A critical role of AREG for bleomycin-induced skin fibrosis

Abstract

We report our discovery of an important player in the development of skin fibrosis, a hallmark of scleroderma. Scleroderma is a fibrotic disease, affecting 70,000 to 150,000 Americans. Fibrosis is a pathological wound healing process that produces an excessive extracellular matrix to interfere with normal organ function. Fibrosis contributes to nearly half of human mortality. Scleroderma has heterogeneous phenotypes, unpredictable outcomes, no validated biomarkers, and no effective treatment. Thus, strategies to slow down scleroderma progression represent an urgent medical need. While a pathological wound healing process like fibrosis leaves scars and weakens organ function, oral mucosa wound healing is a scarless process. After re-analyses of gene expression datasets from oral mucosa wound healing and skin fibrosis, we discovered that several pathways constitutively activated in skin fibrosis are transiently induced during oral mucosa wound healing process, particularly the amphiregulin (Areg) gene. Areg expression is upregulated ~ 10 folds 24hrs after oral mucosa wound but reduced to the basal level 3 days later. During bleomycin-induced skin fibrosis, a commonly used mouse model for skin fibrosis, Areg is up-regulated throughout the fibrogenesis and is associated with elevated cell proliferation in the dermis. To demonstrate the role of Areg for skin fibrosis, we used mice with Areg knockout, and found that Areg deficiency essentially prevents bleomycin-induced skin fibrosis. We further determined that bleomycin-induced cell proliferation in the dermis was not observed in the Areg null mice. Furthermore, we found that inhibiting MEK, a downstream signaling effector of Areg, by selumetinib also effectively blocked bleomycin-based skin fibrosis model. Based on these results, we concluded that the Areg-EGFR-MEK signaling axis is critical for skin fibrosis development. Blocking this signaling axis may be effective in treating scleroderma.

RETRACTED ARTICLE: Qilongtian ameliorate bleomycin-induced pulmonary fibrosis in mice via inhibiting IL-17 signal pathway

“…Previous studies have reported that IL-17 can promote inflammation and cancer development by inducing the production of factors such as CXCL5 71 . AREG can be secret by various cells, which can cause the proliferation and differentiation of fibroblasts and protect pulmonary tissue by activating the EGFR signaling pathway to inhibit TNF-α and mediating the apoptotic signaling pathway to reduce damage to alveolar epithelial cells 72 , 73 . Previous studies have reported that AREG, a target gene of IL-17, promotes the development of keratin-forming cell proliferation 74 .…”

Single-cell analysis of human skin identifies CD14+ type 3 dendritic cells co-producing IL1B and IL23A in psoriasis

“…We then asked whether there was a specific marker expression pattern associated with IL1B / IL23A -coexpressing cells, and found that they were characterized by CD83 , an activation marker for DCs ( Zhou and Tedder, 1995 ), AREG and EREG associated with fibrosis ( Zhang et al, 2021 ), and the receptors for glucose and lipids, OLR1 and SLC2A3 ( Yu et al, 2010 ; Fig. 6 f ).…”

Bioinformatic analysis of biological changes involved in pelvic organ prolapse

“…[37] It upregulates fibrosis, a pathological wound healing process, during the development of bleomycin-induced cutaneous fibrosis and is associated with elevated cell proliferation in the dermis. [38] CDKN1A and ATF3 may be involved in the progression of POP through multiple pathways. The progression of POP is closely related to apoptosis, [39] DNA repair, [8] autophagy, [40] and the onset of senescence.…”

“…[37] It upregulates fibrosis, a pathological wound healing process, during the development of bleomycin-induced cutaneous fibrosis and is associated with elevated cell proliferation in the dermis. [38]…”