A novel soluble form of the CSF-1 receptor inhibits proliferation of self-renewing macrophages of goldfish (Carassius auratus L.)

Macrophage colony-stimulating factor (CSF-1) is the principal regulator of the survival, proliferation, and differentiation of macrophages and their precursors. CSF-1 activity is tightly controlled through mechanisms regulating gene expression of CSF-1 and its membrane-bound receptor (CSF-1R), as well as by receptor-mediated endocytosis, metabolic processing, and inhibition of downstream signaling. Herein we describe a novel mechanism for control of CSF-1 activity. Spontaneously growing goldfish (Carassius auratus L.) macrophages actively produced a soluble form of CSF-1R (sCSF-1R) that appears to compete for ligand binding with membrane CSF-1R. The sCSF-1R transcript encodes only for the ligand-binding portion of the receptor, but is derived from a full-length mRNA species as determined by sequence analysis. Gene expression was associated with decreased proliferation and differentiation of primary macrophages, decreased growth factor activity in culture supernatants, and marked phenotypic changes that culminated in apoptotic cell death. Recombinant sCSF-1R inhibited macrophage proliferation at nanomolar concentrations. Antibodies against recombinant sCSF-1R identified native sCSF-1R in primary macrophage culture supernatants and fish serum, and suggested the presence of endogenous mechanisms temporally regulating sCSF-1R release. This is the first report of a soluble CSF-1R and points to intrinsic mechanisms of hematopoietic control that may be conserved across evolution in discrete self-renewing macrophage populations.