SIRL-1 deficiency reveals pro-inflammatory IL-8 axis in inflammatory bowel disease: a novel diagnostic ratio

Inflammatory Bowel Disease (IBD), including Ulcerative Colitis and Crohn's Disease, is characterized by chronic intestinal inflammation, neutrophil infiltration and elevated pro-inflammatory cytokines like Interleukin-8 (IL-8). While pro-inflammatory mechanisms are well-studied, the contribution of intrinsic inhibitory immune checkpoints to IBD pathogenesis is less understood. This study aimed to assess the expression and function of Signal Inhibitory Receptor on Leukocytes-1 (SIRL-1) in IBD and to evaluate the diagnostic utility of the SIRL-1/IL-8 ratio.

Peripheral venous blood was collected from 90 participants (IBD patients and healthy volunteers). Neutrophil SIRL-1 protein expression was quantified by flow cytometry, while VSTM1 (SIRL-1 gene) and IL-8 messenger RNA levels were measured by RT-qPCR. Serum IL-8 concentrations were determined using a flow cytometry microbead array. Statistical analyses included Mann-Whitney U tests, Kruskal-Wallis tests, Spearman correlations, and Receiver Operating Characteristic (ROC) curve analysis.

IBD patients exhibited significant downregulation of SIRL-1 protein and VSTM1 messenger RNA in peripheral blood neutrophils. This downregulation was constitutive in Crohn's Disease, irrespective of disease activity. Conversely, serum IL-8 levels were significantly elevated in IBD cohort, driven primarily by the active Ulcerative Colitis subgroup, whereas Crohn's Disease patients did not show significant elevation. A significant inverse correlation was observed between neutrophil SIRL-1 expression and serum IL-8 (r = -0.5789, p = 0.0118). Crucially, the SIRL-1/IL-8 ratio demonstrated superior diagnostic accuracy for distinguishing IBD from healthy controls (AUC = 0.82), outperforming individual markers, and was notably effective in Crohn's Disease (AUC = 0.86).

Deficiency in SIRL-1 appears to be a permissive factor for the pro-inflammatory IL-8 axis in IBD. The SIRL-1/IL-8 ratio represents a promising novel diagnostic biomarker that presents enhanced precision by reflecting the imbalance between immune regulation and inflammation. Notably, this ratio revealed superior diagnostic value in Crohn's Disease despite the lack of significant IL-8 elevation, highlighting its utility in capturing intrinsic immune defects.