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Immunomodulatory activity of hyaluronidase is associated with metabolic adaptations during acute inflammation

ABSTRACT: Objective and design: Investigate survival outcomes, and immunological and metabolomic effects of hyaluronidase (Hz) treatment during mouse models of acute inflammation and sepsis. Methods: Survival of C57Bl/6 mice was monitored after lethal challenge with lipopolysaccharide (LPS) or cecal and ligation puncture (CLP)-induced sepsis and treated with Hz or saline. Mice were also challenged with LPS and treated with Hz for leukocyte counting, cytokine quantification and determination of metabolomic profiles in the peritoneal fluid. Results: Hz treatment improved survival outcomes after lethal challenge with LPS or CLPinduced sepsis. LPS challenge promoted acute neutrophil accumulation and production of interleukin-1β (IL-1β) and IL-6 in the peritoneum, whereas Hz treatment suppressed neutrophil infiltration and cytokine production. We further characterized the metabolomic alterations caused by LPS challenge, which predicted activity of metabolic pathways related to fatty acids and eicosanoids. Hz treatment had a profound effect over the metabolic response, reflected by reductions of the relative levels of fatty acids. Conclusion: Collectively, these data demonstrate that Hz treatment is associated with metabolic reprogramming of pathways that sustain the inflammatory response.

ORGANISM(S): Mouse Mus Musculus

TISSUE(S): Peritoneal Fluid

DISEASE(S): Sepsis

SUBMITTER: Luiz Gustavo Gardinassi

PROVIDER: ST001255 | MetabolomicsWorkbench | Thu Sep 26 00:00:00 BST 2019

REPOSITORIES: MetabolomicsWorkbench

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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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Immunomodulatory activity of hyaluronidase is associated with metabolic adaptations during acute inflammation

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