bims-traimu Biomed News
on Trained immunity
Issue of 2024–09–01
eight papers selected by
Yantong Wan, Southern Medical University
  1. Stroke alters the innate immune memory and drives inflammatory cardiac dysfunction.
  2. Dietary sodium modulates mTORC1-dependent trained immunity in macrophages to accelerate CKD development.
  3. Trained brain-heart biofeedback lowers heart rate.
  4. Central innate immunization induces tolerance against post-traumatic stress disorder-like behavior and neuroinflammatory responses in male mice.
  5. Phagosome Isolation with Magnetic Beads and Purification of Toll-Like Receptor (TLR) Complexes in Phagosomes.
  6. Local therapy with combination TLR agonists stimulates systemic anti-tumor immunity and sensitizes tumors to immune checkpoint blockade.
  7. Endothelial Cell Dysfunction Due to Molecules Secreted by Macrophages in Sepsis.
  8. Nanocarrier design for pathogen-inspired innate immune agonist delivery.
  1. Nat Cardiovasc Res. 2024 Aug;3(8): 887
    Stroke alters the innate immune memory and drives inflammatory cardiac dysfunction.
    Gerburg Schwaerzer.
      
    DOI:  https://doi.org/10.1038/s44161-024-00526-9
  2. Biochem Pharmacol. 2024 Aug 23. pii: S0006-2952(24)00488-X. [Epub ahead of print]229 116505
    Dietary sodium modulates mTORC1-dependent trained immunity in macrophages to accelerate CKD development.
    Huihui Chen, Jie Song, Li Zeng, Jie Zha, Jiefu Zhu, Anqun Chen, Yu Liu, Zheng Dong, Guochun Chen.
      Chronic Kidney Disease (CKD) is a significant global health issue linked to dietary habits, especially high salt intake. However, the precise mechanisms driving this progression remain incompletely understood. This study reveals that a high-salt diet intensifies macrophage trained immunity, leading to a marked pro-inflammatory response upon repeated pathogenic exposures, as evidenced by increased renal damage and fibrosis. Under high-salt conditions, there was an induction of CD45+F4/80+ macrophage infiltration into the renal tissue, accompanied by heightened production of inflammatory cytokines. Distinct responses were observed between circulating and resident renal macrophages to a high-salt diet, with a notable upsurge in the migration of pro-inflammatory macrophages, driven by CCL2-CCR2 signaling and aberrant mTORC1 pathway activation. Treatment with rapamycin-liposome effectively reduced this inflammatory cascade by mitigating mTORC1 signaling. Transplantation of monocytes from CKD mice with a high-salt diet significantly exacerbates renal inflammatory damage in the host mice, showing increased migratory tendency and inflammatory activity. The cell co-culture experiment further confirmed that macrophages derived from CKD mice, particularly those under conditions of high salt exposure, significantly induced apoptosis and inflammatory responses in renal tubular cells. Taken together, recurrent exposure to LPS elicits the activation of trained immunity, consequently augmenting inflammatory response of monocytes/macrophages in the involved kidneys. The high-salt diet exacerbates this phenomenon, attributable at least in part to the overactivation of the mTORC1 pathway. This research emphasizes the importance of dietary modulation and targeted immunological interventions in slowing CKD progression, providing new insights into mTORC1-mediated pathophysiological mechanisms and potential management strategies for CKD.
    Keywords:  Chronic kidney disease; High-salt diet; Inflammation; Macrophages; Trained Immunity; mTOR
    DOI:  https://doi.org/10.1016/j.bcp.2024.116505
  3. Nat Cardiovasc Res. 2024 Jul;3(7): 775
    Trained brain-heart biofeedback lowers heart rate.
    Gerburg Schwaerzer.
      
    DOI:  https://doi.org/10.1038/s44161-024-00518-9
  4. Brain Behav Immun. 2024 Aug 26. pii: S0889-1591(24)00571-3. [Epub ahead of print]
    Central innate immunization induces tolerance against post-traumatic stress disorder-like behavior and neuroinflammatory responses in male mice.
