Dataset Information

Peripheral priming induces plastic transcriptomic and proteomic responses in circulating neutrophils required for pathogen containment

ABSTRACT: Neutrophils rapidly respond to inflammation and infection, but to which degree their functional trajectories after mobilization from the bone marrow can be shaped within the circulation remains vague. Phenotypic changes of circulating neutrophils caused by systemic inflammation are thought to result from several factors, including a “left shift” of the neutrophil compartment towards younger bone marrow-derived subsets. However, experimental limitations have so far hampered neutrophil research in human disease. Here, using innovative fixation and single-cell-based toolsets, we profile the human and murine neutrophil transcriptome and proteome during steady state and bacterial infection. We find that peripheral priming of circulating neutrophils leads to plastic shifts dominated by conserved upregulation of antimicrobial genes across neutrophil substates, facilitating pathogen containment. We show the TLR4/NF-κB-signaling dependent upregulation of canonical neutrophil activation markers like CD177/NB-1 during acute inflammation, resulting in functional shifts in vivo. Importantly, blocking de novo RNA synthesis in circulating neutrophils abrogates these plastic shifts and prevents the adaptation of antibacterial neutrophil programs by upregulation of distinct effector molecules upon infection. In summary, these data underline transcriptional plasticity as a relevant mechanism of functional neutrophil reprogramming during acute infection to foster bacterial containment within the circulation. This adds to the understanding of competing modes of adaptation to inflammatory challenges by the neutrophil compartment.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Neutrophil, Blood

DISEASE(S): Cardiovascular System Disease

SUBMITTER: Oliver Popp

LAB HEAD: Rainer Kaiser

PROVIDER: PXD048335 | Pride | 2024-05-21

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	Raw_acute.bacterial.infection.raw	Raw
	Results_acute.bacterial.infection.xlsx	Xlsx
	checksum.txt	Txt
	uniprot_human_iso_up000005640_2022-03.fasta	Fasta

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Peripheral priming induces plastic transcriptomic and proteomic responses in circulating neutrophils required for pathogen containment.

Kaiser Rainer R Gold Christoph C Joppich Markus M Loew Quentin Q Akhalkatsi Anastassia A Mueller Tonina T TT Offensperger Felix F Droste Zu Senden Augustin A Popp Oliver O di Fina Lea L Knottenberg Viktoria V Martinez-Navarro Alejandro A Eivers Luke L Anjum Afra A Escaig Raphael R Bruns Nils N Briem Eva E Dewender Robin R Muraly Abhinaya A Akgöl Sezer S Ferraro Bartolo B Hoeflinger Jonathan K L JKL Polewka Vivien V Khaled Najib Ben NB Allgeier Julian J Tiedt Steffen S Dichgans Martin M Engelmann Bernd B Enard Wolfgang W Mertins Philipp P Hubner Norbert N Weckbach Ludwig L Zimmer Ralf R Massberg Steffen S Stark Konstantin K Nicolai Leo L Pekayvaz Kami K

Science advances 20240322 12

Neutrophils rapidly respond to inflammation and infection, but to which degree their functional trajectories after mobilization from the bone marrow are shaped within the circulation remains vague. Experimental limitations have so far hampered neutrophil research in human disease. Here, using innovative fixation and single-cell-based toolsets, we profile human and murine neutrophil transcriptomes and proteomes during steady state and bacterial infection. We find that peripheral priming of circul ...[more]

PMID: 38517968

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Project description:Although the accumulation of neutrophils in the lungs and airways is common to many inflammatory lung diseases, including acute lung injury, the alterations that neutrophils undergo as they leave the peripheral circulation and migrate into the lungs have not been well characterized. Human volunteers were exposed to endotoxin by bronchoscopic instillation. The resulting air space neutrophil accumulation and peripheral blood neutrophils were isolated 16 h later, compared with circulating neutrophils isolated before or after to the pulmonary endotoxin exposure, and compared with circulating neutrophils exposed to endotoxin in vitro. Microarray analysis was performed on air space, circulatory, and in vitro endotoxin-stimulated neutrophils. Functional analysis included the determination of neutrophil apoptosis, chemotaxis, release of cytokines and growth factors, and superoxide anion release. Dramatic gene expression differences were apparent between air space and circulating neutrophils: approximately 15% of expressed genes have altered expression levels, including broad increases in inflammatory- and chemotaxis-related genes, as well as antiapoptotic and IKK-activating pathways. Functional analysis of air space compared with circulating neutrophils showed increased superoxide release, diminished apoptosis, decreased IL-8-induced chemotaxis, and a pattern of IL-8, macrophage inflammatory protein-1beta, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha release different from either unstimulated or LPS-stimulated circulating neutrophils. Many of these changes are not elicited by in vitro treatment with endotoxin. Limited differences were detected between circulating neutrophils isolated before and 16 h after pulmonary endotoxin instillation. These results suggest that neutrophils sequestered in the lung become fundamentally different from those resident in the circulation, and this difference is distinct from in vitro activation with endotoxin.