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

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