Distinguishing Sepsis From Infection by Neutrophil Dysfunction: A Promising Role of CXCR2 Surface Level

Abstract

Sepsis is one of the well-established diseases with specific patterns of neutrophil dysfunctions. Previous studies demonstrated sepsis-related neutrophil dysfunctions in comparison with subjects without infection. Since sepsis and infection are recently recognized as distinctive processes, whether these neutrophil dysfunctions are associated with sepsis or infection are not known. Therefore, we longitudinally compared neutrophil functions, widely-cited as exhibiting sepsis-related changes, between patients with septic shock and infection. The surface level of cluster of differentiation 64 (CD64), C-C motif chemokine receptor 2 (CCR2), C-X-C motif chemokine receptor 2 (CXCR2); apoptosis; and NETosis were measured from peripheral blood neutrophils for seven consecutive days using flow cytometry. The between-group comparisons of neutrophil functions were made both on a day-by-day basis and as linear regression between time and measured neutrophil functions (sepsis status included as model predictors). Our study found that, among neutrophil functions studied, only CXCR2 surface level is associated with sepsis. At disease onset, CXCR2 level decrease, with a dose-response relationship with clinical severity. Its level reverts to resemble infected patients by the end of the week. The relationship between CD64 surface level, CCR2 surface level, NETosis, and sepsis are mediated through the effect of infection. Apoptosis activity between these groups are similar, hence, not sepsis-related.

The Concentration of Large Extracellular Vesicles Differentiates Early Septic Shock From Infection

“…Our study found that, in septic shock patients, most plasma-derived EVs are of non-leukocyte origins (i.e., platelet-EVs, erythrocyte-EVs, endothelial cells-EVs; ranked in descending order of plasma concentration). Interestingly, neutrophil-derived EVs only constitute a minority of plasma EVs despite the existing sepsis and infection-induced neutrophil dysfunctions ( 10 ) and previous publications highlighting the association between neutrophil EVs and the inflammatory process of sepsis ( 26 , 27 ). These findings emphasize an important role of blood cells of non-leukocyte origin in modulating and propagating the hyperinflammatory reactions of sepsis and infection.…”

“…The result gained from this design is a mixed effect of infection and sepsis rather than sepsis itself. As pointed out by the latest sepsis definition (2) and demonstrated by a published work of our group (10), immune alterations that occurred in sepsis and infection differ and should be addressed by the study design. In addition, the cross-sectional nature of previous studies omits the dynamicity of sepsis; hence, their results may not be able to apply to patients presenting at different time points during the disease course.…”

A Bittersweet Response to Infection in Diabetes; Targeting Neutrophils to Modify Inflammation and Improve Host Immunity

“…There are multiple causative mechanisms for aberrant neutrophil migration with both the neutrophil and the endothelium shown to be altered in the diabetic microenvironment. Internalisation of the chemokine receptor CXCR2 was associated with reduced migration in a study of sepsis in mice with alloxan induced diabetes, which is a shared neutrophil dysfunction mechanism common to non-diabetes sepsis models ( 107 , 110 ). CXCR2 expression is downregulated by TLR2 signalling, which involves G protein coupled receptor kinase-2 (GRK2) ( 111 ).…”

Exponential magnetophoretic gradient for the direct isolation of basophils from whole blood in a microfluidic system

“…We believe that our i-BID platform, performed on basophils, has strong potential to accelerate immune functional assays for this cell type, such as the basophil activation test for allergy assessment ( 24 ). It will also be of interest to apply the i-BID platform to isolate other cell types, such as neutrophils to investigate their dysfunction for sepsis diagnosis ( 68 ), or T-cells for enzyme linked immunosorbent assay (ELISA)-based interferon-gamma (IFN- γ ) release assays for tuberculosis diagnosis ( 69 ).…”