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    Pharmacological validation of targets regulating CD14 during macrophage differentiation.

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    Author
    Jimenez-Duran, G; Luque-Martin, R; Patel, M; Koppe, E; Bernard, S; Sharp, C; Buchan, N; Rea, C; de Winther, MPJ; Turan, N; ...
    Date
    2020-11
    Source Title
    EBioMedicine
    Publisher
    Elsevier BV
    University of Melbourne Author/s
    Masters, Seth; Wells, Christine
    Affiliation
    Medical Biology (W.E.H.I.)
    Anatomy and Neuroscience
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Jimenez-Duran, G., Luque-Martin, R., Patel, M., Koppe, E., Bernard, S., Sharp, C., Buchan, N., Rea, C., de Winther, M. P. J., Turan, N., Angell, D., Wells, C. A., Cousins, R., Mander, P. K. & Masters, S. L. (2020). Pharmacological validation of targets regulating CD14 during macrophage differentiation.. EBioMedicine, 61, pp.103039-. https://doi.org/10.1016/j.ebiom.2020.103039.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/252613
    DOI
    10.1016/j.ebiom.2020.103039
    Open Access at PMC
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648121
    Abstract
    The signalling receptor for LPS, CD14, is a key marker of, and facilitator for, pro-inflammatory macrophage function. Pro-inflammatory macrophage differentiation remains a process facilitating a broad array of disease pathologies, and has recently emerged as a potential target against cytokine storm in COVID19. Here, we perform a whole-genome CRISPR screen to identify essential nodes regulating CD14 expression in myeloid cells, using the differentiation of THP-1 cells as a starting point. This strategy uncovers many known pathways required for CD14 expression and regulating macrophage differentiation while additionally providing a list of novel targets either promoting or limiting this process. To speed translation of these results, we have then taken the approach of independently validating hits from the screen using well-curated small molecules. In this manner, we identify pharmacologically tractable hits that can either increase CD14 expression on non-differentiated monocytes or prevent CD14 upregulation during macrophage differentiation. An inhibitor for one of these targets, MAP2K3, translates through to studies on primary human monocytes, where it prevents upregulation of CD14 following M-CSF induced differentiation, and pro-inflammatory cytokine production in response to LPS. Therefore, this screening cascade has rapidly identified pharmacologically tractable nodes regulating a critical disease-relevant process.

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