Kingfisher Biotech Circular
M-CSF: More than just a macrophage growth factor
M-CSF (also called CSF-1) has long been
known to induce macrophage differentiation in culture. However, studies in
CSF-1-deficient (op/op) mice highlight the varied roles of M-CSF in everything
from development and fertility, to bone remodeling and tissue repair, to immune
surveillance.
M-CSF (macrophage
colony-stimulating factor) is a well-described homodimeric cytokine, believed
to be secreted by proteolytic cleavage of a membrane-bound precursor, and has 3
differentially spliced isoforms. (1) M-CSF is recognized by CSF-1R, which is
expressed on the surface of mononuclear phagocytes. (2) IL34 is the only other
known ligand of CSF-1R, shares no sequence homology to M-CSF, and is thought to
bind a different domain on CSF-1R. (3, 4) Despite these differences, both M-CSF
and IL-34 control the differentiation, survival and proliferation of
mononuclear phagocytes, including monocytes, macrophages, dendritic cells,
Langerhans cells, microglia, and osteoclasts. The differences observed between
M-CSF and IL-34 function are thought to be due primarily to differential
expression patterns. (5)
Although initially
described as a macrophage growth factor, M-CSF expression has since been shown
to be critical in numerous pathways. Osteopetrotic (op/op) mutant mice have
severe deficiencies in many mononuclear phagocyte populations, including
osteoclasts, monocytes, and macrophages, resulting in osteopetrosis and
impaired fertility. This deficiency results from a spontaneous null mutation in
the CSF-1 gene. (6) Further, humans lacking CSF-1R function develop
leukoencephalopathy, and increased CSF-1R signaling is associated with the
development and poor prognosis of cancer, highlighting the importance of M-CSF
and IL-34 in regulating immune homeostasis. In fact, a variety of inflammatory
conditions and malignancies have been correlated to increased levels of M-CSF,
including rheumatoid arthritis. (7) Administration of CSF-1 as a therapeutic
has been explored and shows promise in promoting tissue repair, and inhibition
of CSF-1 or CSF-1R may have applications in cancer treatment. (8)
Homologs of human
M-CSF identified by HomoloGene are found in chimpanzees, rhesus macaques, dog,
cow, mouse, and rat. (1) Further, avian orthologs for M-CSF, IL-34, and CSF-1R
have been found and shown to function in monocytic proliferation. (9) M-CSF
also displays some reactivity across species, with human and porcine M-CSF
interacting with CSF-1R from human, pig, mouse, dog and cat. Murine M-CSF has
some cross-reactivity to both pig and feline CSF-1R. (10, 11) Together, these
data suggest evolutionary conservation of M-CSF across vertebrates, emphasizing
the importance of M-CSF and the monocytic phagocytes.
M-CSF is well
known for its role in the proliferation, differentiation and survival of
monocytic phagocytes. However, as an appreciation is gained for the widespread
necessity of these cells throughout many organ systems, our understanding of
the importance of M-CSF continues to grow. M-CSF regulation is critical to
maintaining homeostasis, and dysregulation impacts development, fertility,
inflammation, osteoclastogenesis, immunity, and cancer development and
progression.
References
1.
NCBI. Gene ID:1435, CSF-1 [Homo sapiens]. [Last update: 8 Sept, 2013].
2.
L.J.
Guilbert and E.R. Stanley, J. Cell Biol. 85, 153 (1980).
3.
X. Ma et al.,
Structure 20, 676 (2012).
4.
H. Liu
et al., Biochim. Biophys. Acta 1824,
938 (2012).
5.
S. Wei et al.,
J. Leukoc. Biol. 88, 495
(2010).
6.
W.
Wiktor-Jedrzejczak et al., Proc.
Natl. Acad. Sci. USA 87, 4828 (1990).
7.
Y. Nakamichi et al.,
J. Bone Miner. Metab. (2013).
[epub ahead of print] PMID: 23740288.
8.
D.A.
Hume and K.P. MacDonald, Blood 119, 1810 (2012).
9.
V.
Garceau et al., J. Leukoc. Biol. 87,
753 (2010).
10.
D.J.
Gow et al., Cytokine 60, 793 (2012).
11.
D.J.
Gow et al., Cytokine 61, 630 (2013).
09/2013
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Copyright 2013, Kingfisher Biotech, Inc.
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