bims-traimu 2023-09-17 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2023–09–17
nine papers selected by
Yantong Wan, Southern Medical University

Macrophage memory: Types, mechanisms, and its role in health and disease.
Altered DNA methylation underlies monocyte dysregulation and innate exhaustion memory in sepsis.
Injury-experienced satellite cells retain long-term enhanced regenerative capacity.
Protection against lethal sepsis following immunization with Candida species varies by isolate and inversely correlates with bone marrow tissue damage.
Ultra-efficient radio-immunotherapy for reprogramming the hypoxic and immunosuppressive tumor microenvironment with durable innate immune memory.
Control of nutrient uptake by IRF4 orchestrates innate immune memory.
LPS induces SGPP2 to participate metabolic reprogramming in endothelial cells.
Metformin induces tolerogenicity of dendritic cells by promoting metabolic reprogramming.
Over but not gone: lingering epigenetic effects of COVID-19.

Immunology. 2023 Sep 13.

Macrophage memory: Types, mechanisms, and its role in health and disease.

Xu-Hui Fang, Zhi-Jing Li, Chun-Yan Liu, Gil Mor, Ai-Hua Liao.

  On the basis of the mechanisms of action and characteristics of immune effects, immunity is commonly categorized into innate and adaptive immunity. Adaptive immunity is associated with the response to non-self-entities and is characterized by high specificity and memory properties. In contrast, innate immunity has traditionally been considered devoid of memory characteristics. However, an increasing number of studies have sought to challenge this conventional immunological dogma and shown that innate immune cells exhibit a more robust and rapid response to secondary stimulation, thus providing evidence of the immunological memory in innate immunity. Macrophages, which are among the most important innate immune cells, can also acquire memory phenotype that facilitates the mediation of recall responses. Macrophage memory is a relatively new concept that is revolutionizing our understanding of macrophage biology and immunological memory and could lead to a new class of vaccines and immunotherapies. In this review, we describe the characteristics and mechanisms of macrophage memory, as well as its essential roles in various diseases.

Keywords:  endowed immunity; epigenetic reprogramming; macrophage memory; trained immunity

DOI:  https://doi.org/10.1111/imm.13697
bioRxiv. 2023 Aug 31. pii: 2023.08.30.555580. [Epub ahead of print]

Altered DNA methylation underlies monocyte dysregulation and innate exhaustion memory in sepsis.

Blake A Caldwell, Yajun Wu, Jing Wang, Liwu Li.

Innate immune memory is the process by which pathogen exposure elicits cell-intrinsic states to alter the strength of future immune challenges. Such altered memory states drive monocyte dysregulation during sepsis, promoting pathogenic behavior characterized by pro-inflammatory, immunosuppressive gene expression in concert with emergency hematopoiesis. Epigenetic changes, notably in the form of histone modifications, have been shown to underlie innate immune memory, but the contribution of DNA methylation to this process remains poorly understood. Using an ex vivo sepsis model, we discovered broad changes in DNA methylation throughout the genome of exhausted monocytes, including at several genes previously implicated as major drivers of immune dysregulation during sepsis and Covid-19 infection (e.g. Plac8 ). Methylome alterations are driven in part by Wnt signaling inhibition in exhausted monocytes, and can be reversed through treatment with DNA methyltransferase inhibitors, Wnt agonists, or immune training molecules. Importantly, these changes are recapitulated in septic mice following cecal slurry injection, resulting in stable changes at critical immune genes that support the involvement of DNA methylation in acute and long-term monocyte dysregulation during sepsis.

DOI: https://doi.org/10.1101/2023.08.30.555580
Stem Cell Res Ther. 2023 09 12. 14(1): 246

Injury-experienced satellite cells retain long-term enhanced regenerative capacity.

Jacopo Morroni, Anna Benedetti, Lorenza Esposito, Marco De Bardi, Giovanna Borsellino, Carles Sanchez Riera, Lorenzo Giordani, Marina Bouche, Biliana Lozanoska-Ochser.

