARP-1

DOI:  https://doi.org/10.1016/j.imbio.2024.152833
Nat Commun. 2024 Jul 02. 15(1): 5545

Epithelial cells maintain memory of prior infection with Streptococcus pneumoniae through di-methylation of histone H3.

Christine Chevalier, Claudia Chica, Justine Matheau, Adrien Pain, Michael G Connor, Melanie A Hamon.

Epithelial cells are the first point of contact for bacteria entering the respiratory tract. Streptococcus pneumoniae is an obligate human pathobiont of the nasal mucosa, carried asymptomatically but also the cause of severe pneumoniae. The role of the epithelium in maintaining homeostatic interactions or mounting an inflammatory response to invasive S. pneumoniae is currently poorly understood. However, studies have shown that chromatin modifications, at the histone level, induced by bacterial pathogens interfere with the host transcriptional program and promote infection. Here, we uncover a histone modification induced by S. pneumoniae infection maintained for at least 9 days upon clearance of bacteria with antibiotics. Di-methylation of histone H3 on lysine 4 (H3K4me2) is induced in an active manner by bacterial attachment to host cells. We show that infection establishes a unique epigenetic program affecting the transcriptional response of epithelial cells, rendering them more permissive upon secondary infection. Our results establish H3K4me2 as a unique modification induced by infection, distinct from H3K4me3 or me1, which localizes to enhancer regions genome-wide. Therefore, this study reveals evidence that bacterial infection leaves a memory in epithelial cells after bacterial clearance, in an epigenomic mark, thereby altering cellular responses to subsequent infections and promoting infection.

DOI: https://doi.org/10.1038/s41467-024-49347-1
Commun Biol. 2024 Jul 05. 7(1): 817

Glutamate oxaloacetate transaminase 1 is dispensable in macrophage differentiation and anti-pathogen response.

Lishan Zhang, Zhengyi Wu, Xuanhui Qiu, Jia Zhang, Shih-Chin Cheng.

Macrophages play a pivotal role in orchestrating the immune response against pathogens. While the intricate interplay between macrophage activation and metabolism remains a subject of intense investigation, the role of glutamate oxaloacetate transaminase 1 (Got1) in this context has not been extensively assessed. Here, we investigate the impact of Got1 on macrophage polarization and function, shedding light on its role in reactive oxygen species (ROS) production, pathogen defense, and immune paralysis. Using genetically modified mouse models, including both myeloid specific knockout and overexpression, we comprehensively demonstrate that Got1 depletion leads to reduced ROS production in macrophages. Intriguingly, this impairment in ROS generation does not affect the resistance of Got1 KO mice to pathogenic challenges. Furthermore, Got1 is dispensable for M2 macrophage differentiation and does not influence the onset of LPS-induced immune paralysis. Our findings underscore the intricate facets of macrophage responses, suggesting that Got1 is dispensable in discrete immunological processes.

DOI: https://doi.org/10.1038/s42003-024-06479-w
Cell Rep. 2024 Jul 04. pii: S2211-1247(24)00781-2. [Epub ahead of print]43(7): 114452

Hypoxia and inflammation induce synergistic transcriptome turnover in macrophages.

Edward M C Courvan, Roy R Parker.

  Macrophages are effector immune cells that experience substantial changes to oxygenation when transiting through tissues, especially when entering tumors or infected wounds. How hypoxia alters gene expression and macrophage effector function at the post-transcriptional level remains poorly understood. Here, we use TimeLapse-seq to measure how inflammatory activation modifies the hypoxic response in primary macrophages. Nucleoside recoding sequencing allows the derivation of steady-state transcript levels, degradation rates, and transcriptional synthesis rates from the same dataset. We find that hypoxia produces distinct responses from resting and inflammatory macrophages. Hypoxia induces destabilization of mRNA transcripts, though inflammatory macrophages substantially increase mRNA degradation compared to resting macrophages. Increased RNA turnover results in the upregulation of ribosomal protein genes and downregulation of extracellular matrix components in inflammatory macrophages. Pathways regulated by mRNA decay in vitro are differentially regulated in tumor-associated macrophages implying that mixed stimuli could induce post-transcriptional regulation of macrophage function in solid tumors.

Keywords:  CP: Immunology; RNA decay; hypoxia; inflammation; macrophages

DOI:  https://doi.org/10.1016/j.celrep.2024.114452
Front Immunol. 2024 ;15 1397722

Exosome-shuttled miR-150-5p from LPS-preconditioned mesenchymal stem cells down-regulate PI3K/Akt/mTOR pathway via Irs1 to enhance M2 macrophage polarization and confer protection against sepsis.

