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Amphiregulin, also known as AREG, is a protein synthesized as a transmembrane glycoprotein with 252 aminoacids and it is encoded by the AREG gene. in humans.
It is a critical autocrine growth factor as well as a mitogen for , , and . It is a ligand for epidermal growth factor (EGF) and it is related to TGF alpha (TGF-alpha). This protein interacts with the Epidermal growth factor receptor (EGFR) to promote the growth of normal epithelial cells.
While epithelial-derived amphiregulin can promote tissue repair, several immune cells are found to express it in cases of tissue damage, so amphiregulin is part of the crosstalk between immune and epithelial cells.
A population of immune cells that is found to increase its amphiregulin expression after tissue damage, is the innate lymphoid cell 2 (ILC2) population. This has been observed in several organs, such as the lung, the intestine, and the skin. The expression of amphiregulin by ILC2s can be induced by interleukin 33 (IL-33). Also, in skin derived ILC2s, amphiregulin expression was regulated by the interaction of killer-cell lectin-like receptor G1 (KLRG1) with E-cadherin. After intestinal damage, activated intestinal ILC2s produce amphiregulin which enhances the production of mucin by epithelial cells, increases the expression of Claudin-1 and promotes the activity of Goblet cell. These functions of amphiregulin lead to increased junction strength, as well as the strengthening of the mucus layer.
Tissue resident regulatory T cells (Tregs) can also express amphiregulin to promote tissue repair. In the skeletal muscle, the IL-33 receptor (ST2) expressing Tregs have a distinct T-cell receptor (TCR) repertoire, and TCR signals don't seem to be required for amphiregulin production, but this process can be dependent on the IL-33/ST2 (or IL-33 receptor) pathway and the expression of interleukin 18 receptor (IL-18R) on tissue resident Tregs. Also, amphiregulin that is expressed from these Tregs can further enhance their function, forming an autocrine positive feedback loop. Amphiregulin-expressing tissue resident Tregs have been observed in the lung, where most of them are CD44hiCD62Llo and they express higher levels of CD103, programmed cell death protein 1 (PD-1), glucocorticoid-induced TNFR-related protein (GITR), cytotoxic T-lymphocyte antigen 4 (CTLA-4) and KLRG1. They have been found in injured muscles, where this population has been associated with eosinophil influx, and the production of amphiregulin could enhance the colony-forming efficiency and myogenic differentiation of skeletal muscle satellite cells in vitro, increasing muscle healing. In the inflamed colon, Gata3+Helios+ Tregs express high levels of amphiregulin too. Moreover, Tregs that express amphiregulin, along with keratinocyte growth factor (KGF), CD39 and CD73, act on Parenchyma to promote tissue repair and regeneration.
Some unconventional T cells have been associated with the promotion of tissue repair by amphiregulin in a direct or in an indirect manner. After intestinal damage, mucosal-associated invariant T (MAIT) cells produce amphiregulin that leads to epithelial cell turnover and enhances the activity of goblet cells. Also, a pro-repair response by amphiregulin produced by ILC2s and Tregs, that is dependent on IL-33 signaling, is induced by gamma delta (γδ) T cells that produce interleukin 17A (IL-17A). This correlation between IL-17A-producing γδ T cells and amphiregulin has been observed in the lungs and in the oral mucosa.
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