Autoimmunity, cancer and COVID-19 abnormally activate wound healing pathways: critical role of inflammation

Abstract

Recent evidence indicates that targeting IL-6 provides broad therapeutic approaches to several diseases. In patients with cancer, autoimmune diseases, severe respiratory infections [e.g. coronavirus disease 2019 (COVID-19)] and wound healing, IL-6 plays a critical role in modulating the systemic and local microenvironment. Elevated serum levels of IL-6 interfere with the systemic immune response and are associated with disease progression and prognosis. As already noted, monoclonal antibodies blocking either IL-6 or binding of IL-6 to receptors have been used/tested successfully in the treatment of rheumatoid arthritis, many cancer types, and COVID-19. Therefore, in the present review, we compare the impact of IL-6 and anti-IL-6 therapy to demonstrate common (pathological) features of the studied diseases such as formation of granulation tissue with the presence of myofibroblasts and deposition of new extracellular matrix. We also discuss abnormal activation of other wound-healing-related pathways that have been implicated in autoimmune disorders, cancer or COVID-19.

Keywords: Cancer stroma; Granulation tissue; IL-6; Inflammation; Myofibroblast; Peripheral nerve injury; Rheumatoid arthritis; SARS-CoV-2; Wound healing.

Fig. 1

Active scar contains numerous α-smooth muscle actin (SMA)-positive myofibroblasts surrounded by extracellular matrix (a). Myofibroblasts and infiltrating immune cells produce IL-6 (b) and TGF-β1 (c); specificity of the reaction was verified by negative (isotype) control (d). While numerous SMA-positive fibroblasts can be isolated from an early active scar (e), the fibroblasts prepared from a quiescent scar are devoid of SMA expression (f). Nuclei are counterstained with DAPI (scale bar, 100 µm)

Fig. 2

Longitudinal cryostat sections through rat sciatic nerve distal to compression for 14 days (a–d). The sections were immunostained with rabbit polyclonal anti-IL-6 (a), anti-IL-6R (b), anti-gp130 (c) or anti-STAT3 (d) (all red signals). Arrowheads indicate the position of activated Schwann cells that displayed immunopositive staining. Representative sections through the fourth lumbar dorsal root ganglion were removed from intact rats (e, g, i, k) and those operated on triplet ligature to compress the sciatic nerve for 14 days (f, h, j, l). The sections were immunostained with rabbit polyclonal antibodies against IL-6 (e, f), IL-6R (g, h), gp130 (i, j) or STAT3 (k, l). Cell nuclei were stained using Hoechst [scale bars, 35 µm (a–d) and 30 µm (e–l), respectively]

Fig. 3

Numerous fibroblasts isolated from the skin metastasis of cutaneous malignant melanoma exhibit α-smooth muscle actin (SMA, red signal). These fibroblasts/myofibroblasts also produce extracellular matrix molecule fibronectin (green signal). Nuclei were counterstained with DAPI (scale bar, 100 µm)

Fig. 4

Comparative analysis of a lung abscess (a1–g1) and lungs destructed by COVID-19 (a2–g2). The structure of the lungs is seriously altered in patients suffering from both diseases, as visible in the figures depicting haematoxylin and eosin staining (a1, a2). Negative control using isotype control antibodies (b1, b2) is included to confirm specificity of the following immunohistochemical reactions using horse radish peroxidase (HRP)-tagged antibodies and AEC (red) substrate. Expression of IL-6 was significantly lower in the lungs of the patient without COVID-19 (c1) than in the lungs of the patient with COVID-19 (c1). A similar trend was observed for the expression of TGF-β1 (d1, d2), type I collagen (e1, e2) and fibronectin (f1, f2). While in the non-COVID lungs SMA expression was limited to the smooth muscle cells in the wall of vessels and bronchiole (g1), numerous SMA-positive myofibroblasts were found in the COVID-19 lungs (g2). The presence of type I collagen in peribronchial fibrous tissue (h1) and SMA in vessels (h2) was visualized in the positive control confirming reactivity of primary antibodies. Nuclei were counterstained with Gill’s haematoxylin (scale bar, 100 µm)

Fig. 5

Interleukin-6 (IL-6) signalling can be therapeutically regulated at several checkpoints. (1) The production of IL-6 can be diminished (e.g. using curcumin). (2) Once released, the bioavailability of IL-6 can be diminished by neutralizing antibodies (mAb) (e.g. siltuximab). (3) Another therapeutic approach can be based on targeting the interleukin-6 receptor (IL-6R) and/or its soluble form (sIL-6R) (e.g. tocilizumab, sarilumab). This can prevent IL-6R from binding to the cytokine IL-6 and formation of the active cytokine–receptor complex. Alternatively, antibodies or small-molecule inhibitors against the receptor or signal transducer gp130 can prevent the binding of the activated complex (IL-6/IL-6R or IL-6/sIL-6R) to signal transducer glycoprotein gp130 (e.g. bazedoxifene). (4) Antibodies raised against epitopes of signal transducer gp130 can also prevent the binding of the activated complexes (IL-6/IL-6R or IL-6/sIL-6R) (e.g. B-R3). (5) The soluble form of the signal transducer molecule (sgp130) binds the active complex of IL-6/sIL-6R (e.g. olamkicept). This has an inhibitory effect on trans-signalling by reduction of available sIL-6R. It can also help to sequestrate free IL-6. (6) Inhibitors of gp130 kinase activity prevent phosphorylation (P) of downstream signalling molecules (JAKs, STATs, PI3K, MAPK) (e.g. baricitinib), with their consequent translocation to the nucleus, where they regulate target gene transcription. Examples of drugs were selected from Španko et al. (2021)

Fig. 6

The diagram demonstrates the role of inflammation (with emphasis on IL-6) in wound healing, cancer and severe/critical COVID-19 infection. While wound re-epithelization arrests the activity of granulation tissue and reduces inflammation, this negative feedback fails to act in the case of cancer and severe/critical COVID-19, worsening the prognosis of patients