bims-traimu 2024-04-14 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2024–04–14
nine papers selected by
Yantong Wan, Southern Medical University

The helminth-derived peptide, FhHDM-1, reverses the trained phenotype of NOD bone-marrow-derived macrophages and regulates proinflammatory responses.
GM-CSF receptor expression determines opposing innate memory phenotypes at different stages of myelopoiesis.
Endotoxin tolerance ameliorates lipopolysaccharide/D-galactosamine-induced acute liver failure by negative regulation of the NF-κB/NLRP3 and activation of Nrf2/HO-1 via Sitr1.
Survivors of polymicrobial sepsis are refractory to G-CSF-induced emergency myelopoiesis and hematopoietic stem and progenitor cell mobilization.
The metabolic cofactor Coenzyme A enhances alternative macrophage activation via MyD88-linked signaling.
Early-life exercise induces immunometabolic epigenetic modification enhancing anti-inflammatory immunity in middle-aged male mice.
Itaconate as a key player in cardiovascular immunometabolism.
Preconditioning-induced facilitation of lactate release from astrocytes is essential for brain ischemic tolerance.
Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids.

Eur J Immunol. 2024 Apr 05. e2350643

The helminth-derived peptide, FhHDM-1, reverses the trained phenotype of NOD bone-marrow-derived macrophages and regulates proinflammatory responses.

Susel Loli Quinteros, Nathaniel W Snyder, Adam Chatoff, Fiona Ryan, Bronwyn O'Brien, Sheila Donnelly.

  We implicate a phenotype of trained immunity in bone-marrow-derived macrophages in the onset and progression of type 1 diabetes in nonobese diabetic mice. Treatment with FhHDM-1 reversed immune training, reducing histone methylation and glycolysis, and decreasing proinflammatory cytokine production to the same level as macrophages from nondiabetic immune-competent BALB/c mice.

Keywords:  FhHDM‐1; Helminth therapy; Macrophage; Trained immunity; Type 1 diabetes

DOI:  https://doi.org/10.1002/eji.202350643
Blood. 2024 Apr 11. pii: blood.2024024330. [Epub ahead of print]

GM-CSF receptor expression determines opposing innate memory phenotypes at different stages of myelopoiesis.

Paula Guerrero, Cristina Bono, María Sobén, Andrea Guiu, Quen J Cheng, M Luisa Gil, Alberto Yáñez.

Inflammatory responses must be tightly coordinated with the activation of emergency myelopoiesis to produce potent myeloid cells that fight infection without causing excessive host damage. Here, we show that GM-CSF programs myeloid committed progenitors to produce trained macrophages (increased cytokine response), but programs the upstream non-committed LKS+ progenitors to produce tolerized macrophages (decreased cytokine response). In myeloid progenitors, GM-CSF strongly activates STAT5, ERK and Akt-mTOR signaling pathways, which are essential to establish a training program, whereas in LKS+ progenitors GM-CSF induces NF-κB translocation to the nucleus to establish a tolerization program. These differences arise from higher GM-CSF receptor expression in myeloid progenitors compared to LKS+ cells. We demonstrate that β-catenin regulation of NF-κB nuclear translocation is central in this process. Glycogen synthase kinase 3 (GSK3) inactivation by strong ERK and PI3K-Akt signaling increases cytoplasmic β-catenin levels to block NF-κB nuclear translocation in myeloid progenitors. In contrast, when ERK and PI3K-Akt signaling are weak, active GSK3 causes a decrease in β-catenin, allowing NF-κB nuclear translocation in LKS+ progenitors. Finally, GM-CSF-induced LKS+ tolerization takes place in several murine models of trained immunity and in human CD34+ CD38- progenitors. Our study reveals that in addition to activating myelopoiesis, GM-CSF also programs early and immediate myeloid progenitors to produce opposing immune memory phenotypes. We propose that the inflammatory response from immediate myeloid progenitors may be balanced by the tolerized phenotype of early progenitors, thus providing a mechanism for appropriate resolution of inflammation and protection against a prolonged cytokine storm.

DOI: https://doi.org/10.1182/blood.2024024330
Int Immunopharmacol. 2024 Apr 05. pii: S1567-5769(24)00512-5. [Epub ahead of print]132 111994

Endotoxin tolerance ameliorates lipopolysaccharide/D-galactosamine-induced acute liver failure by negative regulation of the NF-κB/NLRP3 and activation of Nrf2/HO-1 via Sitr1.

Huifang Shi, Xueting Xie, Sijie Zheng, Hong Chen, Chenyi Liu, Shu Li, Mingqin Lu.

