Targeting CSF-1R represents an effective strategy in modulating inflammatory diseases.

Colony-stimulating factor-1 receptor (CSF-1R), also known as FMS kinase, is a type I single transmembrane protein mainly expressed in myeloid cells, such as monocytes, macrophages, glial cells, and osteoclasts. The endogenous ligands, colony-stimulating factor-1 (CSF-1) and Interleukin-34 (IL-34), activate CSF-1R and downstream signaling pathways including PI3K-AKT, JAK-STATs, and MAPKs, and modulate the proliferation, differentiation, migration, and activation of target immune cells. Over the past decades, the promising therapeutic potential of CSF-1R signaling inhibition has been widely studied for decreasing immune suppression and escape in tumors, owing to depletion and reprogramming of tumor-associated macrophages. In addition, the excessive activation of CSF-1R in inflammatory diseases is consecutively uncovered in recent years, which may result in inflammation in bone, kidney, lung, liver and central nervous system. Agents against CSF-1R signaling have been increasingly investigated in preclinical or clinical studies for inflammatory diseases treatment. However, the pathological mechanism of CSF-1R in inflammation is indistinct and whether CSF-1R signaling can be identified as biomarkers remains controversial. With the background information aforementioned, this review focus on the dialectical roles of CSF-1R and its ligands in regulating innate immune cells and highlights various therapeutic implications of blocking CSF-1R signaling in inflammatory diseases.

Teleost soluble CSF-1R modulates cytokine profiles at an inflammatory site, and inhibits neutrophil chemotaxis, phagocytosis, and bacterial killing.

Soluble colony stimulating factor-1 receptor (sCSF-1R) is a novel bony fish protein that contributes to the regulation of macrophage proliferation. We recently showed that this soluble receptor is highly upregulated by teleost macrophages in the presence of apoptotic cells. Further, recombinant sCSF-1R inhibited leukocyte infiltration into a challenge site in vivo. Herein, we characterized the mechanisms underlying these changes as a platform to better understand the evolutionary origins of the CSF-1 immune-regulatory axis and inflammation control in teleosts. Using an in vivo model of self-resolving peritonitis, we show that sCSF-1R downregulates chemokine expression and inhibits neutrophil chemotaxis. Soluble CSF-1R also inhibited gene expression of several pro-inflammatory cytokines and promoted the expression of an anti-inflammatory mediator, IL-10. Finally, the phenotype of infiltrating neutrophils changed significantly in the presence of sCSF-1R. Both a reduced capacity for phagocytosis and pathogen killing were observed. Overall, our results implicate sCSF-1R as an important regulator of neutrophil responses in teleosts. It remains unclear whether this represents an inflammation regulatory factor that is unique to this animal group or one that may be evolutionarily conserved and continues to contribute to the regulation of antimicrobial processes at inflammatory sites in higher vertebrates.

Identification of an isoform of colony-stimulating factor 1 receptor mRNA in the rat testis.

Because alternative RNA splicing regulation in the testis is prevalent, we explored testes of Sprague-Dawley rats for existence of alternatively spliced colony-stimulating factor 1 receptor (CSF-1R) mRNA. Using RT-PCR and sequencing, we identified a variant of CSF-1R mRNA that was 284 bp shorter than the full-length CSF-1R transcript. This variant was present in the testis (late fetal stage to adult) and in other organs of rats (7 and 60 days old). The deletion of 284 bp disrupted the open reading frame, resulting in a noncoding mRNA product. When testicular macrophages were stimulated with CSF-1R ligand and lipopolysaccharide, proportionally increased expression of both short isoform and full-length CSF-1R mRNA was observed. Thus, the identified isoform of CSF-1R mRNA may interfere with the expression of full-length CSF-1R mRNA, thereby affecting the biological activity of the ligand/receptor signaling axis in Sprague-Dawley rats.

Chronic morphine treatment selectively suppresses macrophage colony formation in bone marrow.

Opioids have been shown to have diverse effects on the immune system, both in vivo and in vitro, but their interactions on immature progenitor cells have been little studied. We have examined the effects of chronic morphine treatment of mice on colony formation by bone marrow cells in vitro. Bone marrow cells from mice implanted with morphine pellets for 72 h showed a 65% decrease in their response to macrophage colony stimulating factor (M-CSF). In contrast, chronic morphine treatment had no effect on the response of bone marrow cells to granulocyte/macrophage colony stimulating factor (GM-CSF). Removal of the morphine pellets from the mice resulted in a time-dependent reversal of the inhibition of macrophage colony formation, and the inhibition was completely blocked by simultaneous administration of naloxone and morphine pellets to the mice. No inhibition of colony formation was observed in bone marrow cells from mice treated with a single acute dose of morphine. Incubation of bone marrow cells from untreated mice for 7 days with in vitro morphine concentrations as low as 25 microM also reduced macrophage colony formation, and the opioid peptide beta-endorphin was even more potent, significantly reducing macrophage colony formation at concentrations as low as 0.25 microM. In agreement with the in vivo effects, neither opioid in vitro had a significant effect on granulocyte/macrophage colony formation. These results suggest that opioids may significantly alter the maturation of immune cells, which could result in potent effects on overall immune competence.