bims-traimu 2024-04-21 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2024–04–21
eleven papers selected by
Yantong Wan, Southern Medical University

Innate immunity-With an adaptive twist.
The potency of hematopoietic stem cell reprogramming for changing immune tone.
Dihydroartemisinin is an inhibitor of trained immunity through Akt/mTOR/HIF1α signaling pathway.
Squalene-epoxidase-catalyzed 24(S),25-epoxycholesterol synthesis promotes trained-immunity-mediated antitumor activity.
STING-dependent trained immunity contributes to host defense against Clostridium perfringens infection via mTOR signaling.
A Robust In Vitro Culture Model and Generation of Memory Monocytes.
Ambient PM2.5 and Specific Sources Increase Inflammatory Cytokine Responses to Stimulators and Reduce Sensitivity to Inhibitors.
Brain endothelial GSDMD activation mediates inflammatory BBB breakdown.
The Hippo kinases control inflammatory Hippo signaling and restrict bacterial infection in phagocytes.
Mimicking bacterial infection in male mice changes sperm small RNA profiles and multigenerationally alters offspring behavior and physiology.
TLR5 agonist in combination with anti-PD-1 treatment enhances anti-tumor effect through M1/M2 macrophage polarization shift and CD8+ T cell priming.

Immunol Rev. 2024 Apr 17.

Innate immunity-With an adaptive twist.

Steven Z Josefowicz, Joseph C Sun.



Keywords:  cell lineages and subsets; innate immune memory; innate immunity; innate lymphoid cells; memory; monocytes/macrophages; natural killer cells; trained immunity

DOI:  https://doi.org/10.1111/imr.13334
Immunol Rev. 2024 Apr 17.

The potency of hematopoietic stem cell reprogramming for changing immune tone.

Andrew W Daman, Jin Gyu Cheong, Laura Berneking, Steven Z Josefowicz.

  Innate immune memory endows innate immune cells with antigen independent heightened responsiveness to subsequent challenges. The durability of this response can be mediated by inflammation induced epigenetic and metabolic reprogramming in hematopoietic stem and progenitor cells (HSPCs) that are maintained through differentiation to mature immune progeny. Understanding the mechanisms and extent of trained immunity induction by pathogens and vaccines, such as BCG, in HSPC remains a critical area of exploration with important implications for health and disease. Here we review these concepts and present new analysis to highlight how inflammatory reprogramming of HSPC can potently alter immune tone, including to enhance specific anti-tumor responses. New findings in the field pave the way for novel HSPC targeting therapeutic strategies in cancer and other contexts of immune modulation. Future studies are expected to unravel diverse and extensive effects of infections, vaccines, microbiota, and sterile inflammation on hematopoietic progenitor cells and begin to illuminate the broad spectrum of immunologic tuning that can be established through altering HSPC phenotypes. The purpose of this review is to draw attention to emerging and speculative topics in this field where we posit that focused study of HSPC in the framework of trained immunity holds significant promise.

Keywords:  PIE‐seq; epigenetics; hematopoietic stem and progenitor cells; inflammatory hematopoiesis; innate immune memory; myelopoiesis; snRNA/ATAC‐seq; trained immunity

DOI:  https://doi.org/10.1111/imr.13335
Exp Cell Res. 2024 Apr 16. pii: S0014-4827(24)00143-5. [Epub ahead of print] 114052

Dihydroartemisinin is an inhibitor of trained immunity through Akt/mTOR/HIF1α signaling pathway.

Yu Gao, Zhen-Zhen Liu, Jia-Bao Zhang, Cheng-Kai Zhou, Jian-Gang Zhang, Xiao-Qi Lin, Qi Yin, Wei Chen, Yong-Jun Yang.

