Role in tissue repair Generally, amphiregulin is considered to be a part of type 2 mediated resistance and tolerance, the latter of which occurs by promoting the reestablishment of tissue integrity after damage that is due to acute or chronic inflammation. Its involvement in tissue repair can be explained by its dual role, as amphiregulin can induce mitogenic signals, but it can also lead to cell differentiation of
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 cells. These functions of amphiregulin lead to increased junction strength, as well as the strengthening of the mucus layer. 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
CD44hi
CD62Llo 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. Moreover, Tregs that express amphiregulin, along with
keratinocyte growth factor (KGF),
CD39 and
CD73, act on
parenchymal cells to promote tissue repair and regeneration.
Cancer Overexpression of amphiregulin is connected with cancer of the breast, prostate, colon, pancreas, lung, spleen, and bladder.
Fibrosis Chronic elevation of amphiregulin levels has been associated with
fibrosis in several organs.
ILC2s are drivers of liver, skin, and pulmonary fibrosis, and their expression of
interleukin 13 (IL-13) and amphiregulin is implicated in this process. Moreover, macrophage-derived amphiregulin is involved in the
transforming growth factor beta (TGF-β)-induced fibrosis too, as it has been found to activate latent TGF-β through the activation of integrin-αV complex. In the liver, ongoing necrosis leads to the activation of hepatic ILC2s which release amphiregulin along with IL-13. The release of them activates the
hepatic stellate cells that transform into
myofibroblasts, and ultimately promotes liver fibrosis. == Inflammation ==