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

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.

The biological role of the CXCL12/CXCR4 axis in esophageal squamous cell carcinoma

“…CXCL12 is constitutively expressed by bone marrow stromal cells and is therefore referred to as stromal cell-derived factor-1 17 . CXCR4 is a member of the GPCR family, comprising 352 amino acid residues, and is expressed in hematopoietic stem/ progenitor, pre-B, and endothelial cells [18][19][20][21] . CXCR4 is reported to be upregulated in at least 23 different hematopoietic and nonhematopoietic tumors, including esophageal cancer [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] .…”

Dynamic and Differential Expression of Duplicated Cxcr4/Cxcl12 Genes Facilitates Antiviral Response in Hexaploid Gibel Carp

“…Our results indicate that cxcr4bs and cxcl12as should play a dominant role in immune response and confirm the specific ligand-receptor recognitions of Cxcl12b and Cxcr4a ( 48 , 70 ). Although derived from the common ancestor ( 71 ), the expression patterns of duplicated genes evolved divergently after separation. For example, a common carp cxcl12b ( Cccxcl12b ) exhibits highest identity with Cgcxcl12b-B , and they are both highly expressed in the brain ( 72 ).…”

Diversity of Rainbow Trout Blood B Cells Revealed by Single Cell RNA Sequencing

“…Mammalian CXCR4 has been suggested as a marker for an initial common lymphoid progenitor in mice [56] and for differentiated plasmablasts or plasma cells both in mice and humans [57,58]. Several studies have analyzed the evolution and function of cxcr4 genes in teleost fish showing the presence of either two paralog genes designated as cxcr4a and cxcr4b [59][60][61] or even four gene copies in cyprinids [62]. Our results identified four different genes annotated as rainbow trout CXCR4-like, which all seemed expressed in B cells.…”

“…On the other hand, the other two genes encoding homologues of the molecule previously designated as CXCR4a (LOC110516585 and LOC110530627) showed differential expression in cluster 1 and cluster 5, respectively. A previous study in fish pointed to the duplication of CXCR4 genes in teleosts evolving to a gene subfunctionalization that may stabilize the immune system controlling teleost hematopoietic stem/progenitor cell (HSPC) homeostasis [61]. In addition, these authors suggested that HSPCs expressing CXCR4a preferentially bind LPS, whereas those expressing CXCR4b preferentially bind SDF-1 reflecting different pathways of immune cell differentiation [61].…”

“…A previous study in fish pointed to the duplication of CXCR4 genes in teleosts evolving to a gene subfunctionalization that may stabilize the immune system controlling teleost hematopoietic stem/progenitor cell (HSPC) homeostasis [61]. In addition, these authors suggested that HSPCs expressing CXCR4a preferentially bind LPS, whereas those expressing CXCR4b preferentially bind SDF-1 reflecting different pathways of immune cell differentiation [61]. Our analysis focused in B cells seems to indicate that CXCR4 relates to an advanced state of maturation, but with different rainbow trout CXCR4 molecules carrying out a differential regulation of specific B cell subpopulations.…”