Fibrosis is a common and intractable condition associated with various pathologies. It is characterized by accumulation of an excessive amount of extracellular matrix molecules that primarily include collagen type I. IL-6 is a profibrotic cytokine that is elevated in the prototypic fibrotic autoimmune condition systemic sclerosis and is known to induce collagen I expression, but the mechanism(s) behind this induction are currently unknown. Using healthy dermal fibroblasts in vitro, we analyzed the signaling pathways that underscore the IL-6-mediated induction of collagen. We show that IL-6 trans signaling is important and that the effect is dependent on STAT3; however, the effect is indirect and mediated through enhanced TGF-β signaling and the classic downstream cellular mediator Smad3. This is due to induction of the bone morphogenetic protein (BMP) antagonist Gremlin-1, and we show that Gremlin-1 is profibrotic and is mediated through canonical TGF-β signaling.

SSc is an autoimmune disease characterized by inflammation and extracellular matrix deposition that ultimately leads to loss of organ function. T cells appear to play a prominent role in its pathogenesis. The evidence for this comes from their being at the site of fibrosis, their activated phenotype and alteration in their number and frequency in peripheral blood. This review examines the role of T cells in the pathogenesis of SSc and specifically examines the key soluble profibrotic mediators (IL-4, IL-6, IL-13) secreted by Th2 cells and their interactions with fibroblasts that deposit excess extracellular matrix leading to fibrosis. We finally examine possible therapeutic options in targeting T-cell mediators to disrupt the cellular interactions between T cells and fibroblasts that serve to drive the fibrotic response. One of the factors driving fibrosis is IL-6 and this can be neutralized in vivo not only to limit IL-6-driven tissue fibrosis but concomitantly to suppress switching of Tregs to Th17 T cells that will provide more IL-6, thus perpetuating the fibrosis. Taken together, these data implicate the role of T cells in SSc and suggest that Th2-polarized T cells and the fibrotic mediators subsequently released directly induce fibrosis. Targeting such cytokines may be therapeutic not only in SSc but more generally in diseases where fibrosis is directed by inflammatory signals.

Summary: Systemic sclerosis (SSc) is an idiopathic systemic autoimmune disease. It is characterized by a triad of hallmarks: immune dysfunction, fibrosis and vasculopathy. Immune dysfunction in SSc is characterized by the activation and recruitment of immune cells and the production of autoantibodies and cytokines. How immune abnormalities link the fibrosis and vasculopathy in SSc is poorly understood. A plethora of immune cell types are implicated in the immunopathogenesis of SSc, including T cells, B cells, dendritic cells, mast cells and macrophages. How these different cell types interact to contribute to SSc is complicated, and can involve cell-to-cell interactions and communication via cytokines, including transforming growth factor (TGF)-β, interleukin (IL)-6 and IL-4. We will attempt to review significant and recent research demonstrating the importance of immune cell regulation in the immunopathogenesis of SSc with a particular focus on fibrosis.

MicroRNAs (miRNAs) are small, non-coding RNAs that mediate mRNA cleavage, translational repression or mRNA destabilisation and are around 22–25 nucleotides in length via partial complementary binding to the 3′ untranslated region in target transcripts. They are master regulators of gene expression. Fibrosis is an important cause of morbidity and mortality in the world, and there are currently no accepted treatments for fibrosis. Many novel miRNAs are now associated with fibrosis, both organ-specific and systemic, as in the prototypical fibrotic disease systemic sclerosis. Recently, the targets of these altered miRNAs have been validated and defined new biochemical pathways. Dysregulated miRNAs are amenable to therapeutic modulation. This review will examine the role of miRNAs in fibrosis and the opportunities and challenges of targeting them.

Recreating the structure of human tissues in the laboratory is valuable for fundamental research, testing interventions, and reducing the use of animals. Critical to the use of such technology is the ability to produce tissue models that accurately reproduce the microanatomy of the native tissue. Current artificial cell‐based skin systems lack thorough characterisation, are not representative of human skin, and can show variation. In this study, we have developed a novel full thickness model of human skin comprised of epidermal and dermal compartments. Using an inert porous scaffold, we created a dermal construct using human fibroblasts that secrete their own extracellular matrix proteins, which avoids the use of animal‐derived materials. The dermal construct acts as a foundation upon which epidermal keratinocytes were seeded and differentiated into a stratified keratinised epithelium. In‐depth morphological analyses of the model demonstrated very close similarities with native human skin. Extensive immunostaining and electron microscopy analysis revealed ultrastructural details such as keratohyalin granules and lamellar bodies within the stratum granulosum, specialised junctional complexes, and the presence of a basal lamina. These features reflect the functional characteristics and barrier properties of the skin equivalent. Robustness and reproducibility of in vitro models are important attributes in experimental practice, and we demonstrate the consistency of the skin construct between different users. In summary, a new model of full thickness human skin has been developed that possesses microanatomical features reminiscent of native tissue. This skin model platform will be of significant interest to scientists researching the structure and function of human skin.