Wound-healing defect of CD18−/− mice due to a decrease in TGF-β1 and myofibroblast differentiation

Abstract

We studied the mechanisms underlying the severely impaired wound healing associated with human leukocyte-adhesion deficiency syndrome-1 (LAD1) using a murine disease model. In CD18(-/-) mice, healing of full-thickness wounds was severely delayed during granulation-tissue contraction, a phase where myofibroblasts play a major role. Interestingly, expression levels of myofibroblast markers alpha-smooth muscle actin and ED-A fibronectin were substantially reduced in wounds of CD18(-/-) mice, suggesting an impaired myofibroblast differentiation. TGF-beta signalling was clearly involved since TGF-beta1 and TGF-beta receptor type-II protein levels were decreased, while TGF-beta(1) injections into wound margins fully re-established wound closure. Since, in CD18(-/-) mice, defective migration leads to a severe reduction of neutrophils in wounds, infiltrating macrophages might not phagocytose apoptotic CD18(-/-) neutrophils. Macrophages would thus be lacking their main stimulus to secrete TGF-beta1. Indeed, in neutrophil-macrophage cocultures, lack of CD18 on either cell type leads to dramatically reduced TGF-beta1 release by macrophages due to defective adhesion to, and subsequent impaired phagocytic clearance of, neutrophils. Our data demonstrates that the paracrine secretion of growth factors is essential for cellular differentiation in wound healing.

Differential Roles of Macrophages in Diverse Phases of Skin Repair

“…Furthermore, wounds in the neonatal PU.1 null mouse, which lacks macrophages and neutrophils (but also B cells, mast cells, eosinophils), heal without scar and, surprisingly, with a similar time course as wild-type siblings (13). However, the need of macrophages for physiological repair in adults is supported in recent wound healing studies in various murine knockout models in which impaired wound healing is associated with an attenuated number of macrophages at the wound site (14)(15)(16)(17)(18). Although all of these studies emphasize that leukocytes significantly affect the quality of the healing response, knowledge of these models is limited, because they either do not target pathways mediated exclusively by macrophages or they address a neonate repair response, which is known to differ from healing in the adult organism (19).…”

Expression of integrin β1 by fibroblasts is required for tissue repair in vivo

“…Interestingly, we found that loss of integrin 1 resulted in an increase in expression of integrin 3, providing a possible mechanistic basis for our study. It is also interesting to note that wound healing in the integrin-2-knockout mouse was similar to that in our fibroblast-specific knockout of 1 integrin (Peters et al, 2005). Here, the mechanisms underlying the severely impaired wound healing were associated with a severe reduction of neutrophils and macrophages into the wounds, causing a lack of secreted TGF1.…”

Dynamic role of myofibroblasts in oral lesions

“…Normal wound healing is a well-known phenomenon. It involves a sequence of events including inflammation, proliferation, and tissue remodelling [18,20,21] . Wound closure involves connective tissue deposition, epithelization, and contraction [22] ( Figure 2).…”