  Trained immunity is mechanistically defined as the metabolically and epigenetically mediated long-term functional adaptation of the innate immune system, characterized by a heightened response to a secondary stimulation. Given appropriate activation, trained immunity represents an attractive anti-infective therapeutic target. Nevertheless, excessive immune response and subsequent inflammatory cascades may contribute to pathological tissue damage, indicating that the negative impacts of trained immunity appear to be significant. In this study, we show that innate immune responses such as the production of extracellular traps, pro-inflammatory cytokines, and autophagy-related proteins were markedly augmented in trained BMDMs. Furthermore, heat-killed C. albicans priming promotes the activation of the AIM2 inflammasome, and AIM2-/- mice exhibit impaired memory response induced by heat-killed C. albicans. Therefore, we establish that the AIM2 inflammasome is involved in trained immunity and emerges as a promising therapeutic target for potentially deleterious effects. Dihydroartemisinin can inhibit the memory response induced by heat-killed C. albicans through modulation of mTOR signaling and the AIM2 inflammasome. The findings suggest that dihydroartemisinin can reduce the induction of trained immunity by heat-killed C. albicans in C57BL/6 mice. Dihydroartemisinin is one such therapeutic intervention that has the potential to treat of diseases characterized by excessive trained immunity.

Keywords:  AIM2 inflammasome; C. perfringens; autophagy; dihydroartemisinin; inhibitor; trained immunity

DOI:  https://doi.org/10.1016/j.yexcr.2024.114052
Cell Rep. 2024 Apr 11. pii: S2211-1247(24)00422-4. [Epub ahead of print]43(4): 114094

Squalene-epoxidase-catalyzed 24(S),25-epoxycholesterol synthesis promotes trained-immunity-mediated antitumor activity.

Yongxiang Liu, Zifeng Wang, Huan Jin, Lei Cui, Bitao Huo, Chunyuan Xie, Jiahui Li, Honglu Ding, Huanling Zhang, Wenjing Xiong, Mengyun Li, Hongxia Zhang, Hui Guo, Chunwei Li, Tiantian Wang, Xiaojuan Wang, Wenzhuo He, Zining Wang, Jin-Xin Bei, Peng Huang, Jinyun Liu, Xiaojun Xia.

  The importance of trained immunity in antitumor immunity has been increasingly recognized, but the underlying metabolic regulation mechanisms remain incompletely understood. In this study, we find that squalene epoxidase (SQLE), a key enzyme in cholesterol synthesis, is required for β-glucan-induced trained immunity in macrophages and ensuing antitumor activity. Unexpectedly, the shunt pathway, but not the classical cholesterol synthesis pathway, catalyzed by SQLE, is required for trained immunity induction. Specifically, 24(S),25-epoxycholesterol (24(S),25-EC), the shunt pathway metabolite, activates liver X receptor and increases chromatin accessibility to evoke innate immune memory. Meanwhile, SQLE-induced reactive oxygen species accumulation stabilizes hypoxia-inducible factor 1α protein for metabolic switching into glycolysis. Hence, our findings identify 24(S),25-EC as a key metabolite for trained immunity and provide important insights into how SQLE regulates trained-immunity-mediated antitumor activity.

Keywords:  24(S),25-epoxycholesterol; CP: Cancer; CP: Immunology; antitumor immunity; reactive oxygen species; squalene epoxidase; trained immunity

DOI:  https://doi.org/10.1016/j.celrep.2024.114094
Vet Res. 2024 Apr 15. 55(1): 52

STING-dependent trained immunity contributes to host defense against Clostridium perfringens infection via mTOR signaling.

Zhen-Zhen Liu, Cheng-Kai Zhou, Xiao-Qi Lin, Yu Gao, Xue-Yue Luo, Jia-Bao Zhang, Qi Yin, Liang Zhang, Jian-Gang Zhang, Xin An, Wei Chen, Yong-Jun Yang.

