Causal correlation between inflammatory cytokines and hypertrophic scar based on two-sample Mendelian randomization

Abstract

Hypertrophic scars result from the abnormal proliferation of fibroblasts and the accumulation of collagen after skin injury. In this process, inflammatory cytokines act as crucial regulators. The large − scale release of inflammatory cytokines aberrantly activates fibroblasts. It promotes the proliferation of fibroblasts and the synthesis of collagen, and simultaneously inhibits collagen degradation. The purpose of this study is to investigate the causal correlation between inflammatory cytokines and hypertrophic scars (HS). This study applied a two-sample Mendelian randomization approach (TSMR), leveraging summarized data gathered by genome-wide association studies (GWAS). The inflammatory cytokines (8293 samples) and hypertrophic scar (HS, 207,482 samples) summary data were analyzed to figure out whether there was a causal connection of the two.The inverse variance-weighted (IVW) method was implemented to undertake causal analysis, also sensitivity, heterogeneity, and pleiotropy analyses were performed to further evaluate the results’ stability and dependability.Two inflammatory cytokines, IL-2 and CCL4, were identified as being associated with HS. The IVW analysis demonstrated a positive relationship between IL-2 and the risk of HS (OR = 1.51, 95 % CI = 1.06–2.15, P = 0.02), indicating that IL-2 is a risk factor for hypertrophic scarring, with elevated levels potentially promoting disease progression. In contrast, CCL4 was negatively associated with HS risk (OR = 0.86, 95 % CI = 0.74–0.99, P = 0.03), pointing to the fact CCL4 might function as a protective agent, where lower levels of CCL4 could inhibit scar formation. Sensitivity analyses verified the dependability of the TSMR results (P > 0.05). Our MR analysis indicates a causal correlation between inflammatory cytokines and hypertrophic scars. Specifically, IL-2 promotes hypertrophic scar formation, whereas CCL4 exerts a protective effect, reducing the risk of scar formation. These discoveries imply that inflammatory cytokines have a considerable part to play in the pathogenesis of hypertrophic scarring through modulating its formation.