Fig. 9: Proposed mechanisms of CXCR4hi neutrophil phenotype in skin inflammation.
From: CREB1-driven CXCR4hi neutrophils promote skin inflammation in mouse models and human patients
This study provides insights into the development and role of CXCR4hi neutrophils in skin inflammation. Compared to CXCR4lo neutrophils, CXCR4hi neutrophils exhibit increased capacity for NETs formation, phagocytosis, and degranulation, as well as higher expression of pro-inflammatory mediators, supported by activated glycolysis. CXCR4 expression on neutrophils is induced by CXCL12, IL-25, and TNF, which requires de novo mRNA and protein synthesis and intracellular protein transport, but is not stored in neutrophil granules and regulated by degranulation. CREB1 is activated by phosphorylation on Ser-133 upon stimulation, enabling interaction with its coactivator protein CBP to initiate transcription of CREB-responsive genes, thereby contributing to CXCR4 expression and CXCR4hi neutrophils in skin inflammation. Our data further emphasize the crucial role of CXCR4hi neutrophils in promoting vascular remodeling through lactate and MMP-9 release (B), facilitating immune cell infiltration into tissues, and increasing inflammatory responses (A). Moreover, we identify the CXCR4/CXCL12 axis as a potential therapeutic target for inflammatory skin diseases, with a focus on CREB1, CXCR4/CXCL12, or the formation of NETs. CBP, CREB-binding protein; EC, endothelial cell; MMP9, matrix metallopeptidase 9; NETs; neutrophil extracellular traps; PAD4 i, PAD4 inhibitor. Created with BioRender.com.
