bims-traimu 2024-06-30 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2024‒06‒30
fifteen papers selected by
Yantong Wan, Southern Medical University

BCG Vaccination Suppresses Glucose Intolerance Progression in High-Fat-Diet-Fed C57BL/6 Mice.
Francisella tularensis Live Vaccine Strain training of murine alveolar and bone marrow-derived macrophages.
LL37/self-DNA complexes mediate monocyte reprogramming.
Epigenetic remodeling in insect immune memory.
Vertical Transfer of Maternal Gut Microbes to Offspring of Western Diet-Fed Dams Drives Reduced Levels of Tryptophan Metabolites and Postnatal Innate Immune Response.
BMAL2 promotes eCIRP-induced macrophage endotoxin tolerance.
Extracellular NCOA4 is a mediator of septic death by activating the AGER-NFKB pathway.
Toll-like Receptor Agonist CBLB502 Protects Against Radiation-induced Intestinal Injury in Mice.
Bacterial sepsis triggers stronger transcriptomic immune responses in larger primates.
Single-cell landscape of immunological responses in elderly patients with sepsis.
Macrophage biomimetic nanoparticle-targeted functional extracellular vesicle micro-RNAs revealed via multiomics analysis alleviate sepsis-induced acute lung injury.
Cholinergic macrophages promote the resolution of peritoneal inflammation.
Mechanisms of Flavivirus Cross-Protection against Yellow Fever in a Mouse Model.
Itaconate and dimethyl itaconate upregulate IL-6 production in the LPS-induced inflammation in mice.
Social transmission of inflammation in mice.

Medicina (Kaunas). 2024 May 25. pii: 866. [Epub ahead of print]60(6):

BCG Vaccination Suppresses Glucose Intolerance Progression in High-Fat-Diet-Fed C57BL/6 Mice.

Haruna Arakawa, Masashi Inafuku.

  Background and Objectives: Mycobacterium bovis Bacillus Calmette-Guérin (BCG) vaccine administration has been suggested to prevent glucose metabolism abnormalities and fatty liver in genetically obese ob/ob mice; however, it is not clear whether the beneficial effects of BCG are also observed in the progression of glucose intolerance induced by a high-fat diet (HFD). Therefore, the effects of BCG vaccination on changes in glucose tolerance and insulin response were investigated in HFD-fed C57BL/6 mice. Materials and Methods: We used the BCG Tokyo 172 strain to determine effects on abnormalities in glucose metabolism. For vaccination, five-week-old male mice were injected intraperitoneally with BCG and maintained on a HFD for three weeks. The mice were regularly subjected to intraperitoneal glucose tolerance and insulin tolerance tests (IGTTs and ITTs). These tests were also performed in mice transplanted with bone marrow cells from BCG-vaccinated donor mice. Results: Significant effects of BCG vaccination on blood glucose levels in the IGTTs and ITTs were observed from week 12 of the experiment. BCG vaccination significantly improved changes in fasting glucose and insulin levels, insulin resistance indexes, and glucagon-to-insulin ratios in conjunction with the HFD at the end of the experiment. Significant inhibitory effects in the IGTTs and ITTs on glucose intolerance were also observed with transplantation with bone marrow cells derived from BCG-vaccinated donor mice. Conclusions: BCG vaccination significantly delayed glucose intolerance progression, suggesting a beneficial effect of BCG on the pathogenesis of type 2 diabetes. It has also been suggested that the effects of BCG vaccination may be at least partially due to an immune memory (trained immunity) for hematopoietic stem and progenitor cells of the bone marrow.

Keywords:  BCG; glucose intolerance; insulin resistance; nonalcoholic fatty liver disease; trained immunity

DOI:  https://doi.org/10.3390/medicina60060866
Microbiol Spectr. 2024 Jun 28. e0002824

Francisella tularensis Live Vaccine Strain training of murine alveolar and bone marrow-derived macrophages.

Hamda Khan, Varunika Bhargava, Karen L Elkins.

  Traditionally, successful vaccines rely on specific adaptive immunity by activating lymphocytes with an attenuated pathogen, or pathogen subunit, to elicit heightened responses upon subsequent exposures. However, recent work with Mycobacterium tuberculosis and other pathogens has identified a role for "trained" monocytes in protection through memory-like but non-specific immunity. Here, we used an in vitro co-culture approach to study the potential role of trained macrophages, including lung alveolar macrophages, in immune responses to the Live Vaccine Strain (LVS) of Francisella tularensis. F. tularensis is an intracellular bacterium that replicates within mammalian macrophages and causes respiratory as well as systemic disease. We vaccinated mice with F. tularensis LVS and then obtained lung alveolar macrophages, or derived macrophages from bone marrow. LVS infected and replicated comparably in both types of macrophages, whether naïve or from LVS-vaccinated mice. LVS-infected macrophages were then co-cultured with either naïve splenocytes, splenocytes from mice vaccinated intradermally, or splenocytes from mice vaccinated intravenously. For the first time, we show that immune (but not naïve) splenocytes controlled bacterial replication within alveolar macrophages, similar to previous results using bone marrow-derived macrophage. However, no differences in control of intramacrophage bacterial replication were found between co-cultures with naïve macrophages or macrophages from LVS-vaccinated mice; furthermore, nitric oxide levels and interferon-gamma production in supernatants were largely comparable across all conditions. Thus, in the context of in vitro co-cultures, the data do not support development of trained macrophages in bone marrow or lungs of mice vaccinated with LVS intradermally or intravenously.IMPORTANCE: The discovery of non-specific "trained immunity" in monocytes has generated substantial excitement. However, to date, training has been studied with relatively few microbes (e.g., Mycobacterium bovis Bacille Calmette-Guérin, a live attenuated intracellular bacterium used as a vaccine) and microbial substances (e.g., LPS), and it remains unclear whether training during infection is common. We previously demonstrated that vaccination of mice with Francisella tularensis Live Vaccine Strain (LVS), another live attenuated intracellular bacterium, protected against challenge with the unrelated bacterium Listeria monocytogenes. The present study therefore tested whether LVS vaccination engenders trained macrophages that contributed to this protection. To do so, we used a previous in vitro co-culture approach with murine bone marrow-derived macrophages to expand and study lung alveolar macrophages. We demonstrated that alveolar macrophages can be productively infected and employed to characterize interactions with LVS-immune lymphocytes. However, we find no evidence that either bone marrow-derived or alveolar macrophages are trained by LVS vaccination.

Keywords:  Francisella LVS; alveolar; macrophages; trained immunity

DOI:  https://doi.org/10.1128/spectrum.00028-24
Clin Immunol. 2024 Jun 21. pii: S1521-6616(24)00396-6. [Epub ahead of print]265 110287

LL37/self-DNA complexes mediate monocyte reprogramming.

Aman Damara, Joanna Wegner, Emily R Trzeciak, Antonia Kolb, Mahsa Nastaranpour, Rahul Khatri, Andrea Tuettenberg, Daniela Kramer, Stephan Grabbe, Fatemeh Shahneh.

  LL37 alone and in complex with self-DNA triggers inflammatory responses in myeloid cells and plays a crucial role in the development of systemic autoimmune diseases, like psoriasis and systemic lupus erythematosus. We demonstrated that LL37/self-DNA complexes induce long-term metabolic and epigenetic changes in monocytes, enhancing their responsiveness to subsequent stimuli. Monocytes trained with LL37/self-DNA complexes and those derived from psoriatic patients exhibited heightened glycolytic and oxidative phosphorylation rates, elevated release of proinflammatory cytokines, and affected naïve CD4+ T cells. Additionally, KDM6A/B, a demethylase of lysine 27 on histone 3, was upregulated in psoriatic monocytes and monocytes treated with LL37/self-DNA complexes. Inhibition of KDM6A/B reversed the trained immune phenotype by reducing proinflammatory cytokine production, metabolic activity, and the induction of IL-17-producing T cells by LL37/self-DNA-treated monocytes. Our findings highlight the role of LL37/self-DNA-induced innate immune memory in psoriasis pathogenesis, uncovering its impact on monocyte and T cell dynamics.

Keywords:  LL37/self-DNA complex; Metabolic and epigenetic modifications; Monocyte reprogramming; Psoriasis

DOI:  https://doi.org/10.1016/j.clim.2024.110287
Front Immunol. 2024 ;15 1397521

Epigenetic remodeling in insect immune memory.

Krishnendu Mukherjee, Ulrich Dobrindt.

  The innate immune system of insects can respond more swiftly and efficiently to pathogens based on previous experience of encountering antigens. The understanding of molecular mechanisms governing immune priming, a form of immune memory in insects, including its transgenerational inheritance, remains elusive. It is still unclear if the enhanced expression of immune genes observed in primed insects can persist and be regulated through changes in chromatin structure via epigenetic modifications of DNA or histones, mirroring observations in mammals. Increasing experimental evidence suggests that epigenetic changes at the level of DNA/RNA methylation and histone acetylation can modulate the activation of insects' immune responses to pathogen exposure. Moreover, transgenerational inheritance of certain epigenetic modifications in model insect hosts can influence the transmission of pre-programmed immune responses to the offspring, leading to the development of evolved resistance. Epigenetic research in model insect hosts is on the brink of significant progress in the mechanistic understanding of chromatin remodeling within innate immunity, particularly the direct relationships between immunological priming and epigenetic alterations. In this review, we discuss the latest discoveries concerning the involvement of DNA methylation and histone acetylation in shaping the development, maintenance, and inheritance of immune memory in insects, culminating in the evolution of resistance against pathogens.

Keywords:  DNA methylation; epigenetics; histone acetylation; immune memory; immune priming; insect resistance

DOI:  https://doi.org/10.3389/fimmu.2024.1397521
Nutrients. 2024 Jun 08. pii: 1808. [Epub ahead of print]16(12):

Vertical Transfer of Maternal Gut Microbes to Offspring of Western Diet-Fed Dams Drives Reduced Levels of Tryptophan Metabolites and Postnatal Innate Immune Response.

Kameron Y Sugino, Rachel C Janssen, Rachel H McMahan, Chelsea Zimmerman, Jacob E Friedman, Karen R Jonscher.

  Maternal obesity and/or Western diet (WD) is associated with an increased risk of metabolic dysfunction-associated steatotic liver disease (MASLD) in offspring, driven, in part, by the dysregulation of the early life microbiome. Here, using a mouse model of WD-induced maternal obesity, we demonstrate that exposure to a disordered microbiome from WD-fed dams suppressed circulating levels of endogenous ligands of the aryl hydrocarbon receptor (AHR; indole, indole-3-acetate) and TMAO (a product of AHR-mediated transcription), as well as hepatic expression of Il10 (an AHR target), in offspring at 3 weeks of age. This signature was recapitulated by fecal microbial transfer from WD-fed pregnant dams to chow-fed germ-free (GF) lactating dams following parturition and was associated with a reduced abundance of Lactobacillus in GF offspring. Further, the expression of Il10 was downregulated in liver myeloid cells and in LPS-stimulated bone marrow-derived macrophages (BMDM) in adult offspring, suggestive of a hypo-responsive, or tolerant, innate immune response. BMDMs from adult mice lacking AHR in macrophages exhibited a similar tolerogenic response, including diminished expression of Il10. Overall, our study shows that exposure to maternal WD alters microbial metabolites in the offspring that affect AHR signaling, potentially contributing to innate immune hypo-responsiveness and progression of MASLD, highlighting the impact of early life gut dysbiosis on offspring metabolism. Further investigations are warranted to elucidate the complex interplay between maternal diet, gut microbial function, and the development of neonatal innate immune tolerance and potential therapeutic interventions targeting these pathways.

Keywords:  MASLD; aryl hydrocarbon receptor; fetal programming; gut dysbiosis; innate immunity; macrophage

DOI:  https://doi.org/10.3390/nu16121808
Front Immunol. 2024 ;15 1426682

BMAL2 promotes eCIRP-induced macrophage endotoxin tolerance.

Mian Zhou, Monowar Aziz, Jingsong Li, Alok Jha, Gaifeng Ma, Atsushi Murao, Ping Wang.

  Background: The disruption of the circadian clock is associated with inflammatory and immunological disorders. BMAL2, a critical circadian protein, forms a dimer with CLOCK, activating transcription. Extracellular cold-inducible RNA-binding protein (eCIRP), released during sepsis, can induce macrophage endotoxin tolerance. We hypothesized that eCIRP induces BMAL2 expression and promotes macrophage endotoxin tolerance through triggering receptor expressed on myeloid cells-1 (TREM-1).Methods: C57BL/6 wild-type (WT) male mice were subjected to sepsis by cecal ligation and puncture (CLP). Serum levels of eCIRP 20 h post-CLP were assessed by ELISA. Peritoneal macrophages (PerM) were treated with recombinant mouse (rm) CIRP (eCIRP) at various doses for 24 h. The cells were then stimulated with LPS for 5 h. The levels of TNF-α and IL-6 in the culture supernatants were assessed by ELISA. PerM were treated with eCIRP for 24 h, and the expression of PD-L1, IL-10, STAT3, TREM-1 and circadian genes such as BMAL2, CRY1, and PER2 was assessed by qPCR. Effect of TREM-1 on eCIRP-induced PerM endotoxin tolerance and PD-L1, IL-10, and STAT3 expression was determined by qPCR using PerM from TREM-1-/- mice. Circadian gene expression profiles in eCIRP-treated macrophages were determined by PCR array and confirmed by qPCR. Induction of BMAL2 activation in bone marrow-derived macrophages was performed by transfection of BMAL2 CRISPR activation plasmid. The interaction of BMAL2 in the PD-L1 promoter was determined by computational modeling and confirmed by the BIAcore assay.
Results: Serum levels of eCIRP were increased in septic mice compared to sham mice. Macrophages pre-treated with eCIRP exhibited reduced TNFα and IL-6 release upon LPS challenge, indicating macrophage endotoxin tolerance. Additionally, eCIRP increased the expression of PD-L1, IL-10, and STAT3, markers of immune tolerance. Interestingly, TREM-1 deficiency reversed eCIRP-induced macrophage endotoxin tolerance and significantly decreased PD-L1, IL-10, and STAT3 expression. PCR array screening of circadian clock genes in peritoneal macrophages treated with eCIRP revealed the elevated expression of BMAL2, CRY1, and PER2. In eCIRP-treated macrophages, TREM-1 deficiency prevented the upregulation of these circadian genes. In macrophages, inducible BMAL2 expression correlated with increased PD-L1 expression. In septic human patients, blood monocytes exhibited increased expression of BMAL2 and PD-L1 in comparison to healthy subjects. Computational modeling and BIAcore assay identified a putative binding region of BMAL2 in the PD-L1 promoter, suggesting BMAL2 positively regulates PD-L1 expression in macrophages.
Conclusion: eCIRP upregulates BMAL2 expression via TREM-1, leading to macrophage endotoxin tolerance in sepsis. Targeting eCIRP to maintain circadian rhythm may correct endotoxin tolerance and enhance host resistance to bacterial infection.

Keywords:  BMAL2; PD-L1; circadian; eCIRP; immune tolerance; macrophages

DOI:  https://doi.org/10.3389/fimmu.2024.1426682
Autophagy. 2024 Jun 25.

Extracellular NCOA4 is a mediator of septic death by activating the AGER-NFKB pathway.

Jiao Liu, Yichun Wang, Ling Zeng, Chunhua Yu, Rui Kang, Daniel J Klionsky, Jianxin Jiang, Daolin Tang.

  Sepsis, a life-threatening condition resulting from a dysregulated response to pathogen infection, poses a significant challenge in clinical management. Here, we report a novel role for the autophagy receptor NCOA4 in the pathogenesis of sepsis. Activated macrophages and monocytes secrete NCOA4, which acts as a mediator of septic death in mice. Mechanistically, lipopolysaccharide, a major component of the outer membrane of Gram-negative bacteria, induces NCOA4 secretion through autophagy-dependent lysosomal exocytosis mediated by ATG5 and MCOLN1. Moreover, bacterial infection with E. coli or S. enterica leads to passive release of NCOA4 during GSDMD-mediated pyroptosis. Upon release, extracellular NCOA4 triggers the activation of the proinflammatory transcription factor NFKB/NF-κB by promoting the degradation of NFKBIA/IκB molecules. This process is dependent on the pattern recognition receptor AGER, rather than TLR4. In vivo studies employing endotoxemia and polymicrobial sepsis mouse models reveal that a monoclonal neutralizing antibody targeting NCOA4 or AGER delays animal death, protects against organ damage, and attenuates systemic inflammation. Furthermore, elevated plasma NCOA4 levels in septic patients, particularly in non-survivors, correlate positively with the sequential organ failure assessment score and concentrations of lactate and proinflammatory mediators, such as TNF, IL1B, IL6, and HMGB1. These findings demonstrate a previously unrecognized role of extracellular NCOA4 in inflammation, suggesting it as a potential therapeutic target for severe infectious diseases.

Keywords:  Autophagy receptor; inflammation; lysosomal exocytosis; pattern recognition receptor; sepsis

DOI:  https://doi.org/10.1080/15548627.2024.2372215
In Vivo. 2024 Jul-Aug;38(4):38(4): 1636-1648

Toll-like Receptor Agonist CBLB502 Protects Against Radiation-induced Intestinal Injury in Mice.

Qiong Wang, Junzhao Duan, Jian Hong, Kexin Ding, Fumin Tai, Jie Zhu, Hanjiang Fu, Xiaofei Zheng, Changhui Ge.

  BACKGROUND/AIM: The small intestine is one of the organs most vulnerable to ionizing radiation (IR) damage. However, methods to protect against IR-induced intestinal injury are limited. CBLB502, a Toll-like receptor 5 (TLR5) agonist from Salmonella flagellin, exerts radioprotective effects on various tissues and organs. However, the molecular mechanisms by which CBLB502 protects against IR-induced intestinal injury remain unclear. Thus, this study aimed to elucidate the mechanisms underlying IR-induced intestinal injury and the protective effects of CBLB502 against this condition in mice.MATERIALS AND METHODS: Mice were administered 0.2 mg/kg CBLB502 before IR at different doses for different time points, and then the survival rate, body weight, hemogram, and histopathology of the mice were analyzed.
RESULTS: CBLB502 reduced IR-induced intestinal injury. RNA-seq analysis revealed that different doses and durations of IR induced different regulatory patterns. CBLB502 protected against intestinal injury mainly after IR by reversing the expression of IR-induced genes and regulating immune processes and metabolic pathways.
CONCLUSION: This study preliminarily describes the regulatory mechanism of IR-induced intestinal injury and the potential molecular protective mechanism of CBLB502, providing a basis for identifying the functional genes and molecular mechanisms that mediate protection against IR-induced injury.

Keywords:  CBLB502; Ionizing radiation; TLR5 agonist; intestinal injury; toll-like receptor

DOI:  https://doi.org/10.21873/invivo.13613
Proc Biol Sci. 2024 Jun;291(2025): 20240535

Bacterial sepsis triggers stronger transcriptomic immune responses in larger primates.

Ryan McMinds, Rays H Y Jiang, Swamy R Adapa, Emily Cornelius Ruhs, Rachel A Munds, Jennifer W Leiding, Cynthia J Downs, Lynn B Martin.

  Empirical data relating body mass to immune defence against infections remain limited. Although the metabolic theory of ecology predicts that larger organisms would have weaker immune responses, recent studies have suggested that the opposite may be true. These discoveries have led to the safety factor hypothesis, which proposes that larger organisms have evolved stronger immune defences because they carry greater risks of exposure to pathogens and parasites. In this study, we simulated sepsis by exposing blood from nine primate species to a bacterial lipopolysaccharide (LPS), measured the relative expression of immune and other genes using RNAseq, and fitted phylogenetic models to determine how gene expression was related to body mass. In contrast to non-immune-annotated genes, we discovered hypermetric scaling in the LPS-induced expression of innate immune genes, such that large primates had a disproportionately greater increase in gene expression of immune genes compared to small primates. Hypermetric immune gene expression appears to support the safety factor hypothesis, though this pattern may represent a balanced evolutionary mechanism to compensate for lower per-transcript immunological effectiveness. This study contributes to the growing body of immune allometry research, highlighting its importance in understanding the complex interplay between body size and immunity over evolutionary timescales.

Keywords:  allometry; metabolic theory of ecology; safety factor; transcriptomics

DOI:  https://doi.org/10.1098/rspb.2024.0535
Immun Ageing. 2024 Jun 22. 21(1): 40

Single-cell landscape of immunological responses in elderly patients with sepsis.

Wanxue He, Chen Yao, Kaifei Wang, Zhimei Duan, Shuo Wang, Lixin Xie.

  Sepsis is a dysregulated host response to severe infections, and immune dysfunction plays a crucial role in its pathogenesis. Elderly patients, a special population influenced by immunosenescence, are more susceptible to sepsis and have a worse prognosis. However, the immunopathogenic mechanisms underlying sepsis in elderly patients remain unclear. Here, we performed single-cell RNA sequencing of peripheral blood samples from young and old subjects and patients with sepsis. By exploring the transcriptional profiles of immune cells, we analyzed immune cell compositions, phenotype shifts, expression heterogeneities, and intercellular communication. In elderly patients with sepsis, innate immune cells (e.g., monocytes and DCs) exhibit decreased antigen presentation, presenting an overactive inflammatory and senescent phenotype. However, the immunophenotype of T cells shifted to characterize effector, memory, and exhaustion. Moreover, we identified strong interferon-γ responses of T cells in both aging and sepsis groups and a deranged inflammaging status in elderly sepsis patients. Tregs in elderly patients with sepsis showed increased abundance and enhanced immunosuppressive effects. In addition, metabolism-associated pathways were upregulated in T cells in elderly patients with sepsis, and the lysine metabolism pathway was enriched in Tregs. Cell-cell interaction analysis showed that the expression profile of ligand-receptor pairs was probably associated with aggravated immune dysfunction in elderly patients with sepsis. A novel HLA-KIR interaction was observed between Tregs and CD8 + T cells. These findings illustrate the immunological hallmarks of sepsis in elderly patients, and highlight that immunosuppressive and metabolic regulatory pathways may undergo important alterations in elderly patients with sepsis.

Keywords:  Aging; Immune dysfunction; Immunosenescence; Sepsis; Single-cell sequencing; immunopathogenic mechanisms

DOI:  https://doi.org/10.1186/s12979-024-00446-z
J Nanobiotechnology. 2024 Jun 23. 22(1): 362

Macrophage biomimetic nanoparticle-targeted functional extracellular vesicle micro-RNAs revealed via multiomics analysis alleviate sepsis-induced acute lung injury.

Guozhen Wang, Xiaoxin Ma, Weichang Huang, Shuanghu Wang, Anni Lou, Jun Wang, Yingfeng Tu, Wanfu Cui, Wangmei Zhou, Wenyong Zhang, Yue Li, Shiyu Geng, Ying Meng, Xu Li.

