Involvement of Epithelial-Mesenchymal Transition (EMT) in Autoimmune Diseases

Abstract

Epithelial-mesenchymal transition (EMT) is a complex reversible biological process characterized by the loss of epithelial features and the acquisition of mesenchymal features. EMT was initially described in developmental processes and was further associated with pathological conditions including metastatic cascade arising in neoplastic progression and organ fibrosis. Fibrosis is delineated by an excessive number of myofibroblasts, resulting in exuberant production of extracellular matrix (ECM) proteins, thereby compromising organ function and ultimately leading to its failure. It is now well acknowledged that a significant number of myofibroblasts result from the conversion of epithelial cells via EMT. Over the past two decades, evidence has accrued linking fibrosis to many chronic autoimmune and inflammatory diseases, including systemic sclerosis (SSc), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), and inflammatory bowel diseases (IBD). In addition, chronic inflammatory states observed in most autoimmune and inflammatory diseases can act as a potent trigger of EMT, leading to the development of a pathological fibrotic state. In the present review, we aim to describe the current state of knowledge regarding the contribution of EMT to the pathophysiological processes of various rheumatic conditions.

Keywords: Sjögren’s disease; TGF-β; adaptive immunity; autoimmune disease; chronic inflammation; epithelial to mesenchymal transition; fibrosis; innate immunity; myofibroblast; rheumatic diseases; rheumatoid arthritis; systemic lupus erythematosus; systemic sclerosis.

Figure 1

Morphological modifications during EMT. Epithelial cells are closely held together by different types of cell–cell junctions (i.e., adherens junctions and tight junctions) and form polarized sheets harboring an apico-basal polarity. The loss of E-cadherin (a key component of adherens junctions) is often considered the first event initiating EMT and is rapidly followed by the repression of other cell junction proteins such as zona occludens 1 (ZO-1), occludin, and claudin. Consequently, the dissolution of epithelial cell junctions elicits a loss of apico-basal polarity and triggers cytoskeletal modifications leading to the acquisition of a spindle-shaped morphology. The cells are pushed towards the EMT spectrum in a progressive and reversible manner, from a complete epithelial to complete mesenchymal state. Abbreviations: α-SMA: α-smooth muscle actin; CDH1: E-cadherin; EMT: epithelial–mesenchymal transition; FSP-1: fibroblast specific protein 1; MET: mesenchymal–epithelial transition; SNAI1: Snail family transcriptional repressor 1; TFs: transcription factors; TWIST1: twist family BHLH transcription factor 1; ZEB1: zinc finger E-box binding homeobox 1; ZO-1: zona occludens 1.

Figure 2

Signaling pathways regulating EMT. The encounter between specific ligands and epithelial cells results in the activation of several intracellular signaling pathways that ultimately lead to the expression of core EMT-TFs such as ZEB1/2, SNAI1/2, and TWIST1 that act pleiotropically to induce EMT. These pathways are not well compartmentalized, and some overlap exists to a certain extent between them. The canonical WNT pathway is activated upon the binding of WNT ligands to the Frizzled family of membrane receptors, ensuing the release of β-catenin from the GSK3β–AXIN-APC complex. This enables its translocation to the nucleus, thereby activating TCF and LEF-1 TFs, which promotes the expression of EMT-associated genes. The NOTCH pathway is activated upon binding of DDL or JAG ligands to the NOTCH receptor, leading to the release of the active NOTCH-ICD, which translocates to the nucleus to function as a transcriptional co-activator. The Hedgehog signaling pathway is activated by members of the Hedgehog (HH) ligand family that bind to PTCH receptor and activate SMO, which recruits GLI TFs, further entailing the transcription of EMT target genes. TGFβ activates the TGFβ family of receptors that trigger the phosphorylation and activation of cytoplasmic SMAD2 and SMAD3, which further assemble with SMAD4 to migrate to the nucleus, where they activate the transcription EMT-TFs. SMAD also interacts with β-catenin and NOTCH-ICD, enabling cross-talk between the TGF-β, WNT, and NOTCH pathways. The TGFβ pathway also collaborates with the PI3K–AKT pathway, which in turn triggers the activation of the mTOR and NF-κB and the RAS–RAF–MEK–ERK signaling axis. These pathways are also triggered by the binding of several growth factors to their cognate receptors. The binding of several cytokines to their receptors triggers the phosphorylation and activation of JAKs and STATs. STAT dimers activate the transcription of genes encoding core EMT-TFs. Abbreviations: AKT: protein kinase B; AXIN: axis inhibition protein; DHH: desert hh; DLL: Delta-like; EGF: epidermal growth factor; EMT: epithelial–mesenchymal transition; ERK: extracellular signal-regulated kinase; FGF: fibroblast growth factor; GSK-3β: glycogen synthase kinase-3β; HGF: hepatocyte growth factor; IHH: Indian Hedgehog; JAG: jagged; JAK: Janus kinase; LEF-1: lymphoid enhancer binding factor 1; MAPK: mitogen-activated protein kinase; MEK: MAP kinase; mTOR: mammalian target of rapamycin; NF-κB: nuclear factor-κB; NOTCH-ICD: NOTCH receptor intracellular domain; PI3K: phosphoinositide 3-kinase; PTCH: patched; RTKs: receptor tyrosine kinases; SHH: sonic hh; SMAD: homolog of the Drosophila protein, mothers against decapentaplegic (Mad) and the Caenorhabditis elegans protein Sma; SMO: smoothened; SNAI1: snail family transcriptional repressor 1; STAT: signal transducers and activators of transcription; TβRI: TGFβ receptor type I; TβRII: TGFβ receptor type II; TCF: T cell factor; TFs: transcription factors; TGF-β: transforming growth factor-β; TWIST1: twist family BHLH transcription factor 1; VEGF: vascular endothelial growth factor; ZEB1: zinc finger E-box binding homeobox 1.Created with Biorender.com (accessed on 20 August 2023).

