The role of G protein-coupled receptor in neutrophil dysfunction during sepsis-induced acute respiratory distress syndrome

Abstract

Sepsis is defined as a life-threatening dysfunction due to a dysregulated host response to infection. It is a common and complex syndrome and is the leading cause of death in intensive care units. The lungs are most vulnerable to the challenge of sepsis, and the incidence of respiratory dysfunction has been reported to be up to 70%, in which neutrophils play a major role. Neutrophils are the first line of defense against infection, and they are regarded as the most responsive cells in sepsis. Normally, neutrophils recognize chemokines including the bacterial product N-formyl-methionyl-leucyl-phenylalanine (fMLP), complement 5a (C5a), and lipid molecules Leukotriene B4 (LTB4) and C-X-C motif chemokine ligand 8 (CXCL8), and enter the site of infection through mobilization, rolling, adhesion, migration, and chemotaxis. However, numerous studies have confirmed that despite the high levels of chemokines in septic patients and mice at the site of infection, the neutrophils cannot migrate to the proper target location, but instead they accumulate in the lungs, releasing histones, DNA, and proteases that mediate tissue damage and induce acute respiratory distress syndrome (ARDS). This is closely related to impaired neutrophil migration in sepsis, but the mechanism involved is still unclear. Many studies have shown that chemokine receptor dysregulation is an important cause of impaired neutrophil migration, and the vast majority of these chemokine receptors belong to the G protein-coupled receptors (GPCRs). In this review, we summarize the signaling pathways by which neutrophil GPCR regulates chemotaxis and the mechanisms by which abnormal GPCR function in sepsis leads to impaired neutrophil chemotaxis, which can further cause ARDS. Several potential targets for intervention are proposed to improve neutrophil chemotaxis, and we hope that this review may provide insights for clinical practitioners.

A novel anoikis-related gene signature predicts prognosis in patients with sepsis and reveals immune infiltration

“…Using the prognostic model, septic patients were divided into high-risk group and low-risk group to further study the different patterns of immune infiltration. Neutrophils and T cells exhibited higher scores within the high-risk group, consistent with prior investigations 22 , 40 . Several researches have been shown that neutrophil dysfunction stands as a pivotal contributor to multiple organ failure in sepsis, and the compromised migration of neutrophils bears direct implications for sepsis prognosis 40 – 43 .…”

“…Neutrophils and T cells exhibited higher scores within the high-risk group, consistent with prior investigations 22 , 40 . Several researches have been shown that neutrophil dysfunction stands as a pivotal contributor to multiple organ failure in sepsis, and the compromised migration of neutrophils bears direct implications for sepsis prognosis 40 – 43 . Moreover, T cell-mediated immune responses also play a crucial role in sepsis.…”

“…CXCL8 also possesses the ability to activate monocytes, CD8 T cells, and mast cells, thereby contributing to the initiation of immune responses 39 . During the onset of sepsis, the neutrophils recognize the chemotactic signals from CXCL8, promoting their migration to sites of infection and contributing to the series of responses associated with sepsis development 40 . In the present study, the new prognostic model based on the ARGs would shed light on sepsis development and potential treatment strategies.…”

Interpreting biologically informed neural networks for enhanced proteomic biomarker discovery and pathway analysis

“…6 ). Additionally, the BINN highlighted several pathways with relevance to ARDS such as the G-coupled protein receptors-pathway 49 , which contributed to the Signal Transduction pathway as being one of the most important (Fig. 6) .…”

S100A8/A9hi neutrophils induce mitochondrial dysfunction and PANoptosis in endothelial cells via mitochondrial complex I deficiency during sepsis

“…During sepsis, neutrophils are often the first immune cells to be recruited to infected sites [ 7 ]. Calprotectin (S100a8/a9), a heterodimeric Ca 2+ -binding protein mainly released by neutrophils, is thought to induce prolonged inflammation and endothelial injury through binding with its receptors, including toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE) [ 8 – 10 ].…”