Peyers Patch B cells undergo cell death via neutrophil-released toxic DNA following sterile tissue injury

Tuz, A. A.; Beer, A.; Gallert, M.; Ttoouli, D.; Ghosh, S.; Sata, S. P.; Kraus, A.; Zwirnlein, F.; Kaygusuz, V.; Lakovic, V.; Qefalia, A.; Antler, M.; Korste, S.; Kaltwasser, B.; Abdelrahman, H.; Mohamud-Yusuf, A.; Wang, C.; Haeusler, L.; Lueong, S.; Stenzel, M.; Frank, B.; Koehrmann, M.; Siveke, J.; Totzeck, M.; Hoffmann, D.; Grueneboom, A.; Hagemann, N.; Hasenberg, A.; Sickmann, A.; Chen, J.; Hermann, D. M.; Gunzer, M.; Singh, V.

doi:10.1101/2022.11.09.515763

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bioRxiv · 10.1101/2022.11.09.515763

Peyers Patch B cells undergo cell death via neutrophil-released toxic DNA following sterile tissue injury

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Abstract

Lymphocyte contraction (LC) in central immune organs is a concomitant of sterile tissue injury, for example after stroke. Intestinal Peyers patches (PP) harbor large numbers of B cells, but how sterile tissue injury leads to LC in PP has not been explored. We observed rapid and macroscopically evident shrinkage of PP after stroke and myocardial infarction. Light-sheet fluorescence microscopy and flow cytometry revealed a strong reduction in the number of PP-resident B cells. Mechanistically, tissue injury triggered the activation of neutrophils that released B cell-toxic neutrophil extracellular traps (NETs) decorated with citrullinated histone-H3. Antibody-mediated or genetically induced neutrophil-loss, NETs-degradation or blockade of their generation completely reversed B cell loss and preserved the tissue architecture of PP. We also found NET-like elements in human post-stroke plasma. Hence, we propose that targeting NET-generation or -function counteracts post-injury B cell contraction in PP and thereby maintains immune homeostasis at mucosal barriers. In briefHigh numbers of B cells reside in the intestinal Peyers patches. Tuz et al. revealed that in response to sterile tissue injury, activated neutrophils release histone-decorated DNA into the circulation which induces B cell death. The loss of B cells results in the shrinkage of Peyers patches and reduced amounts of secretory IgA. HighlightsO_LIStroke and myocardial infarction induce the melting of Peyers patch C_LIO_LILight-sheet microscopy and cytometry revealed B cell loss in Peyers patch C_LIO_LIPost-injury activated neutrophils release NETs and trigger B cell death C_LIO_LIInhibition of NETs rescues B cell loss and degeneration of Peyers patch C_LI

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Tuz, A. A., Beer, A., Gallert, M., Ttoouli, D., Ghosh, S., Sata, S. P., Kraus, A., Zwirnlein, F., Kaygusuz, V., Lakovic, V., Qefalia, A., Antler, M., Korste, S., Kaltwasser, B., Abdelrahman, H., Mohamud-Yusuf, A., Wang, C., Haeusler, L., Lueong, S., Stenzel, M., Frank, B., Koehrmann, M., Siveke, J., Totzeck, M., Hoffmann, D., Grueneboom, A., Hagemann, N., Hasenberg, A., Sickmann, A., Chen, J., Hermann, D. M., Gunzer, M., Singh, V.. 2022-11-09. Peyers Patch B cells undergo cell death via neutrophil-released toxic DNA following sterile tissue injury. https://doi.org/10.1101/2022.11.09.515763

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