    Minxiu Ye, Haojie Zhu, Xu Lu, Rongrong Yang, Hanxiao Wang, Jie Peng, Hainan Pan, Yunli Fang, Ruiting Shi, Fu Li, Zhuo Chen, Wenfeng Hu, Chao Huang.
      Post-traumatic stress disorder (PTSD) is a severe psychiatric disorder associated with abnormally elevated neuroinflammatory responses. Suppression of neuroinflammation is considered to be effective in ameliorating PTSD-like behaviors in rodents. Since pre-stimulation of microglia prior to stress exposure can prevent neuroinflammation, we hypothesized that pre-stimulation of microglia may prevent PTSD in animals. The results show that a single injection of a classical immune stimulant, lipopolysaccharide (LPS), at 50, 100 or 500, but not 10 μg/kg, one day before stress exposure, prevented the anxiety- and fear-like behaviors induced by modified single prolonged stress (mSPS). The time-dependent analysis shows that a single injection of LPS (100 μg/kg) either one or five, but not ten, days before stress prevented mSPS-induced anxiety- and fear-like behaviors. A second low-dose LPS injection 10 days after the first injection or a repeated LPS injection (4 × ) 10 days before stress induced tolerance to mSPS. Mechanistic studies show that a single injection of LPS one day before stress stimulation prevented mSPS-induced increases in levels of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-6 mRNA in the hippocampus and medial prefrontal cortex. Inhibition of microglia by pretreatment with minocycline or depletion of microglia by PLX3397 abolished the preventive effect of low-dose LPS pre-injection on mSPS-induced anxiety- and fear-like behavior and neuroinflammatory responses. These results suggest that pre-stimulation of microglia may prevent the development of PTSD-like behaviors by attenuating the development of neuroinflammatory responses. This could help to develop new strategies to prevent the damaging effects of harmful stress on the brain.
    Keywords:  Lipopolysaccharide; Microglia; Neuroinflammation; PTSD; Prevention
    DOI:  https://doi.org/10.1016/j.bbi.2024.08.049
  5. Methods Mol Biol. 2025 ;2854 171-175
    Phagosome Isolation with Magnetic Beads and Purification of Toll-Like Receptor (TLR) Complexes in Phagosomes.
    Wei Liu, Bo Liu.
      Phagocytosis is a central process by which macrophage cells internalize and eliminate microbes as well as apoptotic cells. The nascent phagosome undergoes a complex maturation process involving sequential fusion with endosomal compartments. The endosomal TLRs, including TLR3, -7, -8, and -9, play a critical role in innate immunity by sensing bacterial or viral nucleic acids and are preferentially transported to the phagosomal membrane of innate immune cells upon activation. Therefore, phagosome isolation is helpful for studies on pathogenic invasion and the functions of phagosome proteins, including endosomal TLRs.
    Keywords:  Endosomal TLR; Organelle purification; Phagosome
    DOI:  https://doi.org/10.1007/978-1-0716-4108-8_17
  6. Oncoimmunology. 2024 ;13(1): 2395067
    Local therapy with combination TLR agonists stimulates systemic anti-tumor immunity and sensitizes tumors to immune checkpoint blockade.
    Francois Xavier Rwandamuriye, Tao Wang, Hanfu Zhang, Omar Elaskalani, Jorren Kuster, Xueting Ye, Breana Vitali, Juliët Schreurs, M Lizeth Orozco Morales, Marck Norret, Cameron W Evans, Rachael M Zemek, K Swaminathan Iyer, W Joost Lesterhuis, Ben Wylie.
