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Lysophosphatidic Acid Stimulation of Amphiregulin Shedding Enhanced Paracrine Role of BM CD11 + Cells
Author(s) -
Liu Tianju,
De Los Santos Francina Gonzalez,
Wu Zhe,
Phan Sem H
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.656.8
Subject(s) - amphiregulin , lysophosphatidic acid , paracrine signalling , microbiology and biotechnology , epidermal growth factor , chemistry , fibroblast , biology , immunology , receptor , cell culture , biochemistry , genetics
Amphiregulin (AREG), an epidermal growth factor receptor ligand, plays an important role in tissue repair and fibrosis. Bone marrow (BM) CD11c + cell‐derived AREG promotes pulmonary fibrosis by activating fibroblast proliferation, migration and collagen expression. Pro‐AREG is a membrane bound protein whose mature soluble form represents the extracellular domain that is cleaved off by ADAM17. However, the precise mechanism of regulation or shedding/release of mature AREG is uncertain. Lysophosphatidic acid (LPA) is a bioactive lipid that mediates diverse cellular responses through interactions with specific G‐protein‐coupled receptors. LPA is implicated in tissue repair and wound healing processes, and elevated in the airspaces of patients with idiopathic pulmonary fibrosis, as well as fibrotic lungs of animal model of fibrosis. LPA is known to be able to induce shedding of TGFβ and AREG from cell surface. The objective of this study was to assess the effects of LPA on shedding of AREG ectodomain from CD11c + cells, and the consequent effect on fibroblast activation. The results showed that LPA caused rapid shedding of AREG from both mouse BM‐derived dendritic cells (BMDC) and human BM CD11c + mononuclear cells as revealed by the decrease in cell surface AREG expression analyzed by flow cytometry. AREG shedding was confirmed by the elevated level of released AREG protein by LPA‐stimulated BMDC as measured by ELISA. To investigate the paracrine activity of AREG released from BMDC, mouse lung fibroblasts were cultured in the presence of conditioned media from LPA‐stimulated BMDC cultures. The data showed that the fibroblast proliferation rate was significantly increased by these AREG containing conditioned media. These findings together indicated that induced LPA in fibrotic lung tissue could stimulate the shedding of AREG from CD11c + BM cells, including dendritic cells, and thus enhanced the paracrine role of CD11c + cells on fibroblast activation in tissue repair and remodeling. They also suggested that targeting the LPA receptor may further mediate its potential therapeutic efficacy for control of tissue fibrosis by reducing AREG shedding. Support or Funding Information NIH grants HL052285 and HL112880.