Ting Zheng, Sipeng Li, Teng Zhang, Wei Fu, Shuchang Liu, Yuxin He, Xiao Wang, Tao Ma.

   Rationale: Sepsis is a life-threatening organ dysfunction and lack of effective measures in the current. Exosomes from mesenchymal stem cells (MSCs) reported to alleviate inflammation during sepsis, and the preconditioning of MSCs could enhance their paracrine potential. Therefore, this study investigated whether exosomes secreted by lipopolysaccharide (LPS)-pretreated MSCs exert superior antiseptic effects, and explored the underlying molecular mechanisms.
Methods: Exosomes were isolated and characterized from the supernatants of MSCs. The therapeutic efficacy of normal exosomes (Exo) and LPS-pretreated exosomes (LPS-Exo) were evaluated in terms of survival rates, inflammatory response, and organ damage in an LPS-induced sepsis model. Macrophages were stimulated with LPS and treated with Exo or LPS-Exo to confirm the results of the in vivo studies, and to explain the potential mechanisms.
Results: LPS-Exo were shown to inhibit aberrant pro-inflammatory cytokines, prevent organ damages, and improve survival rates of the septic mice to a greater extent than Exo. In vitro, LPS-Exo significantly promoted the M2 polarization of macrophages exposed to inflammation. miRNA sequencing and qRT-PCR analysis identified the remarkable expression of miR-150-5p in LPS-Exo compared to that in Exo, and exosomal miR-150-5p was transferred into recipient macrophages and mediated macrophage polarization. Further investigation demonstrated that miR-150-5p targets Irs1 in recipient macrophages and subsequently modulates macrophage plasticity by down-regulating the PI3K/Akt/mTOR pathway.
Conclusion: The current findings highly suggest that exosomes derived from LPS pre-conditioned MSCs represent a promising cell-free therapeutic method and highlight miR-150-5p as a novel molecular target for regulating immune hyperactivation during sepsis.

Keywords:   sepsis; Irs1; exosomes; macrophage; miR-150-5p

DOI:  https://doi.org/10.3389/fimmu.2024.1397722
J Immunol Res. 2024 ;2024 4312908

Advances in Bacterial Lysate Immunotherapy for Infectious Diseases and Cancer.

Md Mijanur Rahman, I Darren Grice, Glen C Ulett, Ming Q Wei.

Antigenic cell fragments, pathogen-associated molecular patterns, and other immunostimulants in bacterial lysates or extracts may induce local and systemic immune responses in specific and nonspecific paradigms. Based on current knowledge, this review aimed to determine whether bacterial lysate has comparable functions in infectious diseases and cancer treatment. In infectious diseases, including respiratory and urinary tract infections, immune system activation by bacterial lysate can identify and combat pathogens. Commercially available bacterial lysates, including OM-85, Ismigen, Lantigen B, and LW 50020, were effective in children and adults in treating respiratory tract infections, chronic obstructive pulmonary disease, rhinitis, and rhinosinusitis with varying degrees of success. Moreover, OM-89, Uromune, Urovac, Urivac, and ExPEC4V showed therapeutic benefits in controlling urinary tract infections in adults, especially women. Bacterial lysate-based therapeutics are safe, well-tolerated, and have few side effects, making them a good alternative for infectious disease management. Furthermore, a nonspecific immunomodulation by bacterial lysates may stimulate innate immunity, benefiting cancer treatment. "Coley's vaccine" has been used to treat sarcomas, carcinomas, lymphomas, melanomas, and myelomas with varying outcomes. Later, several similar bacterial lysate-based therapeutics have been developed to treat cancers, including bladder cancer, non-small cell lung cancer, and myeloma; among them, BCG for in situ bladder cancer is well-known. Proinflammatory cytokines, including IL-1, IL-6, IL-12, and TNF-α, may activate bacterial antigen-specific adaptive responses that could restore tumor antigen recognition and response by tumor-specific type 1 helper cells and cytotoxic T cells; therefore, bacterial lysates are worth investigating as a vaccination adjuvants or add-on therapies for several cancers.

DOI: https://doi.org/10.1155/2024/4312908
Int J Surg. 2024 Jul 05.

Interleukin-1β stimulated macrophage derived exosomes improve myocardial injury in sepsis via regulation of mitochondrial homeostasis: Experimental research.

