Increased Population of CD40+ Fibroblasts Is Associated with Impaired Wound Healing and Chronic Inflammation in Diabetic Foot Ulcers

Abstract

Despite the advancement in the treatment, nonhealing diabetic foot ulcers (DFUs) are an important clinical issue accounting for increased morbidity and risk of amputation. Persistent inflammation, decreased granulation tissue formation, decreased neo-angiogenesis, and infections are common underlying causes of the nonhealing pattern. Fibroblasts play a critical role in granulation tissue formation and angiogenesis and mediate wound healing how fibroblasts regulate inflammation in nonhealing DFUs is a question to ponder. This study aims to investigate the expression of a de-differentiated subpopulation of fibroblasts which are CD40+ (secretory fibroblasts) and increased secretion of IL-6 and IL-8 but have never been reported in DFUs. We characterized 11 DFU tissues and nearby clean tissues histologically and for the presence of inflammation and CD40+ fibroblasts using immunohistochemistry and RT-PCR. The results revealed significantly increased density of CD40+ fibroblasts and differential expression of mediators of inflammation in DFU tissues compared to clean tissue. Increased expression of IL-6, IL-1β, and TNF-α in DFU tissues along with CD40+ fibroblast suggest that CD40+ fibroblasts in DFUs contribute to the chronicity of inflammation and targeting fibroblasts phenotypic switch to decrease secretory fibroblasts may have therapeutic significance to promote healing.