Gram-negative bacillary bacteremia poses a significant threat, ranking among the most severe infectious diseases capable of triggering life-threatening sepsis. Despite the unambiguous involvement of neutrophils in this potentially fatal disease, there are limited data about the molecular signaling mechanisms, phenotype, and function of human neutrophils during the early phase of gram-negative bacillary bacteremia. By using an unbiased proteomics and flow cytometry approach, we identified an antigen-presenting cell (APC)-like phenotype in human peripheral blood neutrophils (PMN) with MHC class II molecule expression in the early phase of bacteremia. Using an in-vitro model of GM-CSF-mediated induction of APC-like phenotype in PMN, we investigated downstream signaling pathways leading to MHC class II expression. GM-CSF stimulation of neutrophils leads to the activation of three major signaling pathways, the JAK-STAT, the mitogen-activated protein kinase (MAPK), and the phosphoinositide 3-kinase (PI3K)-Akt-mTOR pathways, while MHC class II induction is mediated by a MAPK-p38-MSK1-CREB1 signaling cascade and the MHC class II transactivator CIITA in a strictly JAK12 kinase-dependent manner. Our data describing details of signaling pathways inducing MHC class II expression in neutrophils open new possibilities of therapeutic targeting of JAK12 signaling during different stages of gram-negative bacteremia and sepsis.
[doi:10.25345/C5RN30K6J]
[dataset license: CC0 1.0 Universal (CC0 1.0)]
Keywords: MHC ; Phosphoproteomics ; neutrophils
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Alexander Schmidt, Biozentrum, Universtiy of Basel, 4056 Basel, Switzerland, N/A |
Submitting User: | trendsetter |
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