Chunhua Ma, Zhaocong Yang, Jing Wang, Han She, Lei Tan, Xuming Mo, Tao Li, Liangming Liu.

BACKGROUND: The purpose of this study was to investigate the effects of interleukin-1β (IL-1β) stimulation on the protection of macrophage derived exosomes miR-146a (M-IL-exo-146a) on sepsis induced myocardial injury (SMI) in vitro and in vivo.
METHODS: Macrophage derived exosomes (M-exo) and IL-1β stimulated macrophage exosomes (M-IL-exo) were isolated from macrophages of sepsis with or without IL-1β. The expressions of miR-146a in M-exo and M- IL-exo were detected by fluorescence quantitative PCR. Related molecular biology technologies were used to evaluate the role and mechanism of M-exo-146a and M-IL-exo-146a on SMI and the enhancing effect of IL-1β.
RESULTS: Compared with M-exo, the expression of miR-146a in M-IL-exo was significantly increased. M-IL-exo-146a significantly alleviated SMI by decreasing the level of serum myocardial enzymes, serum and myocardial oxidative stress and cytokines, and improved myocardial mitochondrial imbalance. The mechanism responsible for IL-1β enhancing the production of IL-M-exo miR-146a was via JNK-1/2 signal pathway. The mechanism responsible for M-exo-IL-miR-146a protecting SMI was related to miR-146a inhibiting inflammatory response and mitochondrial function via MAPK4/Drp1 signal pathway.
CONCLUSIONS: This study provides a new strategy for the treatment of SMI by delivering IL-1β stimulated macrophage derived exosomes.

DOI: https://doi.org/10.1097/JS9.0000000000001915
Ann Rheum Dis. 2024 Jul 04. pii: ard-2023-224774. [Epub ahead of print]

Acod1-mediated inhibition of aerobic glycolysis suppresses osteoclast differentiation and attenuates bone erosion in arthritis.

Katerina Kachler, Darja Andreev, Shreeya Thapa, Dmytro Royzman, Andreas Gießl, Shobika Karuppusamy, Mireia Llerins Perez, Mengdan Liu, Jörg Hofmann, Arne Gessner, Xianyi Meng, Simon Rauber, Alexander Steinkasserer, Martin Fromm, Georg Schett, Aline Bozec.

   OBJECTIVES: Metabolic changes are crucially involved in osteoclast development and may contribute to bone degradation in rheumatoid arthritis (RA). The enzyme aconitate decarboxylase 1 (Acod1) is known to link the cellular function of monocyte-derived macrophages to their metabolic status. As osteoclasts derive from the monocyte lineage, we hypothesised a role for Acod1 and its metabolite itaconate in osteoclast differentiation and arthritis-associated bone loss.
METHODS: Itaconate levels were measured in human peripheral blood mononuclear cells (PBMCs) of patients with RA and healthy controls by mass spectrometry. Human and murine osteoclasts were treated with the itaconate derivative 4-octyl-itaconate (4-OI) in vitro. We examined the impact of Acod1-deficiency and 4-OI treatment on bone erosion in mice using K/BxN serum-induced arthritis and human TNF transgenic (hTNFtg) mice. SCENITH and extracellular flux analyses were used to evaluate the metabolic activity of osteoclasts and osteoclast progenitors. Acod1-dependent and itaconate-dependent changes in the osteoclast transcriptome were identified by RNA sequencing. CRISPR/Cas9 gene editing was used to investigate the role of hypoxia-inducible factor (Hif)-1α in Acod1-mediated regulation of osteoclast development.
RESULTS: Itaconate levels in PBMCs from patients with RA were inversely correlated with disease activity. Acod1-deficient mice exhibited increased osteoclast numbers and bone erosion in experimental arthritis while 4-OI treatment alleviated inflammatory bone loss in vivo and inhibited human and murine osteoclast differentiation in vitro. Mechanistically, Acod1 suppressed osteoclast differentiation by inhibiting succinate dehydrogenase-dependent production of reactive oxygen species and Hif1α-mediated induction of aerobic glycolysis.
CONCLUSION: Acod1 and itaconate are crucial regulators of osteoclast differentiation and bone loss in inflammatory arthritis.

Keywords:  Arthritis, Experimental; Arthritis, Rheumatoid; Bone Density; Inflammation; Osteoporosis

DOI:  https://doi.org/10.1136/ard-2023-224774