Semaphorin 3F signaling actively retains neutrophils at sites of inflammation

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Plant, Tracie and Eamsamarng, Suttida and Reyes, Leila and Renshaw, Stephen A. and Coelho, Patricia and Morgan, Jessie May and Ellett, Felix E. and Morrison, Tyler and Humphries, Duncan and Watts, Emily R. and Murphy, Fiona and Raffo-Iraolagoitia, Ximena L. and Zhang, Ailiang and Cash, Jenna L. and Loynes, Catherine and Elks, Philip M. and Van Eeden, Freek and Carlin, Leo M. and Furley, Andrew J.W. and Whyte, Moira K.B. and Walmsley, Sarah R. (2020) Semaphorin 3F signaling actively retains neutrophils at sites of inflammation. Journal of Clinical Investigation, 130 (6). pp. 3221-3237. ISSN 0021-9738 (https://doi.org/10.1172/JCI130834)

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Abstract

Neutrophilic inflammation is central to disease pathogenesis, for example, in chronic obstructive pulmonary disease, yet the mechanisms that retain neutrophils within tissues remain poorly understood. With emerging evidence that axon guidance factors can regulate myeloid recruitment and that neutrophils can regulate expression of a class 3 semaphorin, SEMA3F, we investigated the role of SEMA3F in inflammatory cell retention within inflamed tissues. We observed that neutrophils upregulate SEMA3F in response to proinflammatory mediators and following neutrophil recruitment to the inflamed lung. In both zebrafish tail injury and murine acute lung injury models of neutrophilic inflammation, overexpression of SEMA3F delayed inflammation resolution with slower neutrophil migratory speeds and retention of neutrophils within the tissues. Conversely, constitutive loss of sema3f accelerated egress of neutrophils from the tail injury site in fish, whereas neutrophilspecific deletion of Sema3f in mice resulted in more rapid neutrophil transit through the airways, and significantly reduced time to resolution of the neutrophilic response. Study of filamentous-actin (F-actin) subsequently showed that SEMA3Fmediated retention is associated with F-actin disassembly. In conclusion, SEMA3F signaling actively regulates neutrophil retention within the injured tissues with consequences for neutrophil clearance and inflammation resolution.

ORCID iDs

Plant, Tracie, Eamsamarng, Suttida, Reyes, Leila, Renshaw, Stephen A., Coelho, Patricia, Morgan, Jessie May, Ellett, Felix E., Morrison, Tyler, Humphries, Duncan, Watts, Emily R., Murphy, Fiona ORCID logoORCID: https://orcid.org/0000-0001-7925-0632, Raffo-Iraolagoitia, Ximena L., Zhang, Ailiang, Cash, Jenna L., Loynes, Catherine, Elks, Philip M., Van Eeden, Freek, Carlin, Leo M., Furley, Andrew J.W., Whyte, Moira K.B. and Walmsley, Sarah R.;
  • Item type:Article
    ID code:86376
    Dates:
    Date
    Event
    19 March 2020
    Published
    11 March 2020
    Accepted
    5 June 2019
    Submitted
    Notes:Funding Information: We thank K. Survana for procurement and L. Boswell (Shared University Research Facilities, Edinburgh University) for processing tissue sections for histological analysis. S. Johnston for assistance with flow cytometry (QMRI Flow Cytometry & Cell Sorting Facility, Edinburgh University). C. Winchester for critical reading of the manuscript. Mouse lung and neutrophil microscopy was performed in the Beatson Advanced Imaging Resource (BAIR) at the Cancer Research UK Beatson Institute. This work was supported by Wellcome Trust Senior Clinical Fellowship awards (098516 and 209220 to SRW), an MRC Senior Clinical Fellowship award (G0701932 to SAR), a Royal Thai Government PhD studentship (to SE), a Mitchell and Urquhart Charitable Trust award (to SRW), a Wellcome Trust Clinical Fellowship (R43999 to TP), a CRUK Cancer Immunology Project award (C62207/A24495 to SRW), and MRC antimicrobial resistance grant funding through the ShIELD consortium (Sheffield, Edinburgh, Newcastle, and Birmingham). The zebrafish work was further supported by an MRC Centre grant (G0700091). XLRI, LMC, and the BAIR are grateful for core support from Cancer Research UK (A23983 and A17196). Copyright: © 2020, Plant et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. J Clin Invest. 2020;130(6):3221-3237. https://doi.org/10.1172/JCI130834.
    Subjects:Medicine
    Medicine > Pharmacy and materia medica
    Department:Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
    Depositing user: Pure Administrator
    Date deposited:03 Aug 2023 10:20
    Last modified:20 Nov 2024 15:03
    Related URLs:
    URI:https://strathprints.strath.ac.uk/id/eprint/86376
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