  Acute liver failure (ALF) is a potentially fatal disorder characterized by extensive hepatocyte necrosis and rapid decline in liver function. Numerous factors, including oxidative stress, cell death, and inflammatory responses, are associated with its pathogenesis. Endotoxin tolerance (ET) refers to the phenomenon in which the body or cells exhibit low or no response to high-dose lipopolysaccharide (LPS) stimulation after pre-stimulation with low-dose LPS. However, the specific mechanism through which ET regulates LPS/D-galactosamine (D-GalN)-induced ALF remains unclear. An ALF mouse model was established by intraperitoneal injection of D-GalN (400 mg/kg) and LPS (10 mg/kg). A low dose of LPS (0.1 mg/kg/d) was continuously administered to mice for 5 d before modeling to assess the protective effect of ET. The data from this study showed that ET alleviated the inflammatory response in mice with LPS/D-GalN-induced ALF. ET inhibited LPS-induced oxidative damage and pyroptosis in macrophages in vitro. RNA sequencing analysis showed that the NF-κB/NLRP3 pathway was linked to the anti-inflammatory and antioxidative effects of ET. Furthermore, using western blot, RT-qPCR, and immunofluorescence, we verified that ET inhibited the NF-κB/NLRP3 pathway and triggered the Nrf2/HO-1 signaling pathway to attenuate oxidative stress and cell pyroptosis. Sirt1 knockdown reversed this protective effect. In summary, our research elucidates that ET prevents ALF advancement by upregulating Sirt1 levels, triggering the Nrf2/HO-1 signaling axis, and suppressing the NF-κB/NLRP3 signaling cascade to inhibit oxidative stress and cell pyroptosis. Our results provide a mechanistic explanation for the protective effect of ET against ALF.

Keywords:  Acute liver failure; Endotoxin tolerance; Macrophage; NLRP3 inflammasome; Nrf2; Sirt1

DOI:  https://doi.org/10.1016/j.intimp.2024.111994
Stem Cell Reports. 2024 Apr 03. pii: S2213-6711(24)00082-1. [Epub ahead of print]

Survivors of polymicrobial sepsis are refractory to G-CSF-induced emergency myelopoiesis and hematopoietic stem and progenitor cell mobilization.

Nirupam Biswas, Amber Bahr, Jennifer Howard, Jesse L Bonin, Rachel Grazda, Katherine C MacNamara.

  Sepsis survivors exhibit immune dysfunction, hematological changes, and increased risk of infection. The long-term impacts of sepsis on hematopoiesis were analyzed using a surgical model of murine sepsis, resulting in 50% survival. During acute disease, phenotypic hematopoietic stem and progenitor cells (HSPCs) were reduced in the bone marrow (BM), concomitant with increased myeloid colony-forming units and extramedullary hematopoiesis. Upon recovery, BM HSPCs were increased and exhibited normal function in the context of transplantation. To evaluate hematopoietic responses in sepsis survivors, we treated recovered sham and cecal ligation and puncture mice with a mobilizing regimen of granulocyte colony-stimulating factor (G-CSF) at day 20 post-surgery. Sepsis survivors failed to undergo emergency myelopoiesis and HSPC mobilization in response to G-CSF administration. G-CSF is produced in response to acute infection and injury to expedite the production of innate immune cells; therefore, our findings contribute to a new understanding of how sepsis predisposes to subsequent infection.

Keywords:  G-CSF; HSC; HSPC; blood; bone marrow; extramedullary hematopoiesis; mobilization; myelopoiesis; sepsis

DOI:  https://doi.org/10.1016/j.stemcr.2024.03.007
bioRxiv. 2024 Mar 31. pii: 2024.03.28.587096. [Epub ahead of print]

The metabolic cofactor Coenzyme A enhances alternative macrophage activation via MyD88-linked signaling.

Anthony E Jones, Amy Rios, Neira Ibrahimovic, Carolina Chavez, Nicholas A Bayley, Andréa B Ball, Wei Yuan Hsieh, Alessandro Sammarco, Amber R Bianchi, Angel A Cortez, Thomas G Graeber, Alexander Hoffmann, Steven J Bensinger, Ajit S Divakaruni.

