Wound healing: insights into autoimmunity, ageing, and cancer ecosystems through inflammation and IL-6 modulation

Abstract

Wound healing represents a complex and evolutionarily conserved process across vertebrates, encompassing a series of life-rescuing events. The healing process runs in three main phases: inflammation, proliferation, and maturation/remodelling. While acute inflammation is indispensable for cleansing the wound, removing infection, and eliminating dead tissue characterised by the prevalence of neutrophils, the proliferation phase is characterised by transition into the inflammatory cell profile, shifting towards the prevalence of macrophages. The proliferation phase involves development of granulation tissue, comprising fibroblasts, activated myofibroblasts, and inflammatory and endothelial cells. Communication among these cellular components occurs through intercellular contacts, extracellular matrix secretion, as well as paracrine production of bioactive factors and proteolytic enzymes. The proliferation phase of healing is intricately regulated by inflammation, particularly interleukin-6. Prolonged inflammation results in dysregulations during the granulation tissue formation and may lead to the development of chronic wounds or hypertrophic/keloid scars. Notably, pathological processes such as autoimmune chronic inflammation, organ fibrosis, the tumour microenvironment, and impaired repair following viral infections notably share morphological and functional similarities with granulation tissue. Consequently, wound healing emerges as a prototype for understanding these diverse pathological processes. The prospect of gaining a comprehensive understanding of wound healing holds the potential to furnish fundamental insights into modulation of the intricate dialogue between cancer cells and non-cancer cells within the cancer ecosystem. This knowledge may pave the way for innovative approaches to cancer diagnostics, disease monitoring, and anticancer therapy.

Keywords: IL-6; cancer-associated fibroblasts; granulation tissue; myofibroblasts; wound healing.

Figure 1

Schematic presentation of events associated with wound healing over time. The relationship between the presence of inflammatory cells, fibroblasts, myofibroblasts, and reepithelisation across different phases of wound healing is shown.

Figure 2

Schematic presentation of the differences between normal fibroblasts and activated fibroblasts associated with wound healing, scar formation, autoimmunity, and cancer. Fibroblasts from pathological conditions exhibit similar characteristics.

Figure 3

Illustrates the similarities between events in wound repair and cancer. The granulation tissue of the wound/tumour stroma is composed of fibroblasts/cancer-associated fibroblasts (CAFs), macrophages/tumour-associated macrophages (TAMs), and endothelial cells (ECs). Both granulation tissue and stromal elements communicate with normal/malignant epithelial cells through the production of extracellular matrix (ECM) and paracrine secretion of cytokines such as IL-6 and others. While the dialogue between cells of granulation tissue and the proliferating epithelium is switched off after reepithelisation, the unlimited proliferation of cancer cells stimulates further development of stromal tissue. This process leads to the progression of the tumour, its spreading, and subsequent wasting of patients (A). The hierarchy of the steps is disorganised in cancer compared to wound healing (B).