Beer, A. | Search bioRxiv

bioRxiv2022

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

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

immunology↗

bioRxiv2020

Stroke increases the expression of ACE2, the SARS-CoV-2 binding receptor, in murine lungs

BackgroundThe newly emerged severe acute respiratory syndrome coronavirus (SARS-CoV-2) has caused a worldwide pandemic of human respiratory disease. Angiotensin-converting enzyme (ACE) 2 is the key receptor on lung epithelial cells to facilitate initial binding and infection of SARS-CoV-2. The binding to ACE2 is mediated via the spike glycoprotein present on the virus surface. Recent clinical data have demonstrated that patients suffering from stroke are particularly susceptible to severe courses of SARS-CoV-2 infection, thus forming a defined risk group. However, a mechanistic explanation for this finding is lacking. Sterile tissue injuries including stroke induce lymphocytopenia and systemic inflammation that might modulate the expression levels of surface proteins in distant organs. Whether systemic inflammation following stroke can specifically modulate ACE2 expression in the lung has not been investigated. MethodsMice were subjected to transient middle cerebral artery occlusion (MCAO) for 45 min and sacrificed after 24 h and 72 h for analysis of brain and lung tissues. Gene expression and protein levels of ACE2, ACE, IL-6 and IL1{beta} were measured by quantitative PCR and Western blot, respectively. Immune cell populations in lymphoid organs were analyzed by flow cytometry. ResultsStrikingly, 24 h after stroke, we observed a substantial increase in the expression of ACE2 both on the transcriptional and protein levels in the lungs of MCAO mice compared to sham-operated mice. This increased expression persisted until day 3 after stroke. In addition, MCAO increased the expression of inflammatory cytokines IL-6 and IL-1{beta} in the lungs. Higher gene expression of cytokines IL-6 and IL-1{beta} was found in ischemic brain hemispheres and a reduced number of T-lymphocytes were present in the blood and spleen as an indicator of sterile tissue injury-induced immunosuppression. ConclusionsWe demonstrate significantly augmented ACE2 levels and inflammation in murine lungs after experimental stroke. These pre-clinical findings might explain the clinical observation that patients with pre-existing stroke represent a high-risk group for the development of severe SARS-CoV-2 infections. Our studies call for further investigations into the underlying signaling mechanisms and possible therapeutic interventions. HighlightsBrain tissue injury increases ACE2 levels in the lungs Brain injury induces pro-inflammatory cytokine expression in the lungs Brain injury causes parenchymal inflammation and systemic lymphopenia

neuroscience↗