Metabolites and metabolic co-factors can shape the innate immune response, though the pathways by which these molecules adjust inflammation remain incompletely understood. Here we show that the metabolic cofactor Coenzyme A (CoA) enhances IL-4 driven alternative macrophage activation [m(IL-4)] in vitro and in vivo . Unexpectedly, we found that perturbations in intracellular CoA metabolism did not influence m(IL-4) differentiation. Rather, we discovered that exogenous CoA provides a weak TLR4 signal which primes macrophages for increased receptivity to IL-4 signals and resolution of inflammation via MyD88. Mechanistic studies revealed MyD88-linked signals prime for IL-4 responsiveness, in part, by reshaping chromatin accessibility to enhance transcription of IL-4-linked genes. The results identify CoA as a host metabolic co-factor that influences macrophage function through an extrinsic TLR4-dependent mechanism, and suggests that damage-associated molecular patterns (DAMPs) can prime macrophages for alternative activation and resolution of inflammation.

DOI: https://doi.org/10.1101/2024.03.28.587096
Nat Commun. 2024 Apr 10. 15(1): 3103

Early-life exercise induces immunometabolic epigenetic modification enhancing anti-inflammatory immunity in middle-aged male mice.

Nini Zhang, Xinpei Wang, Mengya Feng, Min Li, Jing Wang, Hongyan Yang, Siyu He, Ziqi Xia, Lei Shang, Xun Jiang, Mao Sun, Yuanming Wu, Chaoxue Ren, Xing Zhang, Jia Li, Feng Gao.

Exercise is usually regarded to have short-term beneficial effects on immune health. Here we show that early-life regular exercise exerts long-term beneficial effects on inflammatory immunity. Swimming training for 3 months in male mice starting from 1-month-old curbs cytokine response and mitigates sepsis when exposed to lipopolysaccharide challenge, even after an 11-month interval of detraining. Metabolomics analysis of serum and liver identifies pipecolic acid, a non-encoded amino acid, as a pivotal metabolite responding to early-life regular exercise. Importantly, pipecolic acid reduces inflammatory cytokines in bone marrow-derived macrophages and alleviates sepsis via inhibiting mTOR complex 1 signaling. Moreover, early-life exercise increases histone 3 lysine 4 trimethylation at the promoter of Crym in the liver, an enzyme responsible for catalyzing pipecolic acid production. Liver-specific knockdown of Crym in adult mice abolishes this early exercise-induced protective effects. Our findings demonstrate that early-life regular exercise enhances anti-inflammatory immunity during middle-aged phase in male mice via epigenetic immunometabolic modulation, in which hepatic pipecolic acid production has a pivotal function.

DOI: https://doi.org/10.1038/s41467-024-47458-3
Free Radic Biol Med. 2024 Apr 09. pii: S0891-5849(24)00389-7. [Epub ahead of print]

Itaconate as a key player in cardiovascular immunometabolism.

Wenju Shan, Jun Cui, Yujie Song, Dongxu Yan, Linqi Feng, Yuhong Jian, Wei Yi, Yang Sun.

  Cardiovascular diseases (CVDs) are the leading cause of death globally, resulting in a major health burden. Thus, an urgent need exists for exploring effective therapeutic targets to block progression of CVDs and improve patient prognoses. Immune and inflammatory responses are involved in the development of atherosclerosis, ischemic myocardial damage responses and repair, calcification, and stenosis of the aortic valve. These responses can involve both large and small blood vessels throughout the body, leading to increased blood pressure and end-organ damage. While exploring potential avenues for therapeutic intervention in CVDs, researchers have begun to focus on immune metabolism, where metabolic changes that occur in immune cells in response to exogenous or endogenous stimuli can influence immune cell effector responses and local immune signaling. Itaconate, an intermediate metabolite of the tricarboxylic acid (TCA) cycle, is related to pathophysiological processes, including cellular metabolism, oxidative stress, and inflammatory immune responses. The expression of immune response gene 1 (IRG1) is upregulated in activated macrophages, and this gene encodes an enzyme that catalyzes the production of itaconate from the TCA cycle intermediate, cis-aconitate. Itaconate and its derivatives have exerted cardioprotective effects through immune modulation in various disease models, such as ischemic heart disease, valvular heart disease, vascular disease, heart transplantation, and chemotherapy drug-induced cardiotoxicity, implying their therapeutic potential in CVDs. In this review, we delve into the associated signaling pathways through which itaconate exerts immunomodulatory effects, summarize its specific roles in CVDs, and explore emerging immunological therapeutic strategies for managing CVDs.

Keywords:  Cardiovascular disease; Immunometabolism; Itaconate; Signaling pathway

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.04.218
eNeuro. 2024 Apr 11. pii: ENEURO.0494-23.2024. [Epub ahead of print]

Preconditioning-induced facilitation of lactate release from astrocytes is essential for brain ischemic tolerance.

Yuri Hirayama, Ha Pham Ngoc Le, Hirofumi Hashimoto, Itsuko Ishii, Schuichi Koizumi, Naohiko Anzai.

