The chemokines CXCL8 and CXCL12: molecular and functional properties, role in disease and efforts towards pharmacological intervention

Abstract

Chemokines are an indispensable component of our immune system through the regulation of directional migration and activation of leukocytes. CXCL8 is the most potent human neutrophil-attracting chemokine and plays crucial roles in the response to infection and tissue injury. CXCL8 activity inherently depends on interaction with the human CXC chemokine receptors CXCR1 and CXCR2, the atypical chemokine receptor ACKR1, and glycosaminoglycans. Furthermore, (hetero)dimerization and tight regulation of transcription and translation, as well as post-translational modifications further fine-tune the spatial and temporal activity of CXCL8 in the context of inflammatory diseases and cancer. The CXCL8 interaction with receptors and glycosaminoglycans is therefore a promising target for therapy, as illustrated by multiple ongoing clinical trials. CXCL8-mediated neutrophil mobilization to blood is directly opposed by CXCL12, which retains leukocytes in bone marrow. CXCL12 is primarily a homeostatic chemokine that induces migration and activation of hematopoietic progenitor cells, endothelial cells, and several leukocytes through interaction with CXCR4, ACKR1, and ACKR3. Thereby, it is an essential player in the regulation of embryogenesis, hematopoiesis, and angiogenesis. However, CXCL12 can also exert inflammatory functions, as illustrated by its pivotal role in a growing list of pathologies and its synergy with CXCL8 and other chemokines to induce leukocyte chemotaxis. Here, we review the plethora of information on the CXCL8 structure, interaction with receptors and glycosaminoglycans, different levels of activity regulation, role in homeostasis and disease, and therapeutic prospects. Finally, we discuss recent research on CXCL12 biochemistry and biology and its role in pathology and pharmacology.

Elevated Plasma CXCL8 Concentrations in Significant Fibrosis but Not in Subclinical Rejection After Adult Liver Transplantation

“…17 Higher CXCL8 concentrations have also been reported in a variety of liver inflammatory conditions as well as nonliver inflammatory conditions, for example, severe sepsis or cancer, and are not specific for an alloimmune response, including chronic liver diseases, such as alcoholic liver disease, cholestatic liver diseases, and chronic hepatitis C infection. [13][14][15]18,19 Serum CXCL8 concentrations in the context of chronic liver diseases have been closely linked to cirrhosis, in a previous study with patients with chronic liver disease, and no cirrhosis had CXCL8 serum concentrations comparable to healthy individuals which further supports the association of CXCL8 with fibrosis in our study rather than subclinical inflammation. 15 In the adult liver transplantation field, 1 prospective study analyzed CXCL8 concentrations in 317 samples from 19 patients.…”

“…CXCL8 (formerly known as interleukin-8) is perhaps the most potent neutrophil-attracting chemokine and is produced not only by leukocytes but also by almost any cell that responds to inflammatory stimuli, including hepatocytes. 13,14 In addition to its neutrophil chemoattractant activity, CXCL8 is a potent inducer of smooth muscle and primary hepatic stellate cells and plays an important role in the development of fibrosis. [13][14][15] This is in line with our findings that patients with significant fibrosis had borderline higher concentrations of plasma CXCL8.…”

1,25-dihydroxyvitamin D3 potentiates the innate immune response of peripheral blood mononuclear cells from Japanese Black cattle

“…3). CXCL8 is a chemokine that recruits neutrophils and plays a vital role in the eradication of bacterial infections (Cambier et al, 2023). Meanwhile, the NOS2 gene encodes iNOS, which generates NO that is crucial for eliminating intracellular bacteria such as mycobacteria (Boylan et al, 2020).…”

1,25‐Dihydroxyvitamin D3 potentiates the innate immune response of peripheral blood mononuclear cells from Japanese Black cattle

“…In contrast to previous studies in humans and mice (Khoo et al, 2011; Zhang et al, 2012), 1,25(OH) 2 D 3 did not affect that of TNF in the bovine PBMC (Figure 3). CXCL8 is a chemokine that recruits neutrophils and plays a vital role in the eradication of bacterial infections (Cambier et al, 2023). Meanwhile, the NOS2 gene encodes iNOS, which generates NO that is crucial for eliminating intracellular bacteria such as mycobacteria (Boylan et al, 2020).…”