  Patients who suffer from sepsis typically experience acute lung injury (ALI). Extracellular vesicles (EVs) contain miRNAs, which are potentially involved in ALI. However, strategies to screen more effective EV-miRNAs as therapeutic targets are yet to be elucidated. In this study, functional EV-miRNAs were identified based on multiomics analysis of single-cell RNA sequencing of targeted organs and serum EV (sEV) miRNA profiles in patients with sepsis. The proportions of neutrophils and macrophages were increased significantly in the lungs of mice receiving sEVs from patients with sepsis compared with healthy controls. Macrophages released more EVs than neutrophils. MiR-125a-5p delivery by sEVs to lung macrophages inhibited Tnfaip3, while miR-221-3p delivery to lung neutrophils inhibited Fos. Macrophage membrane nanoparticles (MM NPs) loaded with an miR-125a-5p inhibitor or miR-221-3p mimic attenuated the response to lipopolysaccharide (LPS)-induced ALI. Transcriptome profiling revealed that EVs derived from LPS-stimulated bone marrow-derived macrophages (BMDMs) induced oxidative stress in neutrophils. Blocking toll-like receptor, CXCR2, or TNFα signaling in neutrophils attenuated the oxidative stress induced by LPS-stimulated BMDM-EVs. This study presents a novel method to screen functional EV-miRNAs and highlights the pivotal role of macrophage-derived EVs in ALI. MM NPs, as delivery systems of key sEV-miRNA mimics or inhibitors, alleviated cellular responses observed in sepsis-induced ALI. This strategy can be used to reduce septic organ damage, particularly lung damage, by targeting EVs.

Keywords:  Acute lung injury; Extracellular vesicles; Macrophage membrane nanoparticles; Sepsis; Single-cell RNA sequencing

DOI:  https://doi.org/10.1186/s12951-024-02597-z
Proc Natl Acad Sci U S A. 2024 Jul 02. 121(27): e2402143121

Cholinergic macrophages promote the resolution of peritoneal inflammation.

Shufeng Luo, Huiling Lin, Chong Wu, Lan Zhu, Qiaomin Hua, Yulan Weng, Lu Wang, Xiaoli Fan, Kai-Bo Zhao, Gaoteng Liu, Yuting Wang, Hai-Tian Chen, Li Xu, Limin Zheng.

  The non-neural cholinergic system plays a critical role in regulating immune equilibrium and tissue homeostasis. While the expression of choline acetyltransferase (ChAT), the enzyme catalyzing acetylcholine biosynthesis, has been well documented in lymphocytes, its role in the myeloid compartment is less understood. Here, we identify a significant population of macrophages (Mϕs) expressing ChAT and synthesizing acetylcholine in the resolution phase of acute peritonitis. Using Chat-GFP reporter mice, we observed marked upregulation of ChAT in monocyte-derived small peritoneal Mϕs (SmPMs) in response to Toll-like receptor agonists and bacterial infections. These SmPMs, phenotypically and transcriptionally distinct from tissue-resident large peritoneal macrophages, up-regulated ChAT expression through a MyD88-dependent pathway involving MAPK signaling. Notably, this process was attenuated by the TRIF-dependent TLR signaling pathway, and our tests with a range of neurotransmitters and cytokines failed to induce a similar response. Functionally, Chat deficiency in Mϕs led to significantly decreased peritoneal acetylcholine levels, reduced efferocytosis of apoptotic neutrophils, and a delayed resolution of peritonitis, which were reversible with exogenous ACh supplementation. Intriguingly, despite B lymphocytes being a notable ChAT-expressing population within the peritoneal cavity, Chat deletion in B cells did not significantly alter the resolution process. Collectively, these findings underscore the crucial role of Mϕ-derived acetylcholine in the resolution of inflammation and highlight the importance of the non-neuronal cholinergic system in immune regulation.

Keywords:  acetylcholine; inflammation; macrophages; peritoneal cavity

DOI:  https://doi.org/10.1073/pnas.2402143121
Viruses. 2024 May 24. pii: 836. [Epub ahead of print]16(6):

Mechanisms of Flavivirus Cross-Protection against Yellow Fever in a Mouse Model.

Divya P Shinde, Jordyn Walker, Rachel A Reyna, Dionna Scharton, Brooke Mitchell, Ennid Dulaney, Srinivisa Reddy Bonam, Haitao Hu, Jessica A Plante, Kenneth S Plante, Scott C Weaver.

