Bacterial colonization contributes to pathological scar formation via the regulation of inflammatory response.

BACKGROUND: It has been established that inflammatory factors are involved in the formation of pathological scars. Therefore, pathological scars are regarded to be highly associated with chronic inflammation, whereas what factors contribute to this inflammation remains unclear. OBJECTIVE: To confirm that bacterial colonization is involved in the formation of pathological scars, and to reveal that the persistent inflammatory response mediated by macrophages due to bacterial colonization promotes scar formation. METHODS: This study included 23 normal skin controls and 58 untreated pathological scar samples. To detect the presence of bacteria in surgically-excised scar samples and alterations of histology, as well as bacteria-associated gene levels, histological staining, immunoelectron microscopy, microbiological and cell culture and molecular biology detection methods were employed. The PICRUSt2 tool and BugBase were employed to identify pathways, genes, and phenotypic differences. RESULTS: We found that in pathological scars, bacteria were widely distributed both extracellularly and intracellularly, with intracellular bacteria primarily located in the cytoplasm of macrophages and fibroblasts. A total of 2,260 bacterial species were detected in pathological scars, primarily from the Clostridiales, Burkholderiales, Actinomycetales, and Bacteroidales orders. Moreover, the pathogenicity and motility of colonizing bacteria were positively correlated with the degree of scar hyperplasia and invasiveness. The lysates of four clinically-relevant bacterial species had differential effects on the secretion of inflammatory cytokines from macrophages. When treated macrophage supernatant was added to fibroblasts, collagen secretion was dysregulated, and fibroblast differentiation into myofibroblasts prominently increased. In rat scar model, the expression of inflammatory factors and growth factors in the scar tissue was increased, which activated the TGF-β/Smad signaling pathway, resulting in the increasing of α-SMA. CONCLUSIONS: Persistent activation of macrophages by tissue-colonizing bacteria may be a key factor in promoting inflammatory response and dysregulated collagen deposition in pathological scars, offering a potential new strategy for preventing and treating pathological scars.