The Regulation of Neutrophil Migration in Patients with Sepsis: The Complexity of the Molecular Mechanisms and Their Modulation in Sepsis and the Heterogeneity of Sepsis Patients

Abstract

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Common causes include gram-negative and gram-positive bacteria as well as fungi. Neutrophils are among the first cells to arrive at an infection site where they function as important effector cells of the innate immune system and as regulators of the host immune response. The regulation of neutrophil migration is therefore important both for the infection-directed host response and for the development of organ dysfunctions in sepsis. Downregulation of CXCR4/CXCL12 stimulates neutrophil migration from the bone marrow. This is followed by transmigration/extravasation across the endothelial cell barrier at the infection site; this process is directed by adhesion molecules and various chemotactic gradients created by chemotactic cytokines, lipid mediators, bacterial peptides, and peptides from damaged cells. These mechanisms of neutrophil migration are modulated by sepsis, leading to reduced neutrophil migration and even reversed migration that contributes to distant organ failure. The sepsis-induced modulation seems to differ between neutrophil subsets. Furthermore, sepsis patients should be regarded as heterogeneous because neutrophil migration will possibly be further modulated by the infecting microorganisms, antimicrobial treatment, patient age/frailty/sex, other diseases (e.g., hematological malignancies and stem cell transplantation), and the metabolic status. The present review describes molecular mechanisms involved in the regulation of neutrophil migration; how these mechanisms are altered during sepsis; and how bacteria/fungi, antimicrobial treatment, and aging/frailty/comorbidity influence the regulation of neutrophil migration.

Integrated multi-omics and artificial intelligence to explore new neutrophils clusters and potential biomarkers in sepsis with experimental validation

“…Neutrophils is an effector cell in the innate immune system that helps to fight infection as a first line of defense ( 22 ). Studies showed that sepsis-related neutrophils were dysfunctional and contributed to the multi-organ failure ( 22 ). Among multiple organs, the lung is the first and most frequently injured organ to fail ( 23 ).…”

The Role of Cytokines in Neutrophil Development, Tissue Homing, Function and Plasticity in Health and Disease

“…The mechanisms underlying this process, known as reverse transmigration, are complex and not fully elucidated. CXCL1 leakage from the tissue into the circulation upon breach of the endothelium; damages to the endothelial junctions because of neutrophil elastase secretion triggered by LTB4; the increased expression of CXCL8, prostaglandin E2 (PGE2), lipoxin 4 (LXA4) and cathep-sin C; as well as the inactivation of hypoxia-inducible factor 1 alpha (HIF-1α), are a few of the proposed mechanisms involved in neutrophil reverse transmigration (Figure 4) [90][91][92]. The biological role of this novel process remains to be determined.…”