The role of CXCL8 in chronic nonhealing diabetic foot ulcers and phenotypic changes in fibroblasts: a molecular perspective

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

“…An increased positivity for CD68, MPO, and CD63 suggests the presence of macrophages (CD68), neutrophils (MPO and CD63), and activated platelets and granulocytes (CD63) [ 21 ] and is supported by the increased expression of pro-inflammatory cytokines IL-6, IL-1β, and TNF-α secreted from macrophages in DFU tissues. These findings support that chronic inflammation mediated by persistently infiltrated immune cells and secreted proinflammatory cytokines mediate impaired healing in DFUs [ 2 , 4 , 22 , 23 ]. An increased gene and protein expression of MPO and CD63 in DFU tissues support neutrophil-mediated chronic inflammation [ 24 ].…”

“…The presence of inflammation in the clean tissues is due to the site of tissue collection which was near to DFU area where acute inflammation might be mediating the healing response, but the presence of chronic inflammation suggests the presence of nearby nonhealing tissue. The presence of chronic inflammation in DFU tissues supports the notion that chronic inflammation contributes to the non-healing of DFUs [ 2 , 6 , 7 ]. Persistent inflammation mediated by infiltrating immune cells and secreted cytokines such as TNF-α induces activation of matrix metalloproteinases (MMPs) through mediators of inflammation and regulates collagen content [ 17 ], an important constituent of extracellular matrix and granulation tissue formation.…”

“…This suggests that phenotypic change in fibroblasts may mediate impaired wound healing by mediating chronic inflammation through increased secretion of IL-6 and IL-8. Since, increased expression of IL-8 is associated with nonhealing DFUs [ 2 , 5 ], and fibroblasts acquiring CD40+ secretory phenotype secrete increased IL-6 and IL-8; it is imperative to correlate changing phenotype of fibroblasts in DFUs with nonhealing. This notion is also supported by the presence of five different populations of fibroblasts and changing the density of fibroblasts in nonhealing DFU [ 5 , 34 ].…”

“…The physiological healing process is altered by the prolonged release of pro-inflammatory cytokines, including IL-6, TNF-α, IL-1, and IL-8, and the inappropriately persistent recruitment of immune cells. These factors hold the wound in the inflammatory phase without progressing to the resolution phase [ 2 , 3 , 4 , 5 ]. Studies have demonstrated the upregulation of IL-8 in diabetic wounds compared to non-diabetic populations [ 5 ].…”

“…Fibroblasts play a crucial role in wound healing, and multiple studies have reported that dysregulated function and proliferation of fibroblasts contribute to a nonhealing pattern of wound healing [ 2 , 12 ]. Following the inflammatory phase is the proliferative phase, wherein fibroblasts activate and migrate to the injury site to form granulation tissue.…”