Targeting Systemic Sclerosis from Pathogenic Mechanisms to Clinical Manifestations: Why IL-6?

Abstract

Systemic sclerosis (SS) is a chronic autoimmune disorder, which has both cutaneous and systemic clinical manifestations. The disease pathogenesis includes a triad of manifestations, such as vasculopathy, autoimmunity, and fibrosis. Interleukin-6 (IL-6) has a special role in SS development, both in vascular damage and in the development of fibrosis. In the early stages, IL-6 participates in vascular endothelial activation and apoptosis, leading to the release of damage-associated molecular patterns (DAMPs), which maintain inflammation and autoimmunity. Moreover, IL-6 plays an important role in the development of fibrotic changes by mediating the transformation of fibroblasts into myofibroblasts. All of these are associated with disabling clinical manifestations, such as skin thickening, pulmonary fibrosis, pulmonary arterial hypertension (PAH), heart failure, and dysphagia. Tocilizumab is a humanized monoclonal antibody that inhibits IL-6 by binding to the specific receptor, thus preventing its proinflammatory and fibrotic actions. Anti-IL-6 therapy with Tocilizumab is a new hope for SS patients, with data from clinical trials supporting the favorable effect, especially on skin and lung damage.

Keywords: Tocilizumab; interleukin-6; pulmonary fibrosis; systemic sclerosis.

Figure 1

Potential biomarkers of organ involvement and disease features in SS. Key: TGF: transforming growth factor; GDF-15: growth differentiation factor 15; BAFF: B-cell-activating factor belonging to the tumor necrosis factor family; APRIL: a proliferation-inducing ligand; MMP: matrix metalloproteinases; BNP: brain natriuretic peptide; NT-proBNP: N-terminal-pro hormone BNP; CTG: connective tissue growth factor; mRSS: modified Rodnan total skin thickness score; ILD: interstitial lung disease; IL-6: interleukin 6; DLCO: diffusing capacity of carbon monoxide; PAH: pulmonary arterial hypertension; ICAM-1: intercellular adhesion molecule 1; dcSSc: diffuse cutaneous systemic sclerosis; VEGF: vascular endothelial growth factor; lcSSc: limited cutaneous systemic sclerosis; KL-6: krebs von den Lungen-6; SP-D: surfactant protein-D; CCL2: monocyte chemoattractant protein-1; CXCL4: platelet factor 4; VCAM-1: vascular cell adhesion molecule-1; CRP: C-reactive protein; sCD163: soluble CD163; anti-RNAP III antibodies: anti-RNA polymerase III antibodies; anti-M3R antibodies: anti-human muscarinic receptor M3 antibodies; miRNA let-7d: micro RNA let-7d; GPATCH2L: G-patch domain-containing protein 2-like; CTNND2: catenin delta 2.

Figure 2

The intracellular signaling pathways of IL-6 and the main negative feedback loops that block the production of its biological effects. Key: IL-6: interleukin-6; IL-6R: interleukin-6 receptor; sIL-6R: soluble interleukin-6 receptor; gp130: glycoprotein 130; Jak: janus kinase; STAT: signal transducer and activator of transcription proteins; SOCS3: cytokine 3 signaling suppressor; PIAS3: protein inhibitor of activated STAT 3; ADAM: disintegrin metalloproteases; MCP: monocyte chemoattractant protein-1.

Figure 3

The action of IL-6 on various cells and its local and systemic manifestations. Key: IL-6: interleukin 6; CD: cluster of differentiation; CRP: C-reactive protein; RANKL: activator receptor of nuclear factor kappa-B ligand; VEGF: vascular endothelial growth factor; Treg: regulatory T cells.

Figure 4

Systemic harmful effects of IL-6 on the skin, cardiopulmonary, gastrointestinal and renal system. Key: IL-6, interleukin-6; ADAM17: disintegrin metalloproteases 17; PAH: pulmonary arterial hypertension; DLCO: diffusing capacity of lung for carbon monoxide; FVC: forced vital capacity.