Biology subjects

Autenrieth, S.

Publications and source records attributed to Autenrieth, S..

2 recordsLinked to original sources

bioRxiv2023

Distinct Functional States of Neutrophils by Actin Disassembly and NF-kB/STAT3 Signaling

Polymorphonuclear neutrophils (PMNs) can differentiate into distinct states, which can either exacerbate or resolve inflammation. Our study shows that mice challenged with TLR agonists exhibited PMN differentiation along two major paths characterized by the expression of CCR5 or PD-L1. Similar differentiation was observed in the blood of severe COVID-19 patients and the synovial fluid of osteoarthritis patients. Prolonged in vitro priming of human PMNs modeled the differentiation paths. Actin disassembly favored CCR5 upregulation, while NF-kB activation stabilized the actin cytoskeleton and suppressed the development of CCR5+ PMNs. Additionally, PD-L1 upregulation was triggered by STAT3 signaling and NF-kB activation. Functionally, CCR5 expressing PMNs were pro-NETotic, while PD-L1+ PMNs showed immunosuppressive functions by inhibiting T cell proliferation via PD1. Together, PMN differentiation depended on the priming conditions, and the balance between actin disassembly and NF-kB/STAT3 activation translated the present micro-milieu into phenotypic and functional diversification of PMNs. SynopsisNeutrophils underwent phenotypical and functional diversification both in vivo and in vitro. Actin disassembly led to the generation of CCR5high neutrophils with increased spontaneous NETosis, whereas NF-kB and STAT3 induced PD-L1 expression with T-cell suppressive properties as a deviation from the default pathway. O_LIPMN of mice challenged with TLR agonists develop two distinct phenotypes, CCR5high and PD-L1high. C_LIO_LICCR5 and PD-L1-defined neutrophil phenotypes were found in blood of patients with severe COVID-19 and in the synovial fluid of osteoarthritis patients. C_LIO_LIIn vitro priming induced a similar bifurcation of PMN phenotypes marked by either CCR5 or PD-L1. C_LIO_LIActin disassembly preceded canonical development of CCR5+ PMN. C_LIO_LINF-kB halted actin disassembly by LPL regulation. C_LIO_LIDuring neutrophil priming, STAT3 aided NF-kB in the expression of PD-L1. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=159 HEIGHT=200 SRC="FIGDIR/small/548975v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@10305f3org.highwire.dtl.DTLVardef@17bada8org.highwire.dtl.DTLVardef@c61021org.highwire.dtl.DTLVardef@14ce7f3_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

Enhanced Airway Epithelial Response to SARS-CoV-2 Infection in Children is Critically Tuned by the Cross-Talk Between Immune and Epithelial Cells

To cope with novel virus infections to which no prior adaptive immunity exists, the body strongly relies on the innate immune system. In such cases, including infections with SARS-CoV-2, children tend to fair better than adults. In the context of COVID-19, it became evident that a rapid interferon response at the site of primary infection is key for successful control of the virus and prevention of severe disease. The airway epithelium of children was shown to exhibit a primed state already at homeostasis and to respond particularly well to SARS-CoV-2 infection. However, the underlying mechanism for this priming remained elusive. Here we show that interactions between airway mucosal immune cells and epithelial cells are stronger in children, and via cytokine-mediated signaling lead to IRF-1-dependent upregulation of the viral sensors RIG-I and MDA5. Based on a cellular in vitro model we show that stimulated human peripheral blood mononuclear cells (PBMC) can induce a robust interferon-beta response towards SARS-CoV-2 in a lung epithelial cell line otherwise unresponsive to this virus. This is mediated by type I interferon, interferon-gamma and TNF, and requires induction of both, RIG-I and MDA5. In single cell-analysis of nasal swab samples the same cytokines are found to be elevated in mucosal immune cells of children, correlating with elevated epithelial expression of viral sensors. In vitro analysis of PBMC derived from healthy adolescents and adults confirm that immune cells of younger individuals show increased cytokine production and potential to prime epithelial cells. In co-culture with SARS-CoV-2-infected A549 cells, PBMC from adolescents significantly enhance the antiviral response. Taken together, our study suggests that higher numbers and a more vigorous activity of innate immune cells in the airway mucosa of children tune the set-point of the epithelial antiviral system. This likely is a major contributor to the robust immune response to SARS-CoV-2 in children. Our findings shed light on the molecular underpinnings of the stunning resilience of children towards severe COVID-19, and may propose a novel concept for immunoprophylactic treatments.

immunology↗