  The complete lack of yellow fever virus (YFV) in Asia, and the lack of urban YFV transmission in South America, despite the abundance of the peridomestic mosquito vector Aedes (Stegomyia.) aegypti is an enigma. An immunologically naïve population of over 2 billion resides in Asia, with most regions infested with the urban YF vector. One hypothesis for the lack of Asian YF, and absence of urban YF in the Americas for over 80 years, is that prior immunity to related flaviviruses like dengue (DENV) or Zika virus (ZIKV) modulates YFV infection and transmission dynamics. Here we utilized an interferon α/β receptor knock-out mouse model to determine the role of pre-existing dengue-2 (DENV-2) and Zika virus (ZIKV) immunity in YF virus infection, and to determine mechanisms of cross-protection. We utilized African and Brazilian YF strains and found that DENV-2 and ZIKV immunity significantly suppresses YFV viremia in mice, but may or may not protect relative to disease outcomes. Cross-protection appears to be mediated mainly by humoral immune responses. These studies underscore the importance of re-assessing the risks associated with YF outbreak while accounting for prior immunity from flaviviruses that are endemic.

Keywords:  Zika; cross-protection; dengue; mosquito-borne viruses; mouse model; yellow fever virus

DOI:  https://doi.org/10.3390/v16060836
J Leukoc Biol. 2024 Jun 28. pii: qiae149. [Epub ahead of print]

Itaconate and dimethyl itaconate upregulate IL-6 production in the LPS-induced inflammation in mice.

Maxim Nosenko, Denis Anisov, Ekaterina Gubernatorova, Ekaterina Gorshkova, Yi-Rong Zeng, Dan Ye, Pu Wang, David Finlay, Marina Drutskaya, Sergei Nedospasov.

  Itaconate is one of the most studied immunometabolites produced by myeloid cells during inflammatory response. It mediates a wide range of anti-inflammatory and immunoregulatory effects and plays a role in a number of pathological states, including autoimmunity and cancer. Itaconate and its derivatives are considered as potential therapeutic agents for treatment of inflammatory diseases. While immunoregulatory effects of itaconate have been extensively studied in vitro and using knock-out mouse models, less is known about how therapeutic administration of this metabolite regulates inflammatory response in vivo. Here, we investigate the immunoregulatory properties of exogenous administration of itaconate (ITA) and its derivative dimethyl itaconate (DI) in a mouse model of LPS-induced inflammation. The data show that administration of ITA or DI controls systemic production of multiple cytokines, including increased IL-10 production. However, only DI was able to suppress systemic production of IFNγ and IL-1β. In contrast to in vitro data, administration of ITA or DI in vivo resulted in systemic upregulation of IL-6 in the blood. Electrophilic stress due to ITA or DI was not responsible for IL-6 upregulation. However, inhibition of SDH with dimethyl malonate (DM) also resulted in elevated systemic levels of IL-6 and IL-10. Taken together, our study reports a novel effect of exogenous itaconate and its derivative DI on the production of IL-6 in vivo, with important implications for the development of itaconate-based anti-inflammatory therapies.

Keywords:  SDH; cytokines; immunometabolism

DOI:  https://doi.org/10.1093/jleuko/qiae149
Brain Behav Immun. 2024 Jun 24. pii: S0889-1591(24)00465-3. [Epub ahead of print]

Social transmission of inflammation in mice.

Silvia Castany, Priscila Batista Da Rosa, Kiseko Shionoya, Anders Blomqvist, David Engblom.

The ability to detect and respond to sickness in others promotes survival. Here we show that mouse dams respond to immune challenged pups by mirroring their inflammatory response. Dams with pups subjected to immune challenge displayed a marked induction of inflammatory mediators in both the brain and the periphery, accompanied by an increase in maternal behaviors and corticosterone levels. This social transmission of inflammation did not require physical contact, and it contributed to the stress hormone response in the dams. In adult dyads, interaction with an immune challenged cagemate did not elicit robust inflammatory signaling but induced an increased responsiveness to a subsequent immune challenge. The identification of social transmission of inflammation, or inflammatory responsiveness, may open new avenues for research on social behavior, just like the description of similar phenomena such as observational fear and transmitted pain has done.

DOI: https://doi.org/10.1016/j.bbi.2024.06.024