The immunological function of CXCR2 in the liver during sepsis

Abstract

Background The chemokine receptor CXCR2 and its ligands, especially CXCL8, are crucial mediators for the progression of liver inflammation and liver failure in sepsis. Neutrophils have the highest CXCR2 expression in mice and humans, and their activation via CXCL8 facilitates their migration to the inflamed liver for the clearance of the pathogens and, in turn, the inflammation. Main body In sepsis, the inflammatory insult causes extensive neutrophil migration to the liver that overwhelms the immune response. To compensate for the strong receptor activation, CXCR2 desensitizes, incapacitating the immune cells to efficiently clear pathogens, causing further life-threatening liver damage and uncontrolled pathogen spread. Conclusion CXCR2 function during infection strongly depends on the expressing cell type. It signals pro- and anti-inflammatory effects that may prompt novel cell-type-specific CXCR2-directed therapeutics.

Novel Anti-Enterovirus A71 Compounds Discovered by Repositioning Antivirals from the Open-Source MMV Pandemic Response Box

“…Danirixin and Plerixafor are antagonists of CXCR2 and CXCR4 chemokine receptors, respectively. CXCR2 and CXCR4 are G protein-coupled receptors (GPCR) engaging with several downstream signaling pathways that facilitate various tissue-dependent signals, including cell migration, adhesion, proliferation, survival, and differentiation [ 47 , 48 ]. It has been reported that CXCR2 and CXCR4 can induce apoptosis [ 48 , 49 ].…”

“…CXCR2 and CXCR4 are G protein-coupled receptors (GPCR) engaging with several downstream signaling pathways that facilitate various tissue-dependent signals, including cell migration, adhesion, proliferation, survival, and differentiation [ 47 , 48 ]. It has been reported that CXCR2 and CXCR4 can induce apoptosis [ 48 , 49 ]. Apoptosis regulation is important in EV-A71 replication [ 50 ].…”

Activation of bradykinin receptor B1 promotes desensitization of CXCR2 in neutrophils during severe sepsis and contributes to disease progression in mice

“…In SIRS, elevated proinflammatory cytokines and widespread accumulation of inflammatory cells in vital organs can lead to organ failure, tissue damage and death. Neutrophils, the first line of defense against infection (2, 3), rely on the activation of CXCR2 receptors to effectively migrate to the site of infection (4). However, in sepsis, overproduction of proinflammatory mediators and increased activation of pattern recognition receptors trigger PI3Kγ, leading to phosphorylation of G protein-coupled receptor kinases (GRKs), that can desensitize CXCR2 on neutrophils (4).…”

“…Neutrophils, the first line of defense against infection (2, 3), rely on the activation of CXCR2 receptors to effectively migrate to the site of infection (4). However, in sepsis, overproduction of proinflammatory mediators and increased activation of pattern recognition receptors trigger PI3Kγ, leading to phosphorylation of G protein-coupled receptor kinases (GRKs), that can desensitize CXCR2 on neutrophils (4). Reduced CXCR2 expression together with overexpression of CCR2 impairs neutrophil migration to the site of infection and favors their accumulation in the microvasculature of various organs, leading to multiple organ dysfunction syndrome (2, 3).…”