CXCR4s in Teleosts: Two Paralogous Chemokine Receptors and Their Roles in Hematopoietic Stem/Progenitor Cell Homeostasis

J Immunol. 2020 Mar 1;204(5):1225-1241. doi: 10.4049/jimmunol.1901100. Epub 2020 Jan 20.

Abstract

Hematopoietic stem/progenitor cells (HSPCs) generate the entire repertoire of immune cells in vertebrates and play a crucial role during infection. Although two copies of CXC motif chemokine receptor 4 (CXCR4) genes are generally identified in teleosts, the function of teleost CXCR4 genes in HSPCs is less known. In this study, we identified two CXCR4 genes from a teleost, ayu (Plecoglossus altivelis), named PaCXCR4a and PaCXCR4b. PaCXCR4b was constitutively expressed in ayu HSPCs, whereas PaCXCR4a was induced by LPS treatment. The stromal-derived factor-1-binding activity of CXCR4b was significantly higher than that of CXCR4a, whereas the LPS-binding activity of CXCR4a was significantly higher than that of CXCR4b in the teleosts ayu, large yellow croaker (Larimichthys crocea), and tiger puffer (Takifugu rubripes). CXCR4a+ HSPCs were mobilized into blood by LPS, whereas CXCR4b+ HSPCs were mobilized by leukocyte cell-derived chemotaxin-2. PaSDF-1 and PaCXCR4b, but not PaCXCR4a, inhibited HSPC proliferation by regulating reactive oxygen species levels. Compared with PaCXCR4b+ HSPCs, PaCXCR4a+ HSPCs preferentially differentiated into myeloid cells in ayu by maintaining high stem cell leukemia expression. These data suggest that the two copies of CXCR4s achieve a division of labor in the regulation of teleost HSPC homeostasis, supporting the concept that subfunctionalization after gene duplication in teleosts may stabilize the immune system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / physiology*
  • Fish Proteins / genetics
  • Fish Proteins / immunology*
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / immunology*
  • Homeostasis / genetics
  • Homeostasis / immunology*
  • Leukocytes / cytology
  • Leukocytes / immunology
  • Perciformes / genetics
  • Perciformes / immunology*
  • Reactive Oxygen Species / immunology
  • Receptors, CXCR4 / genetics
  • Receptors, CXCR4 / immunology*
  • Species Specificity
  • Tetraodontiformes / genetics
  • Tetraodontiformes / immunology

Substances

  • Fish Proteins
  • Reactive Oxygen Species
  • Receptors, CXCR4