CXCL5/CXCR2 Axis Related to Neutrophilic Inflammation in Ulcerative Colitis: A Comprehensive Analysis Integrating...

An excessive inflammatory response plays a central role in the pathogenesis of ulcerative colitis (UC), but the specific cytokines involved remain unclear. This study aimed to identify inflammatory factors associated with UC and explore the possible mechanisms of the identified targets.

Protein quantitative trait loci (pQTLs) and expression quantitative trait loci (eQTLs) for inflammatory cytokines were obtained from a genome-wide pQTL study and the eQTL consortium, respectively. Summary data for UC from the exploration and validation cohorts were derived from a genome-wide association study and the Finngen cohort. MR and colocalization analyses were conducted to identify causal associations between inflammatory cytokines and UC. Bioinformatics analyses were employed to explore the involved biological processes of candidate targets. Immunohistochemistry was used to validate the expression of these candidate targets in colon tissues.

Among all inflammatory cytokines, a significant causal association was identified between C-X-C motif chemokine ligand 5 (CXCL5) and UC. Using eQTL data, a significant genetic association was established between the mRNA expression of CXCL5 and its receptor, C-X-C motif chemokine receptor 2 (CXCR2), with UC. Colocalization analysis further supported these identified links. Differential expression analysis confirmed the dysregulation of the CXCL5/CXCR2 axis in UC patients. Enrichment and immune infiltration analysis indicated that the CXCL5/CXCR2 axis was involved in neutrophil chemotaxis and immune activation in UC. Moreover, CXCL5 expression was found to correlate with neutrophil extracellular trap (NET) formation in UC. Immunohistochemistry further confirmed the dysregulation of the CXCL5/CXCR2 axis in colon tissues of UC patients.

The CXCL5/CXCR2 axis has been implicated to play a significant role within a broader inflammatory network that includes Interleukin (IL)-17, NF-κB, and Tumor Necrosis Factor (TNF) signaling pathways. Additionally, this axis interacts with macrophages and T cells, further contributing to the complexity of inflammatory responses in UC.

There is a significant association between CXCL5/CXCR2 and UC under the MR assumption, which is potentially linked with colonic chemotaxis and activation of neutrophils. These findings highlight the potential of CXCL5/CXCR2 as a therapeutic target for UC. However, future functional studies are needed to validate these findings and explore the exact mechanisms by which CXCL5/CXCR2 influences immune cell crosstalk in UC.