Th2 Cytokines IL-4, IL-13, and IL-10 Promote Differentiation of Pro-Lymphatic Progenitors Derived from Bone Marrow Myeloid Precursors.

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  • Additional Information
    • Source:
      Publisher: Mary Ann Liebert, Inc Country of Publication: United States NLM ID: 101197107 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-8534 (Electronic) Linking ISSN: 15473287 NLM ISO Abbreviation: Stem Cells Dev Subsets: MEDLINE
    • Publication Information:
      Original Publication: Larchmont, NY : Mary Ann Liebert, Inc., c2004-
    • Subject Terms:
      Lymphatic Vessels*/metabolism ; Lymphatic Vessels*/pathology ; Neoplasms*/pathology ; Th2 Cells*; Animals ; Bone Marrow/metabolism ; Cell Differentiation ; Cytokines ; Interleukin-10 ; Interleukin-13 ; Interleukin-4/pharmacology ; Ligands ; Macrophage Colony-Stimulating Factor ; Mice
    • Abstract:
      Myeloid-lymphatic endothelial cell progenitors (M-LECP) are a subset of bone marrow (BM)-derived cells characterized by expression of M2-type macrophage markers. We previously showed significant contribution of M-LECP to tumor lymphatic formation and metastasis in human clinical breast tumors and corresponding mouse models. Since M2 type is induced in macrophages by immunosuppressive Th2 cytokines IL-4, IL-13, and IL-10, we hypothesized that these factors might promote pro-lymphatic specification of M-LECP during their differentiation from BM myeloid precursors. To test this hypothesis, we analyzed expression of Th2 cytokines and their receptors in mouse BM cells under conditions leading to M-LECP differentiation, namely, CSF-1 treatment followed by activation of TLR4. We found that under these conditions, all three Th2 receptors were strongly upregulated in >95% of the cells that also secrete endogenous IL-10, but not IL-4 or IL-13 ligands. However, addition of any of the Th2 factors to CSF-1 primed cells significantly increased generation of myeloid-lymphatic progenitors as indicated by co-induction of lymphatic-specific (eg, Lyve-1, integrin-a9, collectin-12, and stabilin-1) and M2-type markers (eg, CD163, CD204, CD206, and PD-L1). Antibody-mediated blockade of either IL-10 receptor (IL-10R) or IL-10 ligand significantly reduced both immunosuppressive and lymphatic phenotypes. Moreover, tumor-recruited Lyve-1 + lymphatic progenitors in vivo expressed all Th2 receptors as well as corresponding ligands, including IL-4 and IL-13, which were absent in BM cells. This study presents original evidence for the significant role of Th2 cytokines in co-development of immunosuppressive and lymphatic phenotypes in tumor-recruited M2-type myeloid cells. Progenitor-mediated increase in lymphatic vessels can enhance immunosuppression by physical removal of stimulatory immune cells. Thus, targeting Th2 pathways might simultaneously relieve immunosuppression and inhibit differentiation of pro-lymphatic progenitors that ultimately promote tumor spread.
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    • Grant Information:
      R01 CA199649 United States CA NCI NIH HHS
    • Contributed Indexing:
      Keywords: Th2 cytokines; lymphangiogenesis; lymphatic endothelial progenitors; myeloid cell differentiation
    • Accession Number:
      0 (Cytokines)
      0 (Interleukin-13)
      0 (Ligands)
      130068-27-8 (Interleukin-10)
      207137-56-2 (Interleukin-4)
      81627-83-0 (Macrophage Colony-Stimulating Factor)
    • Publication Date:
      Date Created: 20220420 Date Completed: 20220613 Latest Revision: 20220722
    • Publication Date:
      20240104
    • Accession Number:
      PMC9232236
    • Accession Number:
      10.1089/scd.2022.0004
    • Accession Number:
      35442077