Biology subjects

Yost, C. C.

Publications and source records attributed to Yost, C. C..

3 recordsLinked to original sources

bioRxiv2026

Dysregulated neutrophil extracellular trap formation is a novel driver of clonogenicity and therapeutic vulnerability in CMML

Chronic myelomonocytic leukemia (CMML) is an aggressive hematologic malignancy characterized by excess inflammatory signaling and clonal myeloproliferation. The relative contribution of neutrophils (PMNs) to the inflammatory milieu in CMML is poorly understood. In this study we sought to understand whether neutrophil extracellular trap (NET) formation, a key mediator of neutrophilic inflammation, is dysregulated in CMML and can be therapeutically targeted with a novel peptide inhibitor of NETosis called neonatal NET-inhibitory factor (nNIF). Here, we demonstrate that baseline NET formation is aberrantly increased in primary CMML PMNs transcriptionally primed for NETosis, and that soluble factors produced during CMML NET formation promote clonogenicity in CMML CD34+ hematopoietic cells matched to the same patient. Further, we show that nNIF and clinical agents under investigation in CMML effectively inhibit NETosis, warranting further study of NET inhibitory agents in this rare disease with limited treatment options.

cancer biology↗

bioRxiv2020

Intestinal infection results in impaired lung innate immunity to secondary respiratory infection.

BackgroundPneumonia and diarrhea are among the leading causes of death worldwide, and epidemiological studies have demonstrated that diarrhea is associated with an increased risk of subsequent pneumonia. Our aim was to determine the impact of intestinal infection on innate immune responses in the lung. MethodsUsing a mouse model of intestinal infection by Salmonella enterica serovar Typhimurium (S. Typhimurium (ST)), we investigated how infection in the gut compartment can modulate immunity in the lungs and impact susceptibility to bacterial (Klebsiella pneumoniae (KP)) challenge. ResultsWe found alterations in frequencies of innate immune cells in lungs of intestinally-infected mice compared to uninfected mice. On subsequent challenge with K. pneumoniae we found that mice with prior intestinal infection have higher lung bacterial burden and inflammation, increased neutrophil margination, and neutrophil extracellular traps (NETs), but lower overall numbers of neutrophils, compared to mice without prior intestinal infection. Total numbers of dendritic cells, innate-like T cells, and natural killer cells were not different between mice with and without prior intestinal infection. ConclusionsTogether, these results suggest that intestinal infection impacts lung innate immune responses, most notably neutrophil characteristics, potentially resulting in increased susceptibility to secondary pneumonia. Article summaryWe show, in a mouse model, that prior intestinal infection with Salmonella Typhimurium leads to increased susceptibility to respiratory Klebsiella pneumoniae infection, which is associated with altered neutrophil responses.

immunology↗

bioRxiv2020

Differential glycosylation of alpha-1-acid glycoprotein (AGP-1) contributes to its functional diversity.

Alpha-1-acid glycoprotein (AGP-1) is a positive acute phase glycoprotein with uncertain functions. Serum AGP-1 (sAGP-1) is primarily derived from hepatocytes and circulates as 12 to 20 different glycoforms. We isolated a glycoform secreted from stimulated human neutrophils (nAGP-1). Its peptide sequence was identical to hepatocyte-derived sAGP-1, but nAGP-1 differed from sAGP-1 in its chromatographic behaviour, electrophoretic mobility, and glycosylation. The function of these two glycoforms also differed. sAGP-1 activated neutrophil adhesion, migration and NETosis in a dose-dependent fashion, while nAGP-1 was ineffective as an agonist for these events. Furthermore, sAGP-1, but not nAGP-1, inhibited LPS-stimulated NETosis. However, nAGP-1 inhibited sAGP-1-stimulated neutrophil NETosis. The discordant effect of the differentially glycosylated AGP-1 glycoforms was also observed in platelets where neither of the AGP-1 glycoforms alone stimulated aggregation of washed human platelets, but sAGP-1, and not nAGP-1, inhibited aggregation induced by Platelet-activating Factor (PAF) or ADP, but not by thrombin. These functional effects of sAGP-1 correlated with intracellular cAMP accumulation and were accompanied by phosphorylation of the PKA substrate Vasodialator stimulated phosphoprotein (VASP) and reduction of Akt, ERK, and p38 phosphorylation. Thus, the sAGP-1 glycoform limits platelet reactivity while nAGP-1 glycoform also limits pro-inflammatory actions of sAGP-1. These studies identify new functions for this acute phase glycoprotein and demonstrate that the glycosylation of AGP-1 controls its effects on two critical cells of acute inflammation.

biochemistry↗