  Clostridium perfringens (C. perfringens) infection is recognized as one of the most challenging issues threatening food safety and perplexing agricultural development. To date, the molecular mechanisms of the interactions between C. perfringens and the host remain poorly understood. Here, we show that stimulator of interferon genes (STING)-dependent trained immunity protected against C. perfringens infection through mTOR signaling. Heat-killed Candida albicans (HKCA) training elicited elevated TNF-α and IL-6 production after LPS restimulation in mouse peritoneal macrophages (PM). Although HKCA-trained PM produced decreased levels of TNF-α and IL-6, the importance of trained immunity was demonstrated by the fact that HKCA training resulted in enhanced bacterial phagocytic ability and clearance in vivo and in vitro during C. perfringens infection. Interestingly, HKCA training resulted in the activation of STING signaling. We further demonstrate that STING agonist DMXAA is a strong inducer of trained immunity and conferred host resistance to C. perfringens infection in PM. Importantly, corresponding to higher bacterial burden, reduction in cytokine secretion, phagocytosis, and bacterial killing were shown in the absence of STING after HKCA training. Meanwhile, the high expression levels of AKT/mTOR/HIF1α were indeed accompanied by an activated STING signaling under HKCA or DMXAA training. Moreover, inhibiting mTOR signaling with rapamycin dampened the trained response to LPS and C. perfringens challenge in wild-type (WT) PM after HKCA training. Furthermore, STING‑deficient PM presented decreased levels of mTOR signaling-related proteins. Altogether, these results support STING involvement in trained immunity which protects against C. perfringens infection via mTOR signaling.

Keywords:   Clostridium perfringens ; STING; innate immune; macrophages; trained immunity

DOI:  https://doi.org/10.1186/s13567-024-01301-1
Methods Mol Biol. 2024 ;2782 81-88

A Robust In Vitro Culture Model and Generation of Memory Monocytes.

Jing Wang, Shuo Geng, Yajun Wu, Liwu Li.

  Innate monocytes can be trained or reprogrammed to adopt distinct memory states, such as low-grade inflammation and immune exhaustion, bearing fundamental relevance to the pathogenesis of both acute diseases such as sepsis as well as chronic diseases such as atherosclerosis. Therefore, it is critically important to develop a regimen for generating memory monocytes in vitro in order to better define key monocyte memory states with diverse potentials for proliferation, differentiation, and activation, as well as underlying mechanisms. Here, we describe an efficient in vitro system to propagate a large number of highly purified murine memory monocytes through sustaining bone marrow-derived monocytes with macrophage colony-stimulating factor (M-CSF, 10 ng/mL)-containing medium, together with other polarization agents such as lipopolysaccharide (LPS) for a 5-day period. This method can yield high-purity monocytes, capable of exhibiting dynamic memory behaviors upon training with various polarizing agents.

Keywords:  Bone marrow culture; Exhaustion; Immune memory generation; Model system; Priming

DOI:  https://doi.org/10.1007/978-1-0716-3754-8_5
Environ Res. 2024 Apr 17. pii: S0013-9351(24)00868-5. [Epub ahead of print] 118964

Ambient PM2.5 and Specific Sources Increase Inflammatory Cytokine Responses to Stimulators and Reduce Sensitivity to Inhibitors.

Gregory E Miller, Veronica Passarelli, Edith Chen, Itai Kloog, Rosalind J Wright, Heresh Amini.

