Cell Li Xiaofei et al reveal that chronic comorbidities are linked through innate immune memory

Editor-in-Chief | Xi Trained Immunity or Innate Immune Memory, as non-antigen-specific immune memory, can provide cross-protection against infection by different pathogens
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The team of Professor Mihai G.
Netea of ​​Radboud University in the Netherlands first proposed the concept of "trained immunity" in 2011
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Subsequent series of studies have shown that epigenetic and metabolic reprogramming of mature innate immune cells such as macrophages, monocytes, and NK cells dominate the formation of trained immune/innate immune memory
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However, how do short-lived mature cells carry months to years of innate immune memory? In 2018, the team of Professor Triantafyllos Chavakis of the Technical University of Dresden answered this question.
They found that the innate immune memory originated from hematopoietic stem/progenitor cells (HSPC) in the bone marrow, and regulates the immune metabolism and myeloid hematopoietic differentiation of HSPC.
function
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Immunity training can improve the body's anti-infection immunity, but its impact on chronic inflammatory diseases and its molecular mechanism are still unclear, which is a key scientific issue in the field of training immunity research
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On April 27, 2022, the team of Professor George Hajishengallis of the University of Pennsylvania (Li Xiaofei and Dr.
Hui Wang are the first authors) and the team of Professor Triantafyllos Chavakis of the Technical University of Dresden jointly published the title of Maladaptive innate immune training in Cell.
The long article of myelopoiesis links inflammatory comorbidities reveals for the first time that peripheral inflammatory signaling-induced innate immune memory at the level of bone marrow hematopoietic stem/progenitor cells promotes chronic inflammatory disease progression and links the molecular mechanisms of chronic comorbidities
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Dr.
Xiaofei Li from Professor George Hajishengallis's team found that one week after transient induction of the non-systemic inflammatory disease periodontitis in mice, hematopoietic stem/progenitor cells (HSPC, Lin−Sca1+cKit+ cells, including long-term hematopoietic stem cells) in the bone marrow of mice , short-term hematopoietic stem cells and pluripotent progenitor cells) showed obvious myeloid differentiation tendency at the cell population level and transcriptome level; the three-week periodontitis model can effectively simulate human chronic periodontitis, and mouse bone marrow HSPC showed More significant myeloid differentiation tendency, and the proportion and number of granulocyte-monocyte progenitor (GMP) and mature myeloid cells such as monocytes and neutrophils in the bone marrow were significantly up-regulated
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After peripheral tissue inflammation subsided, that is, after various immune indexes returned to baseline levels, the myeloid differentiation of bone marrow HSPCs also returned to baseline levels in cell population and single-cell transcriptome levels
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However, when the peripheral tissue inflammation subsided for four weeks, the HSPC, GMP and maturation of HSPC, GMP and maturation of the mice in the experimental group were significantly higher than those in the control group without inflammation after 72 hours of the second immune stimulation, such as LPS stimulation.
Myeloid cells again showed a clear tendency for myeloid differentiation, suggesting that HSPCs acquired innate immune memory associated with previous inflammation
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Subsequently, Dr.
Li Xiaofei found through scATAC-seq analysis that the binding sites of transcription factors related to myeloid differentiation in HSPC, such as SPI1 (PU.
1), C/EBPα and C/EBPε, were significantly in the chromatin open region (NDR) Chromatin accessibility was also significantly enhanced for inflammatory genes such as Il6, Tlr4 and Myd88
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More importantly, compared with the control group, the monocytes and neutrophils derived from the spleen of mice in the experimental group secreted higher levels of inflammatory cells such as IL-6 and TNF-α after being stimulated by LPS in vitro.
factor
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In conclusion, HSPCs with inflammatory innate immune memory can differentiate into more mature myeloid cells with stronger immune response ability
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Subsequently, Li Xiaofei and Dr.
Wang Hui found through bone marrow transplantation experiments that hematopoietic stem cells with inflammatory innate immune memory still showed a clear tendency to myeloid differentiation several months after transplantation into recipient mice, and significantly aggravated the innate immune system in recipient mice.
Inflammatory phenotype of two inflammatory diseases rheumatoid arthritis (CAIA model), while demonstrating that innate immune memory can be transmitted to recipient mice through hematopoietic stem cells
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Interestingly, the researchers also found that hematopoietic stem cells with rheumatoid arthritis (CAIA) innate immune memory can also aggravate the inflammatory phenotype of periodontitis after transplantation into recipient mice, suggesting that innate immune memory is linked to chronic a key node of the disease
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How are inflammatory signals from peripheral tissues transmitted to the bone marrow and ultimately mediate the formation of trained/innate immune memory? The researchers screened inflammatory cytokines in the local inflammatory tissue, serum and bone marrow of mice, and analyzed various types of cells in the bone marrow.
It then acts on mature neutrophils in the bone marrow (CD11b+CD115−Gr-1+cKit−CXCR4−Ly6G+CXCR2+) to induce the secretion of IL-1
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HSPC, as the main acting cell of IL-1 in the bone marrow, activates the internal IL-1 signaling pathway, eventually causing myeloid differentiation and epigenetic modification of inflammatory response-related genes, and promoting the formation of inflammatory innate immune memory
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In conclusion, this study found that peripheral inflammatory signals promote myeloid hematopoietic differentiation and significantly improve the immune response capacity of mature myeloid cells by inducing the formation of IL-1 signaling pathway-dependent innate immune memory in bone marrow HSPCs, thereby improving quantitative and qualitative outcomes.
Accelerates chronic inflammatory responses on two distinct levels
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Thus, the creation of a deleterious positive feedback loop between inflammatory-adapted HSPCs and peripheral inflammation underlies the link between multiple chronic comorbidities
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Therefore, inhibiting the formation of innate immune memory in the bone marrow will effectively break the harmful positive feedback loop and provide a new therapeutic strategy for chronic inflammatory diseases and their comorbidities
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Dr.
Li Xiaofei, the first author of the paper, plans to join the School of Life Science and Technology, Shanghai Jiao Tong University
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Dr.
Li has long been engaged in the research on the pathogenesis and regression mechanism of chronic inflammation/comorbidity
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In the past five years, he has published papers in internationally renowned journals such as Cell, Nature Immunology, Journal of Clinical Investigation and Molecular Aspects of Medicine as the first, co-first or co-corresponding author
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Work is reviewed by Nature Immunology Highlights, F1000Prime Expert Reviewed and Recommended
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At the same time, the work as a collaborator has been published in journals such as Cell (2020), Journal of Clinical Investigation (2021, 2022)
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The laboratory warmly welcomes postdoctoral fellows and graduate students interested in the research on the pathogenesis and resolution of chronic inflammation
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Resume delivery (if you are interested, please send your resume and other materials to): https://jinshuju.
net/f/ZqXwZt or scan the QR code to submit your resume original link: https://doi.
org/10.
1016/j.
cell.
2022.
03.
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