Figure 3

Hypothetical contribution of EMT-like process to the pathophysiology of RA. Upon stimuli such as inflammation (IL-1β, TNF-α and IL-17) or hypoxia, several signaling pathways become activated in normal FLS present in the synovial lining. These EMT signaling pathways culminate with the production of several EMT-related TFs such as SNAI1, HIF-1α and Runx1 leading to the acquisition of more mesenchymal features. These activated FLS called RA-FLS gain migratory and invasive properties together with an increased resistance to apoptosis resulting in the generation of hyperplastic synovial lining. Abbreviations: AKT: protein kinase B; α-SMA: α-smooth muscle actin; CIA: collagen-induced arthritis; EMT: epithelial-mesenchymal transition; HIF1α: hypoxia-inducible factor 1α; IL: interleukin; MMPs: matrix metalloproteases; mTOR: mammalian target of rapamycin; NF-κB: nuclear factor-κB; PI3K: phosphoinositide 3-kinase; RA: rheumatoid arthritis; RA-FLSs: RA fibroblast-like synoviocytes; RUNX1: runt-related transcription factor 1; SMAD: homolog of the Drosophila protein, mothers against decapentaplegic (Mad) and the Caenorhabditis elegans protein Sma; SNAI1: Snail family transcriptional repressor 1; TFs: transcription factors; TGF-β: transforming growth factor-β; TNF: tumor necrosis factor. Created with Biorender.com (accessed on 20 August 2023).

Figure 4

Hypothetical contribution of EMT to the pathophysiology of pSS. Upon stimuli such as inflammation (IL-6, IL-17 and IL-22), several signaling pathways become activated in normal SGEC present in salivary glands. These EMT signaling pathways culminate with the production of several EMT-related TFs such as SNAI1, ZEB1 and ETS1 leading to the acquisition of mesenchymal features. This results in salivary gland fibrosis with the appearance of spindle-shaped morphology of SGEC together with the expression of mesenchymal markers such as vimentin, podoplanin, MMP9 and several collagen types. Abbreviations: ADAMTS: A Disintegrin And Metalloproteinase with Thrombospondin Motifs; COL3A1: collagen type III Alpha 1 chain; EMT: epithelial-mesenchymal transition; ERK: extracellular signal–regulated kinase; IL: interleukin; iSGEC: immortalized SGEC; MMPs: matrix metalloproteases; SGEC: salivary gland epithelial cells; SMAD: homolog of the Drosophila protein, mothers against decapentaplegic (Mad) and the Caenorhabditis elegans protein Sma; SNAI1: Snail family transcriptional repressor; SS: Sjögren’s syndrome; TFs: transcription factors; TGF-β: transforming growth factor-β; ZEB2: zinc finger e-box binding homeobox 2. Created with Biorender.com (accessed on 20 August 2023).