  Ambient exposure to fine particulate matter (PM2.5) is associated with increased morbidity and mortality from multiple diseases. Recent observations suggest the hypothesis that trained immunity contributes to these risks, by demonstrating that ambient PM2.5 sensitizes innate immune cells to mount larger inflammatory response to subsequent bacterial stimuli. However, little is known about how general and durable this sensitization phenomenon is, and whether specific sources of PM2.5 are responsible. Here we consider these issues in a longitudinal study of children. The sample consisted of 277 children (mean age 13.92 years; 63.8% female; 38.4% Black; 32.2% Latinx) who completed baseline visits and were re-assessed two years later. Fasting whole blood was ex vivo incubated with 4 stimulating agents reflecting microbial and sterile triggers of inflammation, and with 2 inhibitory agents, followed by assays for IL-1β, IL-6, IL-8, and TNF-α. Blood also was assayed for 6 circulating biomarkers of low-grade inflammation: C-reactive protein, interleukin-6, -8, and -10, tumor necrosis factor-α, and soluble urokinase-type plasminogen activator receptor. Using machine learning, levels of 15 PM2.5 constituents were estimated for a 50 meter grid around children's homes. Models were adjusted for age, sex, race, pubertal status, and household income. In cross-sectional analyses, higher neighborhood PM2.5 was associated with larger cytokine responses to the four stimulating agents. These associations were strongest for constituents released by motor vehicles and soil/crustal dust. In longitudinal analyses, residential PM2.5 was associated with declining sensitivity to inhibitory agents; this pattern was strongest for constituents from fuel/biomass combustion and motor vehicles. By contrast, PM2.5 constituents were not associated with the circulating biomarkers of low-grade inflammation. Overall, these findings suggest the possibility of a trained immunity scenario, where PM2.5 heightens inflammatory cytokine responses to multiple stimulators, and dampens sensitivity to inhibitors which counter-regulate these responses.

Keywords:  PM(2.5) components; air pollution; children; cytokines; inflammation

DOI:  https://doi.org/10.1016/j.envres.2024.118964
Nature. 2024 Apr 17.

Brain endothelial GSDMD activation mediates inflammatory BBB breakdown.

Chao Wei, Wei Jiang, Ruiyu Wang, Haoyu Zhong, Huabin He, Xinwei Gao, Shilin Zhong, Fengting Yu, Qingchun Guo, Li Zhang, Lisa D J Schiffelers, Bin Zhou, Martin Trepel, Florian I Schmidt, Minmin Luo, Feng Shao.

The blood-brain barrier (BBB) protects the central nervous system from infections or harmful substances1; its impairment can lead to or exacerbate various diseases of the central nervous system2-4. However, the mechanisms of BBB disruption during infection and inflammatory conditions5,6 remain poorly defined. Here we find that activation of the pore-forming protein GSDMD by the cytosolic lipopolysaccharide (LPS) sensor caspase-11 (refs. 7-9), but not by TLR4-induced cytokines, mediates BBB breakdown in response to circulating LPS or during LPS-induced sepsis. Mice deficient in the LBP-CD14 LPS transfer and internalization pathway10-12 resist BBB disruption. Single-cell RNA-sequencing analysis reveals that brain endothelial cells (bECs), which express high levels of GSDMD, have a prominent response to circulating LPS. LPS acting on bECs primes Casp11 and Cd14 expression and induces GSDMD-mediated plasma membrane permeabilization and pyroptosis in vitro and in mice. Electron microscopy shows that this features ultrastructural changes in the disrupted BBB, including pyroptotic endothelia, abnormal appearance of tight junctions and vasculature detachment from the basement membrane. Comprehensive mouse genetic analyses, combined with a bEC-targeting adeno-associated virus system, establish that GSDMD activation in bECs underlies BBB disruption by LPS. Delivery of active GSDMD into bECs bypasses LPS stimulation and opens the BBB. In CASP4-humanized mice, Gram-negative Klebsiella pneumoniae infection disrupts the BBB; this is blocked by expression of a GSDMD-neutralizing nanobody in bECs. Our findings outline a mechanism for inflammatory BBB breakdown, and suggest potential therapies for diseases of the central nervous system associated with BBB impairment.

DOI: https://doi.org/10.1038/s41586-024-07314-2
mBio. 2024 Apr 16. e0342923

The Hippo kinases control inflammatory Hippo signaling and restrict bacterial infection in phagocytes.

Brendyn M St Louis, Sydney M Quagliato, Yu-Ting Su, Gregory Dyson, Pei-Chung Lee.

  The Hippo kinases MST1 and MST2 initiate a highly conserved signaling cascade called the Hippo pathway that limits organ size and tumor formation in animals. Intriguingly, pathogens hijack this host pathway during infection, but the role of MST1/2 in innate immune cells against pathogens is unclear. In this report, we generated Mst1/2 knockout macrophages to investigate the regulatory activities of the Hippo kinases in immunity. Transcriptomic analyses identified differentially expressed genes (DEGs) regulated by MST1/2 that are enriched in biological pathways, such as systemic lupus erythematosus, tuberculosis, and apoptosis. Surprisingly, pharmacological inhibition of the downstream components LATS1/2 in the canonical Hippo pathway did not affect the expression of a set of immune DEGs, suggesting that MST1/2 control these genes via alternative inflammatory Hippo signaling. Moreover, MST1/2 may affect immune communication by influencing the release of cytokines, including TNFα, CXCL10, and IL-1ra. Comparative analyses of the single- and double-knockout macrophages revealed that MST1 and MST2 differentially regulate TNFα release and expression of the immune transcription factor MAF, indicating that the two homologous Hippo kinases individually play a unique role in innate immunity. Notably, both MST1 and MST2 can promote apoptotic cell death in macrophages upon stimulation. Lastly, we demonstrate that the Hippo kinases are critical factors in mammalian macrophages and single-cell amoebae to restrict infection by Legionella pneumophila, Escherichia coli, and Pseudomonas aeruginosa. Together, these results uncover non-canonical inflammatory Hippo signaling in macrophages and the evolutionarily conserved role of the Hippo kinases in the anti-microbial defense of eukaryotic hosts.
IMPORTANCE: Identifying host factors involved in susceptibility to infection is fundamental for understanding host-pathogen interactions. Clinically, individuals with mutations in the MST1 gene which encodes one of the Hippo kinases experience recurrent infection. However, the impact of the Hippo kinases on innate immunity remains largely undetermined. This study uses mammalian macrophages and free-living amoebae with single- and double-knockout in the Hippo kinase genes and reveals that the Hippo kinases are the evolutionarily conserved determinants of host defense against microbes. In macrophages, the Hippo kinases MST1 and MST2 control immune activities at multiple levels, including gene expression, immune cell communication, and programmed cell death. Importantly, these activities controlled by MST1 and MST2 in macrophages are independent of the canonical Hippo cascade that is known to limit tissue growth and tumor formation. Together, these findings unveil a unique inflammatory Hippo signaling pathway that plays an essential role in innate immunity.

Keywords:  KrsA; KrsB; Stk3; Stk4; pathogenesis

DOI:  https://doi.org/10.1128/mbio.03429-23
Brain Behav Immun. 2024 Apr 16. pii: S0889-1591(24)00362-3. [Epub ahead of print]

Mimicking bacterial infection in male mice changes sperm small RNA profiles and multigenerationally alters offspring behavior and physiology.

Huan Liao, Da Lu, Sonali N Reisinger, Elizabeth A Kleeman, Nicholas van de Garde, Carolina Gubert, Anthony J Hannan.