   BACKGROUND: Inflammatory memory or trained immunity is a recently described process in immune and non-immune tissue resident cells, whereby previous exposure to inflammation mediators leads to a faster and stronger responses upon secondary challenge. Whether previous muscle injury is associated with altered responses to subsequent injury by satellite cells (SCs), the muscle stem cells, is not known.
METHODS: We used a mouse model of repeated muscle injury, in which intramuscular cardiotoxin (CTX) injections were administered 50 days apart in order to allow for full recovery of the injured muscle before the second injury. The effect of prior injury on the phenotype, proliferation and regenerative potential of satellite cells following a second injury was examined in vitro and in vivo by immunohistochemistry, RT-qPCR and histological analysis.
RESULTS: We show that SCs isolated from muscle at 50 days post-injury (injury-experienced SCs (ieSCs)) enter the cell cycle faster and form bigger myotubes when cultured in vitro, compared to control SCs isolated from uninjured contralateral muscle. Injury-experienced SCs were characterized by the activation of the mTORC 1 signaling pathway, suggesting they are poised to activate sooner following a second injury. Consequently, upon second injury, SCs accumulate in greater numbers in muscle at 3 and 10 days after injury. These changes in SC phenotype and behavior were associated with accelerated muscle regeneration, as evidenced by an earlier appearance of bigger fibers and increased number of myonuclei per fiber at day 10 after the second injury.
CONCLUSIONS: Overall, we show that skeletal muscle injury has a lasting effect on SC function priming them to respond faster to a subsequent injury. The ieSCs have long-term enhanced regenerative properties that contribute to accelerated regeneration following a secondary challenge.

Keywords:  Inflammatory memory; Muscle regeneration; Repeated injury; Satellite cells

DOI:  https://doi.org/10.1186/s13287-023-03492-4
Infect Immun. 2023 Sep 13. e0025223

Protection against lethal sepsis following immunization with Candida species varies by isolate and inversely correlates with bone marrow tissue damage.

Elizabeth A Lilly, Breah E Bender, Mairi C Noverr, Paul L Fidel.

  Protection against lethal Candida albicans (Ca)/Staphylococcus aureus (Sa) intra-abdominal infection (IAI)-mediated sepsis can be achieved by a novel form of trained innate immunity (TII) involving Gr-1+ myeloid-derived suppressor cells (MDSCs) that are induced by inoculation (immunization) with low virulence Candida species [i.e., Candida dubliniensis (Cd)] that infiltrate the bone marrow (BM). In contrast, more virulent Candida species (i.e., C. albicans), even at sub-lethal inocula, fail to induce similar levels of protection. The purpose of the present study was to test the hypothesis that the level of TII-mediated protection induced by Ca strains inversely correlates with damage in the BM as a reflection of virulence. Mice were immunized by intraperitoneal inoculation with several parental and mutant strains of C. albicans deficient in virulence factors (hyphal formation and candidalysin production), followed by an intraperitoneal Ca/Sa challenge 14 d later and monitored for sepsis and mortality. Whole femur bones were collected 24 h and 13 d after immunization and assessed for BM tissue/cellular damage via ferroptosis and histology. While immunization with standard but not sub-lethal inocula of most wild-type C. albicans strains resulted in considerable mortality, protection against lethal Ca/Sa IAI challenge varied by strain was usually less than that for C. dubliniensis, with no differences observed between parental and corresponding mutants. Finally, levels of protection afforded by the Ca strains were inversely correlated with BM tissue damage (R2 = -0.773). TII-mediated protection against lethal Ca/Sa sepsis induced by Candida strain immunization inversely correlates with BM tissue/cellular damage as a reflection of localized virulence.

