How the interaction with gut microbiota shapes the impact of neutrophils on ischemic brain injury
Immunology
Final Report Abstract
Our work shows that intestinal microbiota induce neutrophil activation after ischemic stroke, resulting in increased cerebral infarct size. These findings are consistent with previous studies reporting an association between systemic neutrophil activation and worse stroke outcomes. Using a microbiota transfer germ-free mouse model and antibiotics-mediated microbiota depletion in conventional specific pathogen-free (SPF) mice, we demonstrated the potential of microbiota targeting to control systemic and cerebral inflammation after stroke. In particular, our mass-spectrometry-based proteomics data revealed that circulating neutrophils from microbiota-deficient mice have very low levels of inflammatory proteins and release reduced levels of circulating DNA as neutrophil extracellular traps (NETs) compared to intestinal microbiota-sufficient mice. Given that microbiota can train innate immunity by priming through pathogen-associated molecular patterns such as peptidoglycan, lipopolysaccharide, and betaglucans, which has recently been shown to contribute to neutrophil activation, we speculate that adverse stroke outcomes in microbiota-sufficient mice may result from these biomolecular interactions. Thus, future studies need to investigate how gut microbiota-derived components interact to influence neutrophil activation after stroke. In addition, we found that stroke induced a rapid decrease in circulating immunoglobulin (Ig) A levels in stroke patients that were significantly associated with increased levels of NETs in their circulation. A similar decrease in IgA levels was revealed in mice under stroke which was associated with a loss of B cells in intestinal lymphoid tissues. The release of NETs from activated neutrophils after stroke was identified as a cause of lymphocyte death. Interestingly, degradation of NETs with DNase-I or inhibition of their release with a NET inhibitor blocked the reduction of intestinal lymphocytes and circulating IgA after stroke. However, identification of the underlying intracellular mechanisms of NET release and cytotoxicity towards lymphocytes requires further research. In stroke patients, increased levels of blood cholesterol may serve as an indicator of worse clinical outcome. In our experimental study using mouse models of stroke, we found that high-fat diet induced hypercholesteremia increased the levels of circulating NETs and inflammatory cytokines as early as three hours after disease onset. These accelerated inflammatory responses lead to increased brain vascular occlusions and cerebral infarcts. In conclusion, the results of our project have opened new opportunities to target gut microbiota and activated neutrophils in the development of therapies for stroke patients.
Publications
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Ischemic stroke and concomitant gastrointestinal complications- a fatal combination for patient recovery. Frontiers in Immunology, 13.
Tuz, Ali A.; Hasenberg, Anja; Hermann, Dirk M.; Gunzer, Matthias & Singh, Vikramjeet
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Stroke and myocardial infarction induce neutrophil extracellular trap release disrupting lymphoid organ structure and immunoglobulin secretion. Nature Cardiovascular Research, 3(5), 525-540.
Tuz, Ali A.; Ghosh, Susmita; Karsch, Laura; Ttoouli, Dimitris; Sata, Sai P.; Ulusoy, Özgür; Kraus, Andreas; Hoerenbaum, Nils; Wolf, Jan-Niklas; Lohmann, Sabrina; Zwirnlein, Franziska; Kaygusuz, Viola; Lakovic, Vivian; Tummes, Hannah-Lea; Beer, Alexander; Gallert, Markus; Thiebes, Stephanie; Qefalia, Altea; Cibir, Zülal ... & Singh, Vikramjeet
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Hypercholesterolemia triggers innate immune imbalance and transforms brain infarcts after ischemic stroke. Frontiers in Immunology, 15.
Tuz, Ali Ata; Hoerenbaum, Nils; Ulusoy, Özgür; Ahmadi, Adel; Gerlach, Alana; Beer, Alexander; Kraus, Andreas; Hasenberg, Anja; Hagemann, Nina; Hermann, Dirk M.; Gunzer, Matthias & Singh, Vikramjeet
