Microbial Pathogenesis 186 (2024) 106463 Available online 28 November 2023 0882-4010/© 2023 Elsevier Ltd. All rights reserved. Amphiregulin in infectious diseases: Role, mechanism, and potential therapeutic targets Chou-Yi Hsu a , Ahmed Faisal Mutee b , Sandra Porras c , Indira Pineda d , Mohammed Ahmed Mustafa e, f, * , Mohamed J. Saadh g, h , Mohaned Adil i , Zainab H. A j a Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan City 71710, Taiwan b Department of Pharmacy, Al-Noor University College, Nineveh, Iraq c Facultad de Mec´ anica, Escuela Superior Polit´ ecnica de Chimborazo (ESPOCH), Panamericana Sur km 1 1/2, Riobamba, 060155, Ecuador d Facultad de Salud Pública, Escuela Superior Polit´ ecnica de Chimborazo (ESPOCH), Panamericana Sur km 1 1/2, Riobamba, 060155, Ecuador e Department of Medical Laboratory Technology, Imam Jaafar AL-Sadiq University, Iraq f Department of Pathological Analyzes, College of Applied Sciences, University of Samarra, Iraq g Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan h Applied Science Research Center, Applied Science Private University, Amman, Jordan i Pharmacy College, Al-Farahidi University, Iraq j Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq A R T I C L E INFO Keywords: AREG EGFR Treg Homeostasis Viral infection Bacterial infection Helminth infection ABSTRACT Amphiregulin (AREG) serves as a ligand for the epidermal growth factor receptor (EGFR) and is involved in vital biological functions, including infammatory responses, tissue regeneration, and immune system function. Upon interaction with the EGFR, AREG initiates a series of signaling cascades necessary for several physiological ac- tivities, such as metabolism, cell cycle regulation, and cellular proliferation. Recent fndings have provided evidence for the substantial role of AREG in maintaining the equilibrium of homeostasis in damaged tissues and preserving epithelial cell structure in the context of viral infections affecting the lungs. The development of resistance to infuenza virus infection depends on the presence of type 1 cytokine responses. Following the eradication of the pathogen, the lungs are subsequently colonized by several cell types that are linked with type 2 immune responses. These cells contribute to the process of repairing and resolving the tissue injury and infammation caused by infections. Following infuenza infection, the activation of AREG promotes the regen- eration of bronchial epithelial cells, enhancing the tissue’s structural integrity and increasing the survival rate of infected mice. In the same manner, mice afficted with infuenza experience rapid mortality due to a subsequent bacterial infection in the pulmonary region when both bacterial and viral infections manifest concurrently inside the same host. The involvement of AREG in bacterial infections has been demonstrated. The gene AREG expe- riences increased transcriptional activity inside host cells in response to bacterial infections caused by pathogens such as Escherichia coli and Neisseria gonorrhea. In addition, AREG has been extensively studied as a mitogenic stimulus in epithelial cell layers. Consequently, it is regarded as a prospective contender that might potentially contribute to the observed epithelial cell reactions in helminth infection. Consistent with this fnding, mice that lack the AREG gene exhibit a delay in the eradication of the intestinal parasite Trichuris muris. The observed delay is associated with a reduction in the proliferation rate of colonic epithelial cells compared to the infected animals in the control group. The aforementioned fndings indicate that AREG plays a pivotal role in facilitating the activation of defensive mechanisms inside the epithelial cells of the intestinal tissue. The precise cellular sources of AREG in this specifc context have not yet been determined. However, it is evident that the increased pro- liferation of the epithelial cell layer in infected mice is reliant on CD4 + T cells. The signifcance of this fnding lies in its demonstration of the crucial role played by the interaction between immunological and epithelial cells in regulating the AREG-EGFR pathway. Additional research is necessary to delve into the cellular origins and signaling mechanisms that govern the synthesis of AREG and its tissue-protective properties, independent of infection. * Corresponding author. Department of Medical Laboratory Technology, Imam Jaafar AL-Sadiq University, Iraq. E-mail address: Mohammed.ahmed.mustafa@sadiq.edu.ig (M. Ahmed Mustafa). Contents lists available at ScienceDirect Microbial Pathogenesis journal homepage: www.elsevier.com/locate/micpath https://doi.org/10.1016/j.micpath.2023.106463 Received 7 October 2023; Received in revised form 21 November 2023; Accepted 23 November 2023