Keywords:  Candida; bone marrow; intra-abdominal infection; polymicrobial infection; sepsis

DOI:  https://doi.org/10.1128/iai.00252-23
Biomaterials. 2023 Sep 05. pii: S0142-9612(23)00311-3. [Epub ahead of print]302 122303

Ultra-efficient radio-immunotherapy for reprogramming the hypoxic and immunosuppressive tumor microenvironment with durable innate immune memory.

Jichun Yang, Chong Zhang, Xiaohui Chen, Daijun Zhou, Zixin Sun, Ruyan Niu, Ying Zhu, Hengyi Chen, Liu Wang, Yi Chen, Yuhan Wang, Yunqian Fu, Ningyu Ma, Jianjun Li, Yang Luo.

  Radiosensitization efficacy of conventional tumor radiosensitizers has been frequently limited by insufficient competence for tumor microenvironment (TME) regulation and unfavorable cellular uptake at biological barriers. Here, we reported an ultra-efficient radiotherapy (RT) strategy by synthesizing an extracellular vesicles (EVs)-encapsulated hollow MnO2 to load metformin (Met@HMnER). It demonstrated significant RT enhancement by morphological control of catalyst and cellular respiratory depression against conventional solid MnO2. Furthermore, the target-modified EVs clothing retains outstanding metformin loading capacity while endowing enhanced biological barrier penetration. A noticeably durable innate immune activation of NK cells was triggered with this nanoplatform via the cGAS-STING pathway. The enhanced immunocompetence was verified on distal metastasis and in-situ recurrence model in vivo, This work paved a new path for synergistic and robust innate immunity in clinical cancer treatment.

Keywords:  Hollow MnO(2); Innate immune effect; Radiotherapy; Tumor microenvironment; Ultra-high efficiency

DOI:  https://doi.org/10.1016/j.biomaterials.2023.122303
Nat Immunol. 2023 Sep 11.

Control of nutrient uptake by IRF4 orchestrates innate immune memory.

Endi K Santosa, Hyunu Kim, Timo Rückert, Jean-Benoît Le Luduec, Aamna J Abbasi, Claire K Wingert, Lila Peters, Joe N Frost, Katharine C Hsu, Chiara Romagnani, Joseph C Sun.

Natural killer (NK) cells are innate cytotoxic lymphocytes with adaptive immune features, including antigen specificity, clonal expansion and memory. As such, NK cells share many transcriptional and epigenetic programs with their adaptive CD8+ T cell siblings. Various signals ranging from antigen, co-stimulation and proinflammatory cytokines are required for optimal NK cell responses in mice and humans during virus infection; however, the integration of these signals remains unclear. In this study, we identified that the transcription factor IRF4 integrates signals to coordinate the NK cell response during mouse cytomegalovirus infection. Loss of IRF4 was detrimental to the expansion and differentiation of virus-specific NK cells. This defect was partially attributed to the inability of IRF4-deficient NK cells to uptake nutrients required for survival and memory generation. Altogether, these data suggest that IRF4 is a signal integrator that acts as a secondary metabolic checkpoint to orchestrate the adaptive response of NK cells during viral infection.

DOI: https://doi.org/10.1038/s41590-023-01620-z
Free Radic Biol Med. 2023 Sep 11. pii: S0891-5849(23)00625-1. [Epub ahead of print]

LPS induces SGPP2 to participate metabolic reprogramming in endothelial cells.

Xin Yi, Meng-Ling Chang, Zeng-Ding Zhou, Lei Yi, Hao Yuan, Jin Qi, Lei Yi, Jing-Ning Huan, Xiao-Qin Huang.

