Dataset Information

Plexin C1 deficiency permits synaptotagmin 7-mediated macrophage migration and enhances mammalian lung fibrosis.

ABSTRACT: Pulmonary fibrosis is a progressive and often fatal condition that is believed to be partially orchestrated by macrophages. Mechanisms that control migration of these cells into and within the lung remain undefined. We evaluated the contributions of the semaphorin receptor, plexin C1 (PLXNC1), and the exocytic calcium sensor, synaptotagmin 7 (Syt7), in these processes. We evaluated the role of PLXNC1 in macrophage migration by using Boyden chambers and scratch tests, characterized its contribution to experimentally induced lung fibrosis in mice, and defined the mechanism for our observations. Our findings reveal that relative to control participants, patients with idiopathic pulmonary fibrosis demonstrate excessive monocyte migration and underexpression of PLXNC1 in the lungs and circulation, a finding that is recapitulated in the setting of scleroderma-related interstitial lung disease. Relative to wild type, PLXNC1-/- mouse macrophages are excessively migratory, and PLXNC1-/- mice show exacerbated collagen accumulation in response to either inhaled bleomycin or inducible lung targeted TGF-?1 overexpression. These findings are ameliorated by replacement of PLXNC1 on bone marrow-derived cells or by genetic deletion of Syt7. These data demonstrate the previously unrecognized observation that PLXNC1 deficiency permits Syt7-mediated macrophage migration and enhances mammalian lung fibrosis.-Peng, X., Moore, M., Mathur, A., Zhou, Y., Sun, H., Gan, Y., Herazo-Maya, J. D., Kaminski, N., Hu, X., Pan, H., Ryu, C., Osafo-Addo, A., Homer, R. J., Feghali-Bostwick, C., Fares, W. H., Gulati, M., Hu, B., Lee, C.-G., Elias, J. A., Herzog, E. L. Plexin C1 deficiency permits synaptotagmin 7-mediated macrophage migration and enhances mammalian lung fibrosis.

SUBMITTER: Peng X

PROVIDER: S-EPMC5102121 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Plexin C1 deficiency permits synaptotagmin 7-mediated macrophage migration and enhances mammalian lung fibrosis.

Peng Xueyan X Moore Meagan M Mathur Aditi A Zhou Yang Y Sun Huanxing H Gan Ye Y Herazo-Maya Jose D JD Kaminski Naftali N Hu Xinyuan X Pan Hongyi H Ryu Changwan C Osafo-Addo Awo A Homer Robert J RJ Feghali-Bostwick Carol C Fares Wassim H WH Gulati Mridu M Hu Buqu B Lee Chun-Geun CG Elias Jack A JA Herzog Erica L EL

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20160908 12

Pulmonary fibrosis is a progressive and often fatal condition that is believed to be partially orchestrated by macrophages. Mechanisms that control migration of these cells into and within the lung remain undefined. We evaluated the contributions of the semaphorin receptor, plexin C1 (PLXNC1), and the exocytic calcium sensor, synaptotagmin 7 (Syt7), in these processes. We evaluated the role of PLXNC1 in macrophage migration by using Boyden chambers and scratch tests, characterized its contributi ...[more]

PMID: 27609773

Similar Datasets

Project description:Extracellular vesicles (EVs) are produced by most known cell types as a form of intercellular communication to influence the physiological function of neighboring cells. During respiratory viral-bacterial coinfection, the preceding antiviral response can lead to an impaired antibacterial response, driven by miscommunication between cells responding to viruses and cells responding to bacteria. Previous studies have shown that antiviral signaling can influence EV cargo and promote antiviral defense in the recipient cell; however, how antiviral EVs may influence host defense against coinfecting microorganisms, specifically bacteria, is not known. Herein, we demonstrated that EVs released from the respiratory epithelium during antiviral signaling alter macrophage inflammatory signaling, induce anti-inflammatory metabolic reprogramming, and impair antibacterial activity against Staphylococcus aureus, a common coinfecting bacterial pathogen. Further proteomic analysis revealed that antiviral EVs are preferentially loaded with pyruvate kinase M2 (PKM2), a metabolic enzyme with immunomodulatory effects, and treatment with antiviral EVs leads to increased PKM2 in macrophages. Moreover, we showed that antiviral EV-treated macrophages displayed enhanced oxidative phosphorylation, a metabolic profile consistent with impaired S. aureus clearance, and that this metabolic state is phenocopied in macrophages treated with a PKM2 activator. Taken together, our findings identify EVs as a component of the epithelial antiviral response that contributes to impaired bacterial clearance through epithelial-macrophage crosstalk and suggest a role for EVs in driving disease progression during respiratory coinfection. IMPORTANCE Miscommunication of antiviral and antibacterial immune signals drives worsened morbidity and mortality during respiratory viral-bacterial coinfections. Extracellular vesicles (EVs) are a form of intercellular communication with broad implications during infection, and here we show that epithelium-derived EVs released during the antiviral response impair the antibacterial activity of macrophages, an innate immune cell crucial for bacterial control in the airway. Macrophages exposed to antiviral EVs display reduced clearance of Staphylococcus aureus as well as altered inflammatory signaling and anti-inflammatory metabolic reprogramming, thus revealing EVs as a source of dysregulated epithelium-macrophage crosstalk during coinfection. As effective epithelium-macrophage communication is critical in mounting an appropriate immune response, this novel observation of epithelium-macrophage crosstalk shaping macrophage metabolism and antimicrobial function provides exciting new insight and improves our understanding of immune dysfunction during respiratory coinfections.

Dataset Information

Plexin C1 deficiency permits synaptotagmin 7-mediated macrophage migration and enhances mammalian lung fibrosis.

Publications

Plexin C1 deficiency permits synaptotagmin 7-mediated macrophage migration and enhances mammalian lung fibrosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets