Inflammation and neuropeptides: the connection in diabetic wound healing

Abstract

Abnormal wound healing is a major complication of both type 1 and type 2 diabetes, with nonhealing foot ulcerations leading in the worst cases to lower-limb amputation. Wound healing requires the integration of complex cellular and molecular events in successive phases of inflammation, cell proliferation, cell migration, angiogenesis and re-epithelialisation. A link between wound healing and the nervous system is clinically apparent as peripheral neuropathy is reported in 30-50% of diabetic patients and is the most common and sensitive predictor of foot ulceration. Indeed, a bidirectional connection between the nervous and the immune systems and its role in wound repair has emerged as one of the focal features of the wound-healing dogma. This review provides a broad overview of the mediators of this connection, which include neuropeptides and cytokines released from nerve fibres, immune cells and cutaneous cells. In-depth understanding of the signalling pathways in the neuroimmune axis in diabetic wound healing is vital to the development of successful wound-healing therapies.

Fig 1. Overview of diabetic wound healing

Diabetes leads to neuropathy, peripheral vascular disease and chronic low grade inflammation, both systemically and peripherally. Neuropathy and chronic low grade inflammation together blunt the acute focused inflammatory response to injury and together with peripheral vascular disease lead to impaired wound healing.

Fig. 2. Effect of diabetic neuropathy and inflammatory dysregulation on wound healing

Diabetes leads to neuropathy and inflammatory dysregulation which manifests in decreased neuropeptide expression and imbalance in the inflammatory cytokine response. Neuropeptides directly affect leukocytes and monocytes thereby further contributing to the imbalance in cytokine expression. In addition, neuropeptides and cytokines also directly affect endothelial cells and keratinocytes thereby reducing their proliferation and leading to decreased angiogenesis, and re-epithelization. Along with decreased angiogenesis, re-epithelization and dysregulation in the remodeling and extracellular matrix deposition affected by disrupted cytokine expression; the final outcome is abnormal wound healing.