Editorial: CSF1R, CSF‐1, and IL‐34, a “ménage à trois” conserved across vertebrates

CSF1R is the unique receptor tyrosine kinase of CSF-1, which regulates mononuclear phagocyte and osteoclast production and cells of the female reproductive tract. IL-34 is another ligand identified recently for human CSF1R. In this issue, CSF-1, IL34, and CSF1R genes are shown to be expressed in birds. The two ligands promote chicken macrophage growth, indicating that the three partners are functionally conserved across vertebrates. They may bind CSF1R in different locations and could exert nonredundant functions, opening new avenues to investigate CSF1R functions in tissue homeostasis as well as in cancer and in inflammation. CSF-1, also known as M-CSF, is a critical regulator of the development, morphology, survival, and functions of tissue macrophages and osteoclasts. These effects are mediated by a unique tyrosine kinase receptor, CSF1R (M-CSFR, CD115), which is encoded by the protooncogene c-fms and is a member of the platelet growth factor receptor family [1]. Csf1r/Csf1r mice exhibit a stronger phenotype than Csf1/Csf1 mice, which suggested that subtle effects of the CSF1R could be mediated by another ligand in addition to CSF-1 [2]. Such a ligand was identified recently in a high-throughput functional screen with human monocytes and designated as IL-34 [3]. Strikingly, in this issue of the Journal of Leukocyte Biology, Garceau et al. [4] provide evidence that on the contrary to other cytokines, CSF-1 and IL-34 are closely conserved across all vertebrates. The authors argue for nonredundant functions of these factors and suggest that CSF-1 and IL-34, which share a similar four-helix bundle structure, may interact with different regions of the CSF1R [4], thus opening unexpected doors in CSF1R signaling investigation in the context of tissue homeostasis as well as inflammation and cancer. CSF-1 exists in three biologically active isoforms in humans, including a membrane-spanning cell-surface glycoprotein, a secreted glycoprotein, and a secreted proteoglycan that contains a single 18-kDa chondroitin sulfate chain. The secreted glycoprotein and the secreted proteoglycan contribute approximately equally to the total circulating CSF-1. These extracellular forms are disulfide-linked homodimers produced by differential proteolytic cleavage of membrane-bound precursors [5]. Two chicken CSF genes, which are the orthologs of human GMCSF (CSF-2) and G-CSF (CSF-3) genes, had been identified in the chicken genome. Garceau et al. [4] demonstrate that the CSF-1 gene also exists in chicken as well as zebra finch genomes. Moreover, they identify two transcripts for chicken CSF-1, arguing that secreted and membrane-anchored forms are conserved and that the proteoglycan may exist as well. Although the cysteine forming an interchain disulfide bond in mammalian and fish CSF-1 does not exist in birds, the four-helix bundle structure and the formation of homodimers may be conserved. The human IL-34 is a secreted homodimeric glycoprotein that binds the immobilized CSF1R extracellular domain with a higher affinity than CSF-1. Coevolution analysis suggests that IL-34 and CSF-1 have evolved independently, the IL-34 gene together with the CSF1R, under stronger evolutionary constraint [4]. The CSF1R is a transmembrane glycoprotein composed of an Ig-like extracellular ligand-binding domain, a hydrophobic transmembrane domain, and an intracellular C-terminal tyrosine kinase domain that includes eight tyrosine residues, known to be phosphorylated in the activated receptor. An annotated CSF1R gene did exist in the chicken genome and was identified also in the zebra finch genome. The intracellular tyrosine kinase domain of CSF1R is highly conserved among species. Conversely, most of the residues forming the CSF-1binding sites are divergent across taxonomic order. Of great importance, the in silico structural analysis presented in this issue predicts that IL-34/CSF1R and CSF-1/CSF1R contact points are com-