title: Mer receptor tyrosine kinase negatively regulates lipoteichoic acid-induced inflammatory response via PI3K/Akt and SOCS3.
abstract: Activation of toll-like receptor (TLR) signaling that initiates an innate immune response to pathogens must be strictly regulated to prevent excessive inflammatory damage in the host. Here, we demonstrate that Mer receptor tyrosine kinase (MerTK) is a negative regulatory molecule in the lipoteichoic acid (LTA)-induced inflammatory response. LTA that activated TLR2 signaling concomitantly induced activation of MerTK signaling in RAW264.7 macrophages, including phosphoinositide 3-kinase (PI3K)/Akt and suppressor of cytokine signaling 3 (SOCS3). Moreover, LTA induced MerTK activation in a time-dependent manner, and LTA-induced MerTK activation was dependent on the ligand Gas6. Additionally, pretreatment with a specific Mer-blocking antibody significantly inhibited LTA-induced phosphorylation of MerTK, while further enhancing LTA-induced phosphorylation of IκB-α and NF-κBp65 as well as production of TNF-α and IL-6. Meanwhile, the antibody blockade of MerTK markedly prevented LTA-induced Akt phosphorylation and SOCS3 expression, both of which were crucial for the inhibition of TLR2-mediated immune response. Collectively, these results suggest, for the first time, that MerTK is an intracellular negative feedback regulator that inhibits the inflammatory response of LTA-stimulated macrophages through the PI3K/Akt pathway and SOCS3 protein.
authors.affiliation: Department of Pulmonary, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei, Anhui 230022, PR China.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Pulmonary, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei, Anhui 230022, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Fang
authors.affiliation: Department of Pulmonary, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei, Anhui 230022, PR China.
authors.forename: Hui-Mei
authors.initials: HM
authors.lastname: Wu
authors.affiliation: Department of Pulmonary, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei, Anhui 230022, PR China.
authors.forename: Pei-Shan
authors.initials: PS
authors.lastname: Ding
authors.affiliation: Department of Pulmonary, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei, Anhui 230022, PR China.
authors.forename: Ke
authors.initials: K
authors.lastname: Xu
authors.affiliation: Department of Pulmonary, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei, Anhui 230022, PR China. Electronic address: rongyuliu@163.com.
authors.forename: Rong-Yu
authors.initials: RY
authors.lastname: Liu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D025461:Feedback, Physiological; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000276:immunology* / Q000378:metabolism; D000067996:RAW 264.7 Cells; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000276:immunology* / Q000378:metabolism; D013682:Teichoic Acids / Q000276:immunology; D000076202:c-Mer Tyrosine Kinase
chemical_list: D008070:Lipopolysaccharides; D011518:Proto-Oncogene Proteins; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D013682:Teichoic Acids; C009900:lipoteichoic acid; D019869:Phosphatidylinositol 3-Kinases; C490767:Mertk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase
keywords: Inflammation; LTA; MerTK; PI3 K/Akt; SOCS3; TLR2