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Intermedin (Adrenomedullin 2) plays a protective role in sepsis by regulating T- and B-cell proliferation and activity

ABSTRACT: Sepsis is a life-threatening condition caused by dysregulated host responses to infection. Intermedin (IMD), a calcitonin family peptide, has been shown to protect against sepsis by alleviating vascular leakage and inflammatory responses. Herein, by using transcriptome sequencing (RNA-Seq), we found that IMD-knockout mice exhibited a primary immunosuppression phenotype characterized by a marked decrease in the expression of T- and B-cell function-related genes. This immunosuppression made the IMD-KO mice more vulnerable to pathogenic invasion than normal mice, and even a mild infection killed nearly half of the IMD-KO mice. IMD is likely to directly promote T- and B-cell proliferation through ERK1/2 phosphorylation. In addition, IMD may regulate T-cell differentiation via Ilr7 and Rag1/2, which control T-cell receptor (TCR) recombination, and may regulate B-cell activity via Pax5, which may be the most multifunctional transcription factor for B cells, regulating at least 170 genes that activate genes necessary for B-cell functions. Exogenous supplementation with IMD restored the expression of T/B-cell-related genes and significantly reduced IMD-KO mouse mortality. Our study reveals for the first time that IMD may play an important role in the adaptive immune response by regulating T- and B-cell proliferation and differentiation and provides translational opportunities for the design of immunotherapies for sepsis or other diseases associated with primary immunodeficiency.

ORGANISM(S): Mus musculus

PROVIDER: GSE214090 | GEO | 2022/10/25

REPOSITORIES: GEO

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Project description:Our experiments examined T-lymphocyte numbers and effector-functions in peritoneal contamination and infection (PCI) a mouse model of sepsis. One of our main questions was how T-lymphocytes reconstitute after sepsis-induced lymphopenia. We investigated the quantitative and qualitative recovery of T lymphocytes for 3.5 months after sepsis with or without IL-7 treatment. Sepsis is an immunological dysfunction against pathogens leading to inflammation with massive cytokine production. Simultaneously immunosuppression occurs e.g. lymphopenia, which is a hallmark of sepsis. The resulting immunosuppression is associated with secondary infections, which are often lethal. Moreover sepsis-survivors are burdened with increased morbidity and mortality for several years after the sepsis episode. The duration and clinical consequences of sepsis induced-immunosuppression are currently unknown. More than 50% of T-cells undergo apoptosis shortly after sepsis-induction. However, 8 days after sepsis onset, surviving mice present normal lymphocyte counts. Theoretically, T-cells could reconstitute in two different ways. Firstly, the diminished pool of T-cells is replenished by newly in thymus produced T-cells with new diverse T-cell-receptors (TCRs). Alternatively, remaining T-cells start to proliferate until reaching normal cell count. If this was the case all divided cells shared the same TCRs as primary cells. This could lead to a narrowed TCR diversity within a quantitative normalized T-cell pool and would be an explanation for the long-lasting immune incompetence. To address the question how T-cells recover from lymphopenia we applied next generation sequencing (NGS) to analyse TCR diversity in septic and healthy mice. One group of septic mice received Interleukin-7 (IL-7), an interleukin which regulates T-cell homeostasis and is a promising therapeutically approach for septic patients. 50000 sequences per mouse were analyzed and the three different groups (controls, sepsis, sepsis + IL-7 treatment) compared regarding their diversity. The sequenced raw data (fastq) are uploaded in this library.

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Intermedin (Adrenomedullin 2) plays a protective role in sepsis by regulating T- and B-cell proliferation and activity

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