Monocyte, Neutrophil and Whole Blood Transcriptome Dynamics Following Ischemic Stroke

Abstract

BackgroundAfter ischemic stroke (IS), peripheral leukocytes infiltrate the damaged region and modulate the response to injury. Peripheral blood cells display distinctive gene expression signatures post IS and these transcriptional programs reflect changes in immune responses to IS. Dissecting the temporal dynamics of gene expression after IS improves our understanding of immune and clotting responses at the molecular and cellular level that are involved in acute brain injury and may assist with time-targeted, cell-specific therapy.MethodsThe transcriptomic profiles from peripheral monocytes, neutrophils, and whole blood from 38 ischemic stroke patients and 18 controls were analyzed with RNAseq as a function of time and etiology after stroke. Differential expression analyses were performed at 0-24 h, 24-48 h, and >48 h following stroke.ResultsUnique patterns of temporal gene expression and pathways were distinguished for monocytes, neutrophils and whole blood with enrichment of interleukin signaling pathways for different timepoints and stroke etiologies. Compared to control subjects, gene expression was generally up-regulated in neutrophils and generally down- regulated in monocytes over all times for cardioembolic, large vessel and small vessel strokes. Self-Organizing Maps identified gene clusters with similar trajectories of gene expression over time for different stroke causes and sample types. Weighted Gene Co- expression Network Analyses identified modules of co-expressed genes that significantly varied with time after stroke and included hub genes of immunoglobulin genes in whole blood.ConclusionsAltogether, the identified genes and pathways are critical for understanding how the immune and clotting systems change over time after stroke. This study identifies potential time- and cell-specific biomarkers and treatment targets.

Neutrophil dynamics and inflammaging in acute ischemic stroke: A transcriptomic review

“…Neutrophin/TRK signaling activates hematopoietic cell survival and neurite outgrowth and differentiation ( Reichardt, 2006 ). GM-CSF signaling, enriched at 48 h after stroke, initiates cell survival and differentiation ( Cox et al, 1992 ; Becker, 1998 ; Lanfranconi et al, 2011 ; Carmona-Mora et al, 2021 , 2022 ). Activation of TGF-β signaling, an N2 marker, exerts both deleterious and neuroprotective post-stroke, including upregulating the anti-inflammatory and anti-apoptosis IL-10 and IL-2 pathways ( Boey et al, 1989 , 1; Perez-de-Puig et al, 2015 ; Carmona-Mora et al, 2022 ).…”

“…GM-CSF signaling, enriched at 48 h after stroke, initiates cell survival and differentiation ( Cox et al, 1992 ; Becker, 1998 ; Lanfranconi et al, 2011 ; Carmona-Mora et al, 2021 , 2022 ). Activation of TGF-β signaling, an N2 marker, exerts both deleterious and neuroprotective post-stroke, including upregulating the anti-inflammatory and anti-apoptosis IL-10 and IL-2 pathways ( Boey et al, 1989 , 1; Perez-de-Puig et al, 2015 ; Carmona-Mora et al, 2022 ). BMP signaling mediates glial scar formation after stroke ( Shin et al, 2012 ) and TGFB3 signaling regulates N1 to N2 neutrophil polarization involved in inflammation resolution ( Cuartero et al, 2013 ; Liao et al, 2014 ; Perez-de-Puig et al, 2015 ).…”

Association between advanced lung cancer inflammation index and all-cause and cardiovascular mortality among stroke patients: NHANES, 1999–2018

“…Elevated levels of inflammation were associated with increased stroke incidence and mortality risk. In stroke patients, markers like interleukin-6 (IL-6), tumor necrosis factor (TNF), and neutrophil counts were markedly increased (4)(5)(6). Hence, stroke was regarded as an inflammatory disease.…”