Plexin C1 deficiency permits synaptotagmin 7-mediated macrophage migration and enhances mammalian lung fibrosis.
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-β1 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.
Department of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
Xueyan
X
Peng
Department of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
Meagan
M
Moore
Department of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
Aditi
A
Mathur
Department of Molecular Microbiology and Immunology, Warren Alpert School of Medicine, Brown University, Providence, Rhode Island, USA.
Yang
Y
Zhou
Department of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
Huanxing
H
Sun
Department of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
Ye
Y
Gan
Department of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
Jose D
JD
Herazo-Maya
Department of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
Naftali
N
Kaminski
Department of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
Xinyuan
X
Hu
Department of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
Hongyi
H
Pan
Department of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
Changwan
C
Ryu
Department of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
Awo
A
Osafo-Addo
Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA; and.
Robert J
RJ
Homer
Department of Medicine, Medical University of South Carolina School of Medicine, Charleston, South Carolina, USA.
Carol
C
Feghali-Bostwick
Department of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
Wassim H
WH
Fares
Department of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
Mridu
M
Gulati
Department of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
Buqu
B
Hu
Department of Molecular Microbiology and Immunology, Warren Alpert School of Medicine, Brown University, Providence, Rhode Island, USA.
Chun-Geun
CG
Lee
Department of Molecular Microbiology and Immunology, Warren Alpert School of Medicine, Brown University, Providence, Rhode Island, USA.
Jack A
JA
Elias
Department of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA; erica.herzog@yale.edu.
Erica L
EL
Herzog
D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D008168:Lung / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000378:metabolism*; D011991:Receptors, Virus / Q000172:deficiency / Q000378:metabolism*; D050857:Synaptotagmins / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D009419:Nerve Tissue Proteins; C492112:Plxna3 protein, mouse; D011956:Receptors, Cell Surface; D011991:Receptors, Virus; C494303:Syt7 protein, mouse; D053773:Transforming Growth Factor beta1; C112038:VESPR semaphorin receptor; D050857:Synaptotagmins
idiopathic pulmonary fibrosis; immunology; interstitial lung disease; scleroderma; semaphorin 7a