  Paternal pre-conceptual exposures, including stress, diet, substance abuse, parasite infection, and viral immune activation via Poly I:C, have been reported to influence the brains and behavior of offspring through sperm epigenetic changes. However, the effects of paternal (F0) pre-conceptual exposure to bacterial-induced immune activation on the behavior and physiology of F1 and F2 generations remain unexplored. We examined this using C57BL/6J mice. Eight-week-old males (F0) received a single intraperitoneal injection of the bacterial mimetic lipopolysaccharide (LPS: 5 mg/kg) or 0.9 % saline (vehicle control) before mating with naïve females at four weeks post-injection. Comprehensive behavioral assessments were conducted to investigate anxiety, social behaviors, depressive-like behaviors and cognition in both the F1 and F2 generations within the age range of 8 to 14 weeks. Results demonstrated that only female offspring of LPS-exposed fathers exhibited reduced anxiety levels in the light/dark box, large open field, and novelty-suppressed feeding test. These F1 female offspring also exhibited heightened sociability in the 3-chambered social interaction test and a reduced preference for saccharin in the saccharin preference test. Additionally, the F1 male offspring of LPS-challenged males demonstrated an increased total distance traveled in the light/dark box and a longer distance covered in the light zone. They also exhibited diminished preference for social novelty in the 3-chambered social interaction test and an elevated novel arm preference index in the Y-maze. In the F2 generation, male descendants of LPS-treated fathers showed reduced latency to feed in the novelty-suppressed feeding test. Additionally, the F2 generation of LPS challenged fathers, but not the F1 generation, displayed enhanced immune response in both sexes after an acute LPS immune challenge (5 mg/kg). Analysis of sperm small noncoding RNA profiles from LPS-treated F0 mice revealed significant changes at 4 weeks after administration of LPS. These changes included three microRNAs, eight PIWI-interacting RNAs, and two transfer RNAs, exhibiting significant upregulation (mmu-miR-146a-5p, mmu-piR-27082 and mmu-piR-29102) or downregulation (mmu-miR-5110, mmu-miR-467e-3p, mmu-piR-22583, mmu-piR-23548, mmu-piR-36341, mmu-piR-50293, mmu-piR-16583, mmu-piR-36507, Mus_musculus_tRNA-Ile-AAT-2-1 and Mus_musculus_tRNA-Tyr-GTA-1-1). Additionally, we detected 52 upregulated small noncoding RNAs (including 9 miRNAs, 41 piRNAs, and 2 tRNAs) and 7 downregulated small noncoding RNAs (3 miRNAs, 3 piRNAs, and 1 tRNA) in the sperm of F1 offspring from LPS-treated males. These findings provide compelling evidence for the involvement of epigenetic mechanisms in the modulation of brain function and immunity, and associated behavioral and immunological traits, across generations, in response to bacterial infection.

Keywords:  Bacterial infection; Brain Development; Immune activation; Paternal epigenetic inheritance; behavior

DOI:  https://doi.org/10.1016/j.bbi.2024.04.017
Cancer Immunol Immunother. 2024 Apr 17. 73(6): 102

TLR5 agonist in combination with anti-PD-1 treatment enhances anti-tumor effect through M1/M2 macrophage polarization shift and CD8+ T cell priming.

Junseok Lee, Keon-Il Im, Sojin Gil, Hyemin Na, Gi-June Min, Nayoun Kim, Seok-Goo Cho.

  Immune checkpoint inhibitors have revolutionized anti-tumor therapy, notably improving treatment responses in various tumors. However, many patients remain non-responsive and do not experience benefits. Given that Toll-like receptors (TLRs) can counteract tumor immune tolerance by stimulating both innate and adaptive immune responses, TLR agonists are being explored as potential immune adjuvants for cancer treatment. In this study, we assessed the potential of enhancing the efficacy of immune checkpoint inhibitors by activating innate immunity with a TLR5 agonist. In a mouse tumor model, combination therapy with TLR5 agonist and anti-PD-1 significantly inhibited tumor growth. The TLR5 agonist shifted the balance from M2-like to M1-like macrophages and upregulated the expression of co-stimulatory molecules in macrophages. Furthermore, TLR5 agonist promoted the activation and tumor infiltration of CD8+ T cells. As a result, the TLR5 agonist augmented the anti-tumor efficacy of anti-PD-1, suggesting its potential in modulating the tumor microenvironment to enhance the anti-tumor response. Our findings point toward the possibility of optimizing immune checkpoint inhibitor therapy using TLR5 agonists.

Keywords:  Cancer immunotherapy; Immune checkpoint; PD-1; TLR5; Tumor-associated macrophages

DOI:  https://doi.org/10.1007/s00262-024-03679-5