  Sepsis often causes organ dysfunction and is manifested in increased endothelial cell permeability in blood vessels. Early-stage inflammation is accompanied by metabolic changes, but it is unclear how the metabolic alterations in the endothelial cells following lipopolysaccharide (LPS) stimulation affect endothelial cell function. In this study, the effects of 1 μg/ml of LPS on the metabolism of human umbilical vein endothelial cells (HUVECs) were investigated, and the metabolic changes after LPS stimulation were explained from the perspective of mRNA expression, chromatin openness and metabolic flux. We found changes in the central metabolism of endothelial cells after LPS stimulation, such as enhanced glycolysis function, decreased mitochondrial membrane potential, and increased production of reactive oxygen species (ROS). Sphingolipid metabolic pathways change at the transcriptome level, and sphingosine-1-phosphatase 2 (SGPP2) was upregulated in LPS-stimulated endothelial cells and zebrafish models. Overexpression of SGPP2 improved cell barrier function, enhanced mitochondrial respiration capacity, but also produced oxidative respiration chain uncoupling. In addition, SGPP2 overexpression inhibited the degradation of HIF-1α protein. The molecular and biochemical processes identified in this study are not only beneficial for understanding the metabolic-related mechanisms of LPS-induced endothelial injury, but also for the discovery of general therapeutic targets for inflammation and inflammation-related diseases.

Keywords:  HUVEC; LPS; Metabolic reprogramming; ROS; Warburg effect

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.09.007
Cell Mol Life Sci. 2023 Sep 09. 80(10): 283

Metformin induces tolerogenicity of dendritic cells by promoting metabolic reprogramming.

Xianmei Liu, Peng Yu, Yujun Xu, Yun Wang, Jin Chen, Fuzhou Tang, Zuquan Hu, Jing Zhou, Lina Liu, Wei Qiu, Yuannong Ye, Yi Jia, Weijuan Yao, Jinhua Long, Zhu Zeng.

  Dendritic cells (DCs) can mediate immune responses or immune tolerance depending on their immunophenotype and functional status. Remodeling of DCs' immune functions can develop proper therapeutic regimens for different immune-mediated diseases. In the immunopathology of autoimmune diseases (ADs), activated DCs notably promote effector T-cell polarization and exacerbate the disease. Recent evidence indicates that metformin can attenuate the clinical symptoms of ADs due to its anti-inflammatory properties. Whether and how the therapeutic effects of metformin on ADs are associated with DCs remain unknown. In this study, metformin was added to a culture system of LPS-induced DC maturation. The results revealed that metformin shifted DC into a tolerant phenotype, resulting in reduced surface expression of MHC-II, costimulatory molecules and CCR7, decreased levels of proinflammatory cytokines (TNF-α and IFN-γ), increased level of IL-10, upregulated immunomodulatory molecules (ICOSL and PD-L) and an enhanced capacity to promote regulatory T-cell (Treg) differentiation. Further results demonstrated that the anti-inflammatory effects of metformin in vivo were closely related to remodeling the immunophenotype of DCs. Mechanistically, metformin could mediate the metabolic reprogramming of DCs through FoxO3a signaling pathways, including disturbing the balance of fatty acid synthesis (FAS) and fatty acid oxidation (FAO), increasing glycolysis but inhibiting the tricarboxylic acid cycle (TAC) and pentose phosphate pathway (PPP), which resulted in the accumulation of fatty acids (FAs) and lactic acid, as well as low anabolism in DCs. Our findings indicated that metformin could induce tolerance in DCs by reprogramming their metabolic patterns and play anti-inflammatory roles in vitro and in vivo.

Keywords:  Autoimmune diseases; Dendritic cells; Immune metabolism; Immune tolerance; Metformin; Tolerant dendritic cells

DOI:  https://doi.org/10.1007/s00018-023-04932-3
Trends Immunol. 2023 Sep 11. pii: S1471-4906(23)00180-1. [Epub ahead of print]

Over but not gone: lingering epigenetic effects of COVID-19.

Brandon T Tran, Ruoqiong Cao, Katherine Y King.

'Long COVID' affects nearly one in five adults who have had coronavirus disease 2019 (COVID-19), yet the mechanisms underlying this disorder remain poorly understood. In a new study, Cheong et al. show that the epigenetic and transcriptional state of myeloid immune cells and their progenitors are durably altered in patients following severe COVID-19.

DOI: https://doi.org/10.1016/j.it.2023.08.012