A sub-lethal ischemic episode (termed preconditioning [PC]) protects neurons in the brain against a subsequent severe ischemic injury. This phenomenon is known as brain ischemic tolerance, and has received much attention from researchers because of its robust neuroprotective effects. We have previously reported that PC activates astrocytes and subsequently upregulates P2X7 receptors, thereby leading to ischemic tolerance. However, the downstream signals of P2X7 receptors that are responsible for PC-induced ischemic tolerance remain unknown. Here, we show that PC-induced P2X7 receptor-mediated lactate release from astrocytes has an indispensable role in this event. Using a transient focal cerebral ischemia model caused by middle cerebral artery occlusion, extracellular lactate levels during severe ischemia were significantly increased in mice who experienced PC; this increase was dependent on P2X7 receptors. In addition, the intracerebroventricular injection of lactate protected against cerebral ischemic injury. In in vitro experiments, although stimulation of astrocytes with the P2X7 receptor agonist BzATP had no effect on the protein levels of monocarboxylate transporter (MCT) 1 and MCT4 (which are responsible for lactate release from astrocytes), BzATP induced the plasma membrane translocation of these MCTs via their chaperone CD147. Importantly, CD147 was increased in activated astrocytes after PC, and CD147-blocking antibody abolished the PC-induced facilitation of astrocytic lactate release and ischemic tolerance. Taken together, our findings suggest that astrocytes induce ischemic tolerance via P2X7 receptor-mediated lactate release.Significance Statement Brain ischemic tolerance refers to an endogenous neuroprotective phenomenon whereby a non-lethal ischemic episode, termed preconditioning (PC), induces resistance to a subsequent severe ischemic injury. This phenomenon has received much attention because of its robust neuroprotective effects. We have previously reported that the PC-evoked activation of astrocytes leads to ischemic tolerance; however, the underlying molecular mechanisms remain unknown. Here, we have demonstrated that PC induces the membrane translocation of lactate transporters in activated astrocytes, thereby promoting lactate release from astrocytes during severe ischemia; this effect likely plays a role in ischemic tolerance. These findings may facilitate the development of new therapeutic strategies for cerebral ischemia.

DOI: https://doi.org/10.1523/ENEURO.0494-23.2024
Nature. 2024 Apr 10.

Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids.

Jean-Philippe Auger, Max Zimmermann, Maria Faas, Ulrich Stifel, David Chambers, Brenda Krishnacoumar, R Verena Taudte, Charlotte Grund, Gitta Erdmann, Carina Scholtysek, Stefan Uderhardt, Oumaima Ben Brahim, Mónica Pascual Maté, Cornelia Stoll, Martin Böttcher, Katrin Palumbo-Zerr, Matthew S J Mangan, Maria Dzamukova, Markus Kieler, Melanie Hofmann, Stephan Blüml, Gernot Schabbauer, Dimitrios Mougiakakos, Uwe Sonnewald, Fabian Hartmann, David Simon, Arnd Kleyer, Anika Grüneboom, Susetta Finotto, Eicke Latz, Jörg Hofmann, Georg Schett, Jan Tuckermann, Gerhard Krönke.

Glucocorticoids represent the mainstay of therapy for a broad spectrum of immune-mediated inflammatory diseases. However, the molecular mechanisms underlying their anti-inflammatory mode of action have remained incompletely understood1. Here we show that the anti-inflammatory properties of glucocorticoids involve reprogramming of the mitochondrial metabolism of macrophages, resulting in increased and sustained production of the anti-inflammatory metabolite itaconate and consequent inhibition of the inflammatory response. The glucocorticoid receptor interacts with parts of the pyruvate dehydrogenase complex whereby glucocorticoids provoke an increase in activity and enable an accelerated and paradoxical flux of the tricarboxylic acid (TCA) cycle in otherwise pro-inflammatory macrophages. This glucocorticoid-mediated rewiring of mitochondrial metabolism potentiates TCA-cycle-dependent production of itaconate throughout the inflammatory response, thereby interfering with the production of pro-inflammatory cytokines. By contrast, artificial blocking of the TCA cycle or genetic deficiency in aconitate decarboxylase 1, the rate-limiting enzyme of itaconate synthesis, interferes with the anti-inflammatory effects of glucocorticoids and, accordingly, abrogates their beneficial effects during a diverse range of preclinical models of immune-mediated inflammatory diseases. Our findings provide important insights into the anti-inflammatory properties of glucocorticoids and have substantial implications for the design of new classes of anti-inflammatory drugs.

DOI: https://doi.org/10.1038/s41586-024-07282-7