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The mechanisms of neutrophil dysfunction during sepsis

ABSTRACT: The project examines the mechanisms of neutrophil dysfunction during sepsis. Our work uncovered the central role of cell free circulating histones in eliminating mature neutrophil in favour of immature cells and characterized the mechanisms that regulate their release following systemic infection. Mature and immature neutrophil Ly6Ghigh and Ly6Glow populations isolated from the spleens of WT and TCRα-deficient mice either naïve or infected with C. albicans were characterized. In addition, these populations were compared to neutrophils isolated from WT mice receiving Clodronate-liposomes and recombinant G-CSF. These studies demonstrated that T-cell derived histones drive the release of G-CSF in the spleen and progressively eliminate mature neutrophils by shortening their lifespan. Finally, we conducted proteomic analysis of plasmas isolated from patients with microbial sepsis to correlate markers of neutrophil death to plasma cytokine and histone levels, confirming the pathogenic role these molecules play during sepsis in humans.

INSTRUMENT(S): TripleTOF 5600

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Blood Plasma

SUBMITTER: Spyros Vernardis

LAB HEAD: Markus Ralser

PROVIDER: PXD032961 | Pride | 2022-12-13

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	B6129S2Tcratm1MomJ_infected_1.wiff	Wiff
	B6129S2Tcratm1MomJ_infected_1.wiff.scan	Wiff
	B6129S2Tcratm1MomJ_infected_2.wiff	Wiff
	B6129S2Tcratm1MomJ_infected_2.wiff.scan	Wiff
	B6129S2Tcratm1MomJ_infected_3.wiff	Wiff

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Project description:The project examines the mechanisms of neutrophil dysfunction during sepsis. Our work uncovered the central role of cell free circulating histones in eliminating mature neutrophil in favour of immature cells and characterized the mechanisms that regulate their release following systemic infection. Mature and immature neutrophil Ly6Ghigh and Ly6Glow populations isolated from the spleens of WT and TCRα-deficient mice either naïve or infected with C. albicans were characterized. In addition, these populations were compared to neutrophils isolated from WT mice receiving Clodronate-liposomes and recombinant G-CSF. These studies demonstrated that T-cell derived histones drive the release of G-CSF in the spleen and progressively eliminate mature neutrophils by shortening their lifespan. Finally, we conducted proteomic analysis of plasmas isolated from patients with microbial sepsis to correlate markers of neutrophil death to plasma cytokine and histone levels, confirming the pathogenic role these molecules play during sepsis in humans.

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