      Toll-like receptor (TLR) agonists are being developed as anti-cancer therapeutics due to their potent immunostimulatory properties. However, clinical trials testing TLR agonists as monotherapy have often failed to demonstrate significant improvement over standard of care. We hypothesized that the anti-cancer efficacy of TLR agonist immunotherapy could be improved by combinatorial approaches. To prevent increased toxicity, often seen with systemic combination therapies, we developed a hydrogel to deliver TLR agonist combinations at low doses, locally, during cancer debulking surgery. Using tumor models of WEHI 164 and bilateral M3-9-M sarcoma and CT26 colon carcinoma, we assessed the efficacy of pairwise combinations of poly(I:C), R848, and CpG in controlling local and distant tumor growth. We show that combination of the TLR3 agonist poly(I:C) and TLR7/8 agonist R848 drives anti-tumor immunity against local and distant tumors. In addition, combination of local poly(I:C) and R848 sensitized tumors to systemic immune checkpoint blockade, improving tumor control. Mechanistically, we demonstrate that local therapy with poly(I:C) and R848 recruits inflammatory monocytes to the tumor draining lymph nodes early in the anti-tumor response. Finally, we provide proof of concept for intraoperative delivery of poly(I:C) and R848 together via a surgically applicable biodegradable hydrogel.
    Keywords:  Cancer immunotherapy; TLR agonists; combination therapy; hydrogel; innate immunity; surgery
    DOI:  https://doi.org/10.1080/2162402X.2024.2395067
  7. Biomolecules. 2024 Aug 09. pii: 980. [Epub ahead of print]14(8):
    Endothelial Cell Dysfunction Due to Molecules Secreted by Macrophages in Sepsis.
    Heng He, Wei Zhang, Luofeng Jiang, Xirui Tong, Yongjun Zheng, Zhaofan Xia.
      Sepsis is recognized as a syndrome of systemic inflammatory reaction induced by dysregulation of the body's immunity against infection. The multiple organ dysfunction associated with sepsis is a serious threat to the patient's life. Endothelial cell dysfunction has been extensively studied in sepsis. However, the role of macrophages in sepsis is not well understood and the intrinsic link between the two cells has not been elucidated. Macrophages are first-line cells of the immune response, whereas endothelial cells are a class of cells that are highly altered in function and morphology. In sepsis, various cytokines secreted by macrophages and endothelial cell dysfunction are inextricably linked. Therefore, investigating how macrophages affect endothelial cells could offer a theoretical foundation for the treatment of sepsis. This review links molecules (TNF-α, CCL2, ROS, VEGF, MMP-9, and NO) secreted by macrophages under inflammatory conditions to endothelial cell dysfunction (adhesion, permeability, and coagulability), refining the pathophysiologic mechanisms of sepsis. At the same time, multiple approaches (a variety of miRNA and medicines) regulating macrophage polarization are also summarized, providing new insights into reversing endothelial cell dysfunction and improving the outcome of sepsis treatment.
    Keywords:  adhesion; endothelial dysfunction; inflammatory factor; macrophage; permeability; sepsis; treatment
    DOI:  https://doi.org/10.3390/biom14080980
  8. Trends Immunol. 2024 Aug 26. pii: S1471-4906(24)00182-0. [Epub ahead of print]
    Nanocarrier design for pathogen-inspired innate immune agonist delivery.
    Griffin I Kane, Meghan L Brassil, Miranda B Diaz-Infante, Prabhani U Atukorale.
      In complex diseases such as cancer, modulating cytokine signatures of disease using innate immune agonists holds therapeutic promise. Novel multi-agonist treatments offer tunable control of the immune system because they are uniquely pathogen inspired, eliciting robust antitumor responses by promoting synergistic cytokine responses. However, the chief strategic hurdle is ensuring multi-agonist delivery to the same target cells, highlighting the importance of using nanomaterial-based carriers. Here, we place nanocarriers in center stage and review the delivery hurdles related to the varying extra- and intracellular localizations of innate immune receptors. We discuss a range of nanomaterials used for multi-agonist delivery, highlighting their respective benefits and drawbacks. Our overarching stance is that rational nanocarrier design is crucial for developing pathogen-inspired multi-agonist immunotherapies.
    Keywords:  cancer immunoengineering, drug delivery; innate immunity; nanoparticles; pathogen-inspired technologies; synergistic cytokine production
    DOI:  https://doi.org/10